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Lactate turnover in fast-moving vertebrates : the control of plasma metabolite fluxes Weber, Jean-Michel 1987

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LACTATE THE  TURNOVER  IN F A S T - M O V I N G  CONTROL OF  PLASMA  VERTEBRATES:  METABOLITE  FLUXES.  By JEAN-MICHEL Lie.  es  Sciences, Universite M.Sc,  A  THESIS THE  de N e u c h a t e l  McGill  SUBMITTED  WEBER  University,  IN  PARTIAL  R E Q U I R E M E N T S FOR DOCTOR  OF  THE  (Switzerland), 1982  FULFILLEMENT DEGREE  OF  PHILOSOPHY  in THE  FACULTY  OF  GRADUATE  (Department  We  accept to  THE  this  thesis  the required  UNIVERSITY  OF  January Q  of  Jean-Michel  STUDIES  Zoology)  as  conforming  standard  B R I T I S H COLUMBIA 1987 Weber,  1987  OF  1978  In  presenting  degree  this  at the  thesis  in  partial  fulfilment  of  University of  British  Columbia,  I agree  freely available for reference and study. copying  of  department publication  this or of  thesis by  this  for scholarly  his thesis  or  her  ^—  purposes  may It  be is  requirements  for  an  L-\J  \J  advanced  that the Library shall make it that permission  for extensive  granted  head  by the  understood  that  for financial gain shall not be allowed without  The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3  DE-6(3/81)  I further agree  representatives.  permission.  Department of  the  of  my  copying  or  my written  i i  ABSTRACT  During  sustained  supplied  with  and  delivery  the  should  be  from it  is  only  important  fuel  substrate  may  fuels  such  as  were:  animals  can  involved the  animals; in  the  rates  received with of As  free  fatty  determine  higher and  2)  level were  acids.  investigate  of  plasma  also  fuel, over  goals  the  an  this other  of  this  as  a  bolus  rates  major  metabolite  by  that  endurance-adapted  to  measured  The  of  attention  but  turnover  lactate  their  realization  advantage  lactate  - using  renewed  oxidizable  whether  plasma  substrates  understanding  the  be  fuels,  f l u x e s and  glycolysis, an  must  exogenous  the  some p e r f o r m a n c e  regulation  whole-organism  turnover  a e r o b i c work.  to  support  has  muscles  oxidizable  to  product  and  of  metabolite  critical  end  glucose 1)  of  and  biochemists  provide  thesis  sedentary  an  amounts  oxygen  Lactate and  for  and  study  therefore  metabolism.  not  of  The  physiologists is  kinds  rates  matched.  regulation exercise  adequate  e x e r c i s e , working  than  factors  turnover  model.  at  Lactate  injection  of  14 [U-  C]lactate  thoroughbred rates were =  in  racehorses,  ranged  from  positively  15.1,  plasma species  r  =  lactate of  skipjack  112  tuna,  Equus to  431  correlated  with  0.92).  This  turnover  caballus. umol lactate  teleost  rates  equivalent size,  Katsuwonus  even  than  In  min "'" -  tuna, kg~\  to  expected  and  support for a  i t operates  and  in  turnover  concentration  is able  though  pelamis,  they (slope  higher  mammalian at  a  much  lower  temperature,  oxidizable resting  fuel  and in  turnover  versus  body  this rates  mass  on  mammalian  species.  the  slope  same  lactate  an  important  species. For comparative  purposes,  of  is  lactate  a , log-log  These  plots  the  classic  as  probably  and  glucose  scale were  f o r a wide  linear,  body  were  mass  and  plotted range  they  of  showed  vs m e t a b o l i c  rate  relationship. Thoroughbred scope  of  40-fold  adaptations by  more  one  the  present  A-V  difference  Their at  study,  lactate and  V^max)  .  -1  min  levels  them  turnover  rate  from  an  23  value  than  other  mammals.  were  measured  v o l % during  exercise  (45 a n d  relationship  plasma 106  to reach  than  the  from  hematocrit  to e x e r c i s e . In  c a r d i a c output  ranged  kg  at  55%  found  in  thoroughbreds  were  showing  the  fluxes  physiological  more  submaximal  on  aerobic  to  lactate 571  9.3  ml  between  turnover min  at rest,  55  kg  - 1  to  -  rate. 1  ,  75.9  and umol  -1  situation  athletes  of  an  increase  allowed  of  r a t e and  to  main  i n response  higher  adjustments  output  lactate  much  investigate  cardiovascular Cardiac  a  to have  their  adjustment  content  turnover  to  of  a half-fold  0^  two  One  likely  i s the a b i l i t y  this  in  are  more.  and  exercise,  rest  mean  or  to exercise  than  maximal  horses  that do than  not  V0 max.  tuna,  the  not e l e v a t e d metabolic  include  sedentary  In  2  contrast  lactate  turnover  compared  with  adaptations  the a b i l i t y  animals.  of  In horses,  rates  other  these  to sustain  with  the of  mammals,  outstanding  higher  lactate  the c o n t r i b u t i o n  of  i v  plasma  lactate  substrate may  i s not  during  at  for  "elite"  the  also  shows  cardiac  is  lactate  variables rate  between  concentration and  cardiac  turnover are,  the  It the  necessarily  is  be  with and  exercise.  and  required  This  turnover  lactate  study  Plasma  that  coarse  and rate.  turnover  between  regulators  proposed  fine  plasma  concentration  rate.  can  energy  oxidize  exercise.  this  oxidation  aerobic to  relationship  output  rate.  during  output  turnover  respectively,  adjustments  correlated  and  lipid  for  lactate  cardiac  and  not  endurance  plasma  of  fuel;  ability  therefore of  minimal,  pathway The  positively  independent  concentration metabolite  both,  are  correlation  rate  is  performance  that  output  major  rates  is  oxidative  exercise.  high  VO^  to  important  their  lactate  flux  an  represent  production  The  oxidation  plasma  metabolite of  plasma  these  two  controls  for  V  TABLE  OF  CONTENTS  Abstract  i i  List  of Tables  ix  List  of Figures  x  Acknowledgements  x i i  CHAPTER  1;  GENERAL  INTRODUCTION  1.1  STATEMENT  1.2  LACTATE  1.3  M E T A B O L I T E TURNOVER  14  1.4  THESIS  16  CHAPTER  2:  LACTATE  AND  OF  PROBLEM  1  METABOLISM  5  OUTLINE  GLUCOSE  2.1  INTRODUCTION  2.2  M A T E R I A L S AND  TURNOVER  IN S K I P J A C K  TUNA  21 METHODS  23  2.2.1  E X P E R I M E N T A L ANIMALS  23  2.2.2  C A T H E T E R I Z A T I O N ..  24  2.2.3  INJECTION BLOOD  2.2.4  OF  LABELED METABOLITES  SAMPLING  M E T A B O L I T E A S S A Y S AND  AND 26  COUNTING  26  vi  2.2.5 2.3  2.4  . 30  2.3.1  LACTATE  TURNOVER  34  2.3.2  G L U C O S E TURNOVER  41  DISCUSSION  46  3:  OF  SUBMAXIMAL  INTRODUCTION  3.2  M A T E R I A L S AND  3.4  STATISTICS  34  3.1  3.3  C A L C U L A T I O N S , AND  RESULTS  CHAPTER ONSET  TERMINOLOGY,  EXERCISE  IN THOROUGHBRED  HORSES  59 METHODS  62  3.2.1  E X P E R I M E N T A L ANIMALS  3.2.2  EXERCISE  3.2.3  BLOOD  3.2.4  METABOLITE ASSAYS  AND  CATHETERIZATION  PROTOCOLS  AND  TISSUE  .. 62 63  SAMPLING  63 65  RESULTS  66  3.3.1  TROT  PROTOCOL  66  3.3.2  CANTER  PROTOCOL  70  3.3.3  MUSCLE  M E T A B O L I T E CONCENTRATIONS  71  DISCUSSION  76  3.4.1  CHANGES  3.4.2  PLASMA START  IN HEMATOCRIT LACTATE  OF  3.4.3  LACTATE  3.4.4  MUSCLE  DURING  CONCENTRATION  EXERCISE AT  THE  EXERCISE FLUXES  TO AND  METABOLITES  77  78 FROM  THE  PLASMA  79 83  vii  CHAPTER  4;  CARDIAC  OUTPUT  THOROUGHBRED  INTRODUCTION  4.2  M A T E R I A L S AND  4.4  CONSUMPTION  OF  EXERCISING  86 METHODS  88  4.2.1  ANIMALS  88  4.2.2  CATHETERIZATIONS  88  4.2.3  EXERCISE  89  4.2.4  C A R D I A C OUTPUT AND  4.2.5  C A L C U L A T I O N S AND  PROTOCOLS BLOOD  OXYGEN  CONTENT  STATISTICS  90 93  RESULTS  93  4.3.1  C A R D I A C PARAMETERS  4.3.2  A-V DIFFERENCES  4.3.3  OXYGEN  93  I N OXYGEN  CONTENT  CONSUMPTION  99 100  DISCUSSION  105  4.4.1  C A R D I A C OUTPUT  105  4.4.2  A-V DIFFERENCE  4.4.3  METABOLIC RATE  CHAPTER  IN OXYGEN  CONTENT  107 109  5;  LACTATE  TURNOVER  CHANGES  IN C A R D I A C  5.1  OXYGEN  HORSES  4.1  4.3  AND  INTRODUCTION  IN E X E R C I S I N G  THOROUGHBRED  HORSES: E F F E C T  OUTPUT  112  OF  viii  5.2  MATERIALS  AND  METHODS AND  114  5.2.1  ANIMALS  CATHETERIZATIONS  5.2.2  E X E R C I S E PROTOCOLS  115  5.2.3  MEASUREMENT  116  5.2.4  CALCULATIONS  OF  114  L A C T A T E TURNOVER  AND  STATISTICS  119  5.3  RESULTS  120  5.4  DISCUSSION  136  5.4.1  L A C T A T E TURNOVER PLASMA  L A C T A T E AS  5.4.2  L A C T A T E CLEARANCE  5.4.3  EFFECT ON  OF  PLASMA  TURNOVER  5.4.4  EFFECT  5.4.5  CONTROL  5.4.6  CONCLUSIONS  REFERENCES  OF  AN  AND  ROLE  OF  OXIDATIVE FUEL  RATE  137 141  METABOLITE  CONCENTRATION  RATE  CHANGES  OF  RATE  14 2 IN CARDIAC  EXOGENOUS F U E L  OUTPUT  SUPPLY  143 145 146  149  ix  LIST  1.  Tissue  metabolite  skipjack 2.  3.  4.  rates  in skipjack  Blood  glucose  Weight,  5.  i n c o n t r o l group  of  age,  resting  heart  of  and  glucose  values and  for  turnover  the  plasma  hematocrit  horses  a n a l y s i s of  min  turnover  43  rate,  thoroughbred  3-4  lactate  36  tuna  and  and  tuna  skipjack  Statistical after  concentrations  concentration  concentration, trained  concentrations  35  metabolite  in  TABLES  tuna  Blood  rate  OF  lactate in  four  , decline  treadmill exercise  67 in  hematocrit  i n thoroughbreds  72  \ 6.  7.  Metabolite canter  i n the  horses  running  middle on  Lactate  turnover  cardiac  output  during 8.  concentrations  Effects output  a  gluteal  and  muscle  after of  on  plasma the  thoroughbred  15  lactate  thoroughbred  75 clearance  rate,  horses  rest  at  and and  127 lactate  rate horses  min  thoroughbred  exercise of  a  treadmill  rate,  of  before  of  concentration  lactate  turnover  and  and  128  cardiac  in 134  X  LIST  1.  Lactate  turnover  2.  R e l a t i o n s h i p between  OF  FIGURES  measurement  in skipjack  lactate  turnover  rate  38  and  lactate  concentration  3.  Glucose  turnover  4.  Relationship  between  body  mass  and  lactate  turnover  .52  5.  R e l a t i o n s h i p between  body  mass  and  glucose  turnover  .56  6.  Plasma  heart  rate,  lactate  hematocrit 7.  Plasma  8.  Model the  9.  10.  in  thoroughbreds changes from  Cardiac  output,  resting  and  rest  heart  content  during  Hematocrit  in  rate,  of  40  skipjack  during  a  heart  during  lactate to  tuna  R  tuna  40-min  a g  trot  R^  canter  exercise  and  volume  82  of  horses  i n thoroughbred  horses,  96 at  exercise  resting  and  98 exercising  thoroughbred  horses 12.  Oxygen  102 consumption  thoroughbred 13.  Lactate of  14.  a  resting  and  exercising 104  activity  decay  thoroughbred  horse  specific  thoroughbred  of  horses  specific  resting  Lactate  ..74  during  submaximal stroke  ....69  and  15-min and  45  and  rate,  e x e r c i s i n g thoroughbred  oxygen and  in  concentration,  transition  rest 11.  i n thoroughbreds  showing  Blood  measurement  concentration,  lactate  hematocrit  in skipjack  tuna  activity  horse  at  rest  decay and  curve  in  the  plasma 123  curve during  of a  a canter  ....  125  xi  15.  Lactate specific thoroughbred trot  16.  17.  activity  horse  at  the  decay  curves  beginning  of  and  a  end  of  the  protocol  Lactate  126  turnover  rate  thoroughbred  horses  Relationship  between  lactate  in resting  and  exercising 131  lactate  turnover  c o n c e n t r a t i o n i n thoroughbred  rate  and  horses  plasma 133  ACKNOWLEDGEMENTS  I  thank  continuous my  the  help  the  Zoology  Wade  of  thesis.  Dept.  and  (UBC)  enough  thoroughbred been  thank  and  progress.  for In  entire  staff  ensure  the  assistance larger most  from  in  the  and  importantly,  I  providing  written  Petersen  problems,  soon  as  without  grant  to  P.W.  endless in a  their  efforts.  Hochachka.  a l l  the  would  not  friendship. on  the  heel  a l l the  Foster,  I of  horse  and  the too  hard  experiments.  Dereck  Wheeldon  transplants  of him  cardiac  for  expert  output  i n much  for his help. Finally, Abe,  Uli and  Gayle  Raul  would  work  Tom  Suarez  attempt  thesis This  Brown,  Hoeger,  discussions,  My  for  worked  deliberate  possible.  to  Trust  Hiroki  Foreman,  Tom  Health  with  thanks  in  and  performed  Louise  out  expedition.  expedition  Harman  heart  thank  helped  efforts  their  environment  blisters  horse  accuse  arguments,  biological as  I  Special  become  Animal the  carried  Newmarket  whole  Ferrie,  human  Richard  Nener,  Joyce  for  encouragement  great  the  their  measurement  patients,  Jennifer  NSERC  of  abandoned  Castellini,  UBC  the  success  temporarily  the  to  Pauline  a  Dobson  without  Newmarket,  catheterizations;  trigger  and  refusing  was  i n Honolulu.  Geoff  experiments  them  project  for providing to  Hochachka  gastronomic  tuna  Brill  wine  possible  Brenda  and  The  R i c h a r d W.  Parkhouse  have  and  intellectual  throughout  research  Peter  was  and to  of  but  Michael Mommsen,  purposely  unthinkable get  never  me  out  have  supported  of  been by  an  1  CHAPTER  1;  GENERAL  1.1  STATEMENT  OF  PROBLEM.  During be  supplied  fuels the  to  oxygen be  with  of  and  adequate  oxidative  Oxygen  quantitative  technically  difficult  a  had  investigation  thesis species ability  to  1)  to for  move  compartment  (from  utilization)  with  have  made  determine fast  sites  of  should  a  large  amount  of  flux  rates  of  For  carbon  this  horse).  metabolite  and  to  through  production  corresponding  ability  compare their  more  the two  of  rates  to of  to  and  goals  turnover  is  reasons,  study  The  quite  fluxes  these  (lactate),  lactate  but of  metabolite  limit  of  understanding  on  the  locomotion,  of  delay  rates  musculature  intensive.  and  delivery  The  metabolite (tuna  exogenous  information is s t i l l  to  must  studied thoroughly,  critically  This  of  s u b s t r a t e s and  active  been  muscles  amounts  the  not,.  labor  this  the  the  measurement  one  species  adapted  to  concerning  and be  and  endogenous  have  the  of  are:  to  fuels  regulation.  because  contracting  addition,  depends  fragmentary  experimental  In  information  decision  of  kinetics  their  kinds  fluxes  metabolism  and  use  fatigue.  fuel  exercise  the  oxidizable  matched.  fuels  sustained exercise,  minimize  onset  INTRODUCTION  this  in  two  their plasma  sites  of  sedentary  2  species, the  2)  and  regulation  using  lactate  to investigate  of whole-organism as  a  model.  concerning  measurement  of  lactate  fluxes  explanation  o f t h e aims  of this  few  with  to  such  over would  their  these  ability  turnover  some  -  background  studies  and t h e  more  detailed  a  be p r e s e n t e d  ?  thesis adapted  lactate  i n the  higher  Animals periods  plasma  able  able  and  muscles  active  muscles  have  the  in  addition  to and  animals  in  their  oxidative  be  a  good  fibers  in  exogenous  t o slow muscle  operate  as open  systems,  to  fibers. fuel  particular),  rarely  could exercise  factors  the use of  be  Because f o r many  higher long  oxidize  endogenous fuels  could  have rates  intramuscular plasma  enough  the than  fuels  lactate  tissues  in  can  (oxidative  turnover  than  has  f o r endurance  higher  the lactate  fuels  exercise  opportunity to  at  high  such  performers fuels  down  oxidizable  performers that  under  of the l i m i t i n g  utilize  very  at moderately  be  endurance  than  endurance-type  The d e p l e t i o n o f endogenous  "good"  plasma.  fluxes  fuels. one  endurance  in their  lactate  above)  to use o x i d i z a b l e  r a t e s because,  substrates  for fast  to support  of time,  t o be  (#1 c i t e d  fluxes  working  to  endurance  this  high  be e x p e c t e d  sedentary  species  will  their  shown  exercise,  of  support  long  (intramuscular)  muscle  work  at high  blood-borne  been  vivo,  plasma  conditions, and  giving  ir\  involved in  metabolite  metabolism  of animals  support  organisms  exercise speeds,  goal  animals  sedentary  from  first  the a b i l i t y  locomotion Do  lactate  factors  paragraphs. The  deals  plasma  Before  information  next  the major  rate  of  sedentary  to deplete  their  3  endogenous  fuel  stores.  Recently,  the  importance  oxidizable  fuel  number  of  researchers investigating  rats,  dogs,  Issekutz  et  Georges for  a  brief  1976;  for  fatty  advantages  performers  sedentary  animals  athletes"  would  substrate  rapidly  thoroughbred  thesis can  shows  of  lactate  have  through  their  as  high horses an  lactate not  than  two  and to  rates.  in  "animal this  Tuna of  and  "elite  groups  of  problem.  This  athlete,  tuna  In  ability, this  than  transport  different the  good  rate  such  or  some  i n plasma,  examples  of  animals  provide  endurance  an  ideal  glucose  compartment.  widely  fuel  an  and  a higher  able  turnover  oxidizable  acids,  be  such  be  be  at  aspect  show  1985  I t can  work,  f o r an  Brooks,  muscles.  of  as  from  be  found  plasma  two  this  expected  do  to  chosen  representing  that,  as  level  1985;  i t can  could  fuels  of  Results  could  lactate  lactate  therefore  were  of  a  because  fatty  lactate  use  given  investigate  support  thoroughbred  may  horses  to  rates  oxidizable  for a  athletes"  organisms  free  Because  other  animals  by  Brooks,  (see  lactate  working  plasma  acids. over  that  an  metabolism  1981).  particular  to  turnover  endurance  animal  rates  than  higher  show  see  al,  as  emphasized  whole-body  et  in  lactate  been  example  exercising  high  faster  has  Okajima  summary),  at  sustain  (for  laboratory,  fuel  mobilized  exercise  humans  a l ,  transported  free  and  Brooks  oxidizable  can  during  of  contrast, and  the  use  is  not  above)  is  species  important. The to  second  characterize  the  goal major  of  this  ways  study  used  by  (#2  cited  vertebrates to  alter  4  the in  flux  rates  response  level.  to  The  limits  of  oxidizable  submaximal  aim  of  maximal  the  study  directly  the  utilization  at  cellular  is  asked:  steady-state  rates  of  to  levels  of  different  hypothesized should  that  allow  oxidative  an  them  muscles,  Maintaining  different  of  should  lactate  rate  of  The  lactate  turnover  rate  species  showing  a  under (Chap.  natural 2)  because  plasma  lactate  Chapter  2,  and An  this  et  increase  animals  to  augment  be  working  muscles  tissues  during  by  wide  range  Tuna  of  teleost  has  to  in  cardiac supply  increasing  It  is  concentration  l a c t a t e supply  to  should  lactate  be  turnover. their  determine  different  rates  muscles to  of  chosen  of  concentration  on  demonstrated  rate  this to  exceeding  output  should  of  a l l the  a  purpose  bring 30  mM  its (see  also  allow  to  their  lactate  in  in  concentrations  for  ability  values  given  rates  lactate  the  (for a  different  clearly  perfusion  Almost  ?  in  was  1979).  exercise.  activity  i n plasma  most  response  levels  in response  a l .  the  in  .lactate  working  the  concentrations Guppy  following different  turnover  lactate  to  would  the  support  plasma  changes  conditions.  Instead,  to  of  very  and  animal  perfusion) effect  lactate production  rate  steady-state  delivery rate  to  lactate concentration of  what  nor  i n plasma  rate  the  determine  plasma,  physical  the  muscles  whole-organism  to  in  substrate  augment  working  the  animals  sustainable  the  allow  muscle  exercise.  plasma  therefore,  with  plasma  do  increase  correlated  of  level.  How  to  at  rates  regulation  -  their  is neither  flux  investigate  question  to  exercise  lactate  the  fuels  lactate-utilizing  increase  in  cardiac  5  output  elicited  oxidative with  by e x e r c i s e goes  fibers  oxidizable  output  cardiac  should  lactate  concentration.  this  fish  cardiac would  represent  this  output  in  and  be  output)  on p l a s m a  specific  of the  altered  under  t o measure  a wide  range  f o r each  part  rate  of this  working  of muscular muscle  glycolytic oxygen,  blood  i n which of  values  racehorse the e f f e c t  (Chap. study  was of  i n cardiac  4 and 5 ) . will  be  given  chapters.  METABOLISM  Lactate study  lactate  experimental  ( i . e . changes  turnover  in  experimentally  the r e s p e c t i v e i n t r o d u c t i o n s to the d i f f e r e n t  LACTATE  change  output  to investigate  perfusion rate  be  the c a r d i a c  and t h e thoroughbred animal  also  relationship  a good  because  over  cardiac  plasma  i t is difficult  metabolite  goals  a  s p e c i e s . A mammalian model  appropriate,  i n whole-body  when  should  and  and  manipulated  this  can  problem  be  as an e x p e r i m e n t a l  changes  1.2  does  conditions,  be more  chosen  More  rate  cannot  accurately  rate,  the slope  and t h e  be b e t t e r s u p p l i e d  lactate)  turnover not  muscles,  c a r d i a c output  turnover modify  to investigate  controlled  in  Tuna  should  (including  Therefore,  lactate  output  animal  muscles  substrates  with  between  flow  these  i s augmented.  correlated  of  of  to working  has  activity  provides  pathway.  with  occupied  the  net  for a  a means  This  a  can  prominent  long  time.  position  Its production  f o r ATP s y n t h e s i s occur  formation  of  without 2  i n the  ATP  through  the presence molecules  by the of per  6  glucose, The  and  primary  glucosyl The  units  main  they  during patients  exercise  metabolism  i_n  vivo  fluxes  and  emerged.  In  quantify  the  whole  possible  glycolysis  for  These  as  stores.  demonstrated with  a  is  in  metabolic lack  the  s k e l e t a l muscles,  and  a  patients  substrate  Haller,  for  energy  1986)  . The  muscles  l a c t a t e , even  under  maximal  the  become new  rates organism the  that (its  this  exercise  Several  recent  lactate  (see  and  more  of  use  of  for  lactate tracers  was  that  decade,  not  an  utilization  at  had  was  also  a  important  and  during  Brooks,  to  for  1985;  clearly  very  submaximal this  been  end-product  role  example  not  measurements  traditional  emphasized  has to  and  have  tracer  allowed  permitted  simply  very  via  flux  metabolism  concentration have  on  concerning  have  and  lactate  solely  available  something  lactate  rest,  studies  of  techniques  lactate  at  widely  last  lactate production  tracer  unique  relied  the  metabolic  level,  of  .information  Over  picture  metabolite  muscle  investigation  during  lacking.  a  Metabolic  that  produce  particular,  with  demonstrate  fuel  was  have  techniques,  but  not  and  measurements,  measurements  only.  (Lewis  recently,  concentration  the  do  glycogen  i n muscle  conditions. Until  lactate  muscle work  afflicted  their  1983).  glycogen  clearly  disease. in  (Mole,  production  i s most  phosphorylase  utilize  utilized  intramuscular  patients  McArdle's  glycogen cannot  from  with  unit  lactate  lactate  dealing  metabolism  glycosyl for  of  called  these  per  derived  origin  disorder enzyme  ATP  substrate  experiments  of  3  of  long),  oxidizable exercise.  second  role  Eldridge,  of  1974;  7  Issekutz  et  lactate best  metabolism  accounts  Moret  e_t  data  in  detail  the  been  et  history  by  The  no  i n these  findings  and  lactate  modern  several  Minaire,  However,  of  .  i n DiPrampero,  a l , 1975;  i s presented the  reviewed  found  1980).  turnover more  be  Krebs  a l ,  1970)  Jorfeldt,  has  can  1980;  Sahlin,  work,  1976;  a_l,  the  authors Hultman  1973;  Mole,  1983; of  describing  significance  metabolism  and  discussion  Before  of  (the  1981;  updated papers.  study  of  studies  recent will  be  reviewed. The when  this  original  study  metabolite procedure  Scheele  (see  original  continue  (see  his  cause  of  not  zinc  blood it  of  ml,  Several thanks or  minimum  of  measured  the  85  ml  days  were  necessary  analytical a  few  first of  use  minutes,  of  perform pure  are  1807,  of  muscle did  not  tissue,  and  contraction  years  later,  and  (1886),  from  living  In  but  the  and  tissues  late  one  enzymes,  sufficient  100  to  measurement!  analysis. 0.1 to  the  1800's,  preferably  concentration  to  the  i t s concentration in time.  by  during  Gaglio  blood,  lactate  of  In  Berzelius  i n muscle  acid  The  described  product  Eighty  lactic  milk.  1780).  i n muscles  isolated  one  and  changes  other,  for  in a  sour  century  translation  However,  each  make  the  as  18th  first  english  then.  they  from  was  Swedish  formation  and dogs  time  1971).  to  to  less,  in  chemical  from  resting a  of  (1887)  that f o r an  determined  lactate,  took  200  1786  i n the  isolated  lactate  lactate  be  Berlinerblau  at  Needham,  study  started  first  published  independently  as  used  identified  contraction  could  lactate was  Scheele,  paper  Berzelius  the  of  ml  give  of  Today, blood  accurate  8  values  (Krebs  isolated,  of  intact  under  the  increased  oxygen  in  proposed  He  their  concept  stimulated  while  lactate  deduced lack  that  frog is  caused  by  of  the  muscle  being  lactate  In  shows  formation  that  direct  cause  recovery  oxygen  consumption.  Hill  and  Meyerhof  showed  a  later  that  lactate  of  glycolysis.  assumed to ATP  years  to  be  release Some  A  few  lactate  attention  movements (1924)  energy  immediate  discovered.  Several  was  and  that be  around blood. muscle  equal  under  researchers  tried  and  of  in  glycogen  of of  oxygen lactate  final  excess 1930)  product  chemical and had  (Kramer  the not  were  was  energy role  yet  of  been  shown  to  e_t a _ l , 1939) .  problem  Hill,  Long  and  blood  of  lactate  and  steady-state to  They  formation  muscles  the  Hill  1920).  the  energy  state  other  Meyerhof,  lactate  skeletal  resting  muscle  should  (see  was  hypoxia  post-exercise  conversion  chemical  focussed  hypothesized  conditions.  of  later,  the  was  the  of  in  demonstrated  removal  i n c o n t r a c t i n g muscles,  years in  1930's,  for  source  between  concentrations  the  necessary  mechanical as  Until  and  indication  the  during  few  the  and  was  impaired  Meyerhof  decrease  an  to  several  (Meyerhof,  was  Araki  under  by  debt" a  specific  conditions  subjected  1920,  "oxygen  and  concentration  formation  produced  exercise, was  hens  the  these  confirmed  species.  discovered  muscle.  lactate  and  was  by  study  lactate  conditions  different  to  that  rabbits,  was  investigate  i s produced  showed  Increased  supply in  i t  lactate  to  physiologists  dogs,  1891).  authors  that  first  After  started  which  animals.  (Araki,  a_l, 1 9 7 5 ) .  researchers  conditions one  et  measure  Lupton lactate  exercise lactate  9  concentration submaximal  in  muscle  exercise,  concentrations  in  Sacks,  Most  1937).  equilibrium clear muscle  procedures  by  done  tissues  studies concluded muscle elevated  muscle.  and  Sacks  group. to in  in  (1937)  Already  quantify  lactate  studies.  Net  lactate  that at  the  back  Already  at  indications for  the  administration  of  blood The in  observed  that  caused  by  the  the  low  oxygen  sucrose  to  and  accumulation oxygen  of  lack  lactate. human  was Cori, of  sampling of  their used  that i t  production  Margaria  through  had  from to  (Bang,  Bang a  submaximal  A-V  increase  intensity 1968).  in  (1936)  transient exercise  value. the  century,  was For  not  was  ( C o l l a z o and  observed 1929).  lactate  availability.  a  example,  subjects  concentration  phenomenon (Cori  sustained  beginning  of  appeared  exercise  steady  as  in not  approach  (estimated  went  not  found  light  the  and  i t was  lactate  Hagenfeldt,  of  formation  lactate  rats  a  that  same  infusion  to  In  concentration  concentration  was  recognized  of  release  and  beginning  decreasing  1925).  Wahren  lactate  rate  with  Sacks  different  they  concentration)  1966;  Wahren,  then,  blood  the  criticized  the  example  similar  concentrations  and  1936;  increase  lactate  during  find  However,  blood  his  condition  blood.  to  lactate  for  exponentially  some  that  utilized  approximately  before  and  for  to  differences  increase  (see  due  changes  showed  usually failed  simply  Sacks  in  they  simultaneously  not  impossible  from  blood  were  Margaria's  was  both  the  tissue  results,  but  between  whether  and  not  Despite  et  was  required the  oral  shown  to  Lewicki,  after  Dill  was  there  glucose al  (1932)  necessarily these  early  10  results,  the  production  automatically including  is  absence  Jobsis  and  known oxygen  kinetics  experiments  produced  at  Donovan,  1983;  Eldridge  e_t  1974;  fuel.  work  by  exercise, had  1923;  the  later  and  than  Jorfeldt, during resting)  1970;  had  to  1959;  McGrail  et  showed  see  these be  McGrail  experiments a  good  substrate  (Brooks  and  as  an  1983; et  al,  earlier  observed  (Barr  et  in  and  (at  take  up  was  from  the 1936;  conducted  using the  and  from  (Ahlborg  energy  It  (active  lactate  supported  active  Bang,  studies  . Without  that,  exercise  lactate  active  .  low  muscles  in  Himwich,  a _ l , 1933)  a l l  for  studies  oxidizable  involved  Also,  was  already  be  tracej:  et. a _ l , 1976;  to  e_t a_l_, 1978)  tracer  Freminet  removing  1978).  period  also,  not  recovery  recovery  1984;  Brooks,  who  lactate  that  a_l,  as  can  recognized  were  (Ahlborg al,  et  well  from  and  lactate  effective in  as  oxygen  recent  Margaria  active  recovery  of  researchers  utilize  people  1984).  been  that  of  lactate  a l _ , 1972;  of  ability  1976;  that  Donovan  et  increased  the  can  muscles  almost  Lactate  presence  results  presence  an  when  lactate  of  seventies  blood  tracers,,  number  more  resting  the  had  number  Connett  Recent  role  role  that  was  the  Issekutz,  Pernow,  measured  intensities) blood  the  in  previously,  ability  Carlson  large  example  Freminet  associated  researchers.  a_l, 1969;  the  a  for  the  1976;  this  muscle  during  al,  quantify  However,  resting  et  indicated  to  a  confirmed  in  1974;  et  As allowed  have  Depocas  Issekutz  by  occur  1968).  rates  al,  to  (see  Stainsby,  high  lack  been  contemporary  now of  l a c t a t e has  oxygen  several  production the  with  of  the  et  al,  metabolic idea  that  metabolism  in  11  skeletal  muscle. Over  to  of  exercise,  process and  following  magnitude  muscles.  and  a l ,  was  produced  under  concept  the  e_t  has  been  observed  Brooks lactate  is  rest,  due  to  1984).  by major  a  (Mole,  the last  lines  measured  proposed e_t  between  the  aul, 1 9 7 3 ;  increase  in  augmenting  work  consumption.  This  few  years  (see  production  and  that  activity  1970).  of lactate are  of  example  show  of  Jorfeldt,  because onset  for  of evidence  a l l conditions  e_t a l , 1 9 7 6 ;  muscle,  1983).  when  no  supporting  the sudden  oxygen  tissues contributing  skeletal  be  s t i l l  co-workers  anaerobiosis  under  balance  could  was  lactate  because  not i n d i c a t e the sudden  Several  Issekutz  no  exercise  blood  observed  over  and  that  (Wasserman  the t i s s u e concentrations  are:  leucocytes  does  thought  and  maximal  i n blood  (Gollnick  explain  challenged  produced  1975;  zero the  to  60%  threshold  Fahey,  (Eldridge,  above  to  production and  1981)  rate  of the exercise  (1976)  threshold"  the  physical  or  Wasserman  recovery  influence  state  submaximal  Margaria  the  at the  of  i t was  muscle  concentration 55  lactate  rest  a_l,  about  concept  in  "anaerobic  lactate  beyond  long,  and d u r i n g  diet,  devoted  removal  of lactate  and d u r a t i o n  or during  recently.  Wasserman blood  include  For very  and  factors  factors  conditions.  of  Many  accumulation  accumulation  view  exercise,  the  at rest  these  this  during  the type  1986).  lactate  man,  l o t of a t t e n t i o n has been  exercise.  of  These  fitness,  at  a  the i n v e s t i g a t i o n of l a c t a t e production  onset  et  the years,  Even  maintained removal.  In  to lactate production  at  erythrocytes,  S k e l e t a l muscle  has  brain, been  and  estimated  12  to  produce  about  of  resting  humans  some  muscle  rest. of  from  stays  and  maintaining muscle being are  a  is  taking  Mole,  exercise,  cells  constant  i n which  no  s t i l l  other  at  least  during  fibers  lactate  and  release  but  lactate take  work  (thereby  up  i n t h e whole  t o have  while  in  i s at  cells  net production  i n blood  an  fate  open  of  lactate  question,  removal  The  performed  glucose  mainly  lactate  other  an  fibers  active  mixed  concentration  into  synthesis recovery these  (Cameron  is true and  of  environment  The  fish  Kormanik,  systems makes  the  liver and  and s k e l e t a l  negligible in  of lactate  blood),  exercise  tissues).  excretion is  the  in liver from  in  (see  for  regard  for lactate  the blood  compartment  with  muscle  of  both  (lactate  direct  occuring  release  of  (glycogen during  the carbohydrate  stores  lactate (Dies  renal  loss  this  -  mainly  1982; K o b a y a s h i the  to the  utilized  gluconeogenesis  mammals  because  exercise i s  glyconeogenesis  amount in  with  from  to replenish  avoiding sense  and a f t e r  pathways  v i a oxidation,  conversion  glucose  during  particularly  disposal.  design  increased,  lactate  of the d i f f e r e n t  same  the production  i n some  quantification  in  Thus,  1983). The  is  i n the blood  the organism  i t i s possible  oxidizing  change  when  faster  way,  and r e l e a s e d and  1980).  because  situation In this  appearing  i s greatly  i t  up  with  lactate  oxidize  n i l ) .  produced  muscle,  these  lactate  and S a h l i n ,  do p r o d u c e  submaximal  concentration lactate  (Hultman  cells  During  lactate  35% o f t o t a l  lost  v i a renal  e_t a _ l , 1 9 6 9 ) . T h e and g i l l  a n d Wood, of  excretion 1980).  lactate  metabolite  to  The the  represents  a  13  very of  valuable  source  oxidation,  lactate clear  are  they  activity  level  fate  lactate  of  understood recent been  of  J.  resting  (1981). of  in  and  More  To  fluxes  drastically  even with  produced  is  to  than  of  a_l,  lactate  comparisons as  no  summarize  in  i_n  resting  exercise. at  rest,  submaximal  Brooks,  1983;  Issekutz  Stanley  et  a^,  1985).  lactate  is  not  only  an  e_t These end  product  thesis  has  Issekutz, fluxes  at  the  e_t  effects  rate  in  the  measured  Mazzeo  the  a^L  in  e_t a l ,  effect  of  kinetics  are  vertebrates  has  of  this  exercising  studies:  the  fluxes  and  they  50%  of  Mazzeo emphasize  plasma  of  other  increase  total  percentage  intensities  of  the  lactate  with  results  of  B.  been  flux  1976;  Most  be  of  least  a_l,  only  Okajima  and  group  work  can  turnover  vivo  and  The  turnover have  animals,  At  by  1985;  of  compared  training.  Lactate  studied  other  the  Brooks,  looked  rates  on  including  this  species.  have  has  high  G.  to  total now  level  relevant  (1984)  of  to  i t is  quantified.  t r a i n i n g on  e_t  at  are  (1983)  (Stanley  oxidized 80%  i t s state  investigated  flux  are  factors  organism  recently,  mammals,  studied.  more  been  blockade  to  substrates,  and  mammalian  Brooks  Interspecific  lactate  on  contributions  i n v e s t i g a t i o n , but  kinetics  Issekutz  beta-adrenergic  been  glyconeogenesis  whole  endurance  humans  restricted  and  laboratories  have  and  and  dogs.  the  rats  animal.  1986),  the  respective  several  animal,  lactate  Donovan  exercising  upon  exclusively  exercise  same  at  on  Katz,  the  under  The  k i n e t i c parameters  performed  and  s t i l l  depend of  i f  work  energy.  gluconeogenesis,  removal that  of  lactate increases  (Donovan e_t a _ l , the  fact  g l y c o l y s i s , but  and 1986; that  i t is  14  also  an  important  particularly  oxidizable substrate  during  submaximal  for skeletal  exercise  i n rats,  muscle,  dogs,  and  humans. Lactate could  production  represent  an  by  important  substrate  to o x i d a t i v e muscles  organisms  can  derive  ability  to  support  trained  or n a t u r a l  movement,  or  study  over  a  levels can  be  manipulated  mechanisms  tool  to control  involved  turnover  rate  exaggerated  All continually  in  (at  the  the  i n the case  METABOLITE  a  of  carbon  (Brooks,  involving should  1985) . I f  from  the study  of  instructive;  be e m p h a s i z e d  fuel  for this  for oxidative  of lactate  i n response  the turnover  in  species.  metabolite  rate  their  the production,  sedentary  exogenous  of values  over  supplying  fluxes,  as a model  Therefore,  fibers  especially  the turnover  range  activity.  experimental  1.3  wide  muscle  advantage  be  with  i t i s a good  2): because  very  work  of lactate  chosen  of  lactate  exercise  compared  was  1):  and  of  to  performers  because  muscles,  plasma  utilization  Lactate  during  athletes should  adaptations  animal  means  performance  high  metabolic  elite  a  glycolytic  to  rate  varies  different of  lactate  wide  range  using  exercise  this  rate.  Also,  the regulatory  control  as an  of  plasma  metabolite  whole-organism  level)  should  be  organism  are  lactate.  TURNOVER  the  body  produced  constituents of a and  utilized  in  living a  process  called  15  turnover  (see  plasma  Hetenyi  et  metabolites  undergoing  have  substrates release  in  of  minor  to  changes  large  and  flux  noticeable  ( a) i f  muscle  metabolism  possible  i f substrate The  rapidly  rate  site(s) if for  or of of  this a  fluxes  metabolite  substrate  exogenous from  tissue,  or  invalid  allow  the  fuel various  other  by  plasma  are  of  a  plasma  the  In  In  reflect ( )  and  R  a  compartment,  level  metabolite  of  the  is  of only  the  is a  is  to  such case  of  measure  or not  rate  oxidative as  of  from  excretion the  turnover  maximal  how  cells,  compartment  (which The  shows  between  utilization  supplied areas  It  blood  lactate).  muscles.  only  understanding  i s exchanged  as  storage  drastically  quantified.  site(s)  being  may  whole-organism  excreted  is  (Wolfe,  concentration.  The  circulation.  represents  uptake  organism  plasma  high.  of  because  appearance  the  rate  of  altered  of  of  q u a n t i f i c a t i o n of  the  be  rates  are  their  often  indeed  such  about  are  through  is  concentration  rate  from  the  to  the  state, however,  their  compound  via  decades  and  the  rate  production  muscles  at  movement  compound  oxidizable this  organs  the  compounds,  dynamic  concentration  and  particular  in  their  rates  turnover  this  tissues, its  these  a  For  can  in  in  into  R  in  utilization  between  particularly fuel  not  changes  a l l other  conclusions  rates  changes  imbalances  disappearance  draw  do  production  addition,  changes  conclusions  Metabolite  without  therefore  circulation  Such  concentration  1984).  used  the  Like  replacement.  plasma  in  therefrom.  rates  are  constant  researchers  a_l, 1983).  liver,  lactate,  case  of at  an  which  working adipose a  large  16  fraction 80%: and  of  see  total  Donovan  Mazzeo  et  oxidizable  A  good  1.4  can  THESIS  and  longer  (1983),  the  compare  two  of  al  than  (1976),  lactate  as  turnover a^,  Wolfe,  substrate supply  are  used  an  rate  1985;  sustainable  fuels  the  The  animals  purpose but  to  problems  concerning  fluxes  explained  i n the  is In  species  used  as  a  addition, whose  plasma  "athletes":  different  two  study  investigates  animal  horse.  general.  exogenous  t o more et  of  from  Stanley et  i f endogenous  thesis  thoroughbred  lactate  importance  e_t a _ l , 1 9 8 6 ;  to  Issekutz  estimated  of  [50%  is  exercise  sparingly.  OUTLINE  outstanding  as  is oxidized  the  be  understanding  This two  can  relevant  last  rate  Brooks  al_ ( 1 9 8 6 ) ]  (Mazzeo  particularly which  and  fuel  measurements 1984) .  turnover  of  use  previous  lactate  to  skipjack this  each  the  model  plasma  the  lactate  turnover tuna  work  one  of  is  them  regulation sections. study  turnover  rate  the  not to  of  In  flux  and  in  to  solve  lactate  both  cases,  regulation  in  is quantified  in  metabolite kinetics  have  never  been  investigated. Chapter skipjack the rate  tuna.  2 The  relationship of  lactate  concentration examination  primary  between turnover  can of  examines  the  reach  lactate goal  plasma  this  lactate  in this values  results  of  turnover  from  rate  chapter  in  i s to  study  c o n c e n t r a t i o n and  teleost  whose  plasma  exceeding  30  this  study  first  mM.  the  the  lactate A  shows  close that  17  cardiovascular metabolite output  adjustments  turnover on  have  an  from  their  at  the  important  working  lactate  their  effect  study not  on  and  this be  lactate  a  model,  cardiovascular  the  i n more  flux  under  rates. part  turnover  and c a r d i a c  example with and  the i t  "elite"  discusses data  homeothermic have  compartment  the  output  aspects  problems  have  ectothermic ability  at rates  to  never  equal  With to  alter  was  3 to  2 also  deals  studies,  the rates  their  of  between  i s shown  across  in  good  the comparison  It  5)  large  measured  particular  lactate  chosen  2): lactate  kinetics  with  a  elicit  i s a very  Chapter  (in  or exceeding  been  to  could  undergo  horse  organisms). move  tuna  (Chapters to  of metabolite  associated  needed  tool  to exercise,  athlete.  species  was  racehorse  and  performed  experimentally  known  response  turnover  conditions).  to  is  n o t be  as a  the  changes,  because  b e .used  fuels  sites:  lactate  investigation  mammalian  between and  (mainly  may  relationship  animal  thoroughbred  in  the  could  3): the thoroughbred  comparative  kinetic  tuna  and  o f an  utilization  rate  been  of oxidizable  plasma  and  animal  changes  species,  changes  and  could  The  cardiovascular  this  These  controlled  of this  this  rate  level.  of cardiovascular  adjustments,  1):  never  alter  detail  i n cardiac  have  may  turnover  plasma  rate  their  they  exercise  second  because  of changes  d i f f e r e n t experimental  problem  metabolite  to  the study  exercised  mammalian  for  sites  influence  the transfer  concentration  Unfortunately,  tuna,  organism  on  Also,  rate.  on  The e f f e c t s  whole  storage  also  turnover  impact  muscles.  between  rate.  metabolite  investigated  may  that  plasma  measured  in  18  rats,  dogs,  and  In lactate  humans.  the  turnover  animal  both  trained  for  order  cardiovascular chapters,  measurement  particularly  with  plasma  lactate  specific  to  a l l  complete to  assess  the  This  the  study  treadmill  is  of  These  timing  steady  state exercise  preliminary  work  the  The  of  general  status were  was was  the  and  of  the  work.  In  later  by  use  3  metabolic  the  present  necessary  the  chapter  3  sampling  4 and  5.  To  thoroughbred were  see  after  on  lactate  and  the main to  have  thesis,  from  of  on  events  the  biopsies of  the  exercise,  events  for  response  one  of  It focusses  chapter  i n plasma  also  in  examines  data  in  sampled  observed  treadmill for  injections  muscle of  of  Chapter  of  used  and  requires  these  part  reported  exercise,  biopsies  this  an  technique  and  impact  assessed.  the  metabolic  submaximal  the  5),  response  submaximal  animals  measurements  this  horses  of  of  determine  the  to  of  c o n c e n t r a t i o n . In  measurements  allowed  onset  respect  a  established.  cardiovascular  the  response  turnover  muscles.  the  on  measured  conditions, are  the  this  this  to  horse,  conditions  to is  3  performance,  rate,  Because  conditions  of  with  lactate  rate  steady-state  associated  for  turnover  such  high  exercise  relevant  lactate how  for  necessary  technique.  and  thoroughbred  turnover  parameters  (Chapters  3 characterizes  the  lactate  lactate  thesis  i n the  submaximal  injection  plasma  the  to  determine of  the  geared  Chapter  horses  measurement  of  measured  racing.  to  when,  is  part  genetically  thoroughbred  bolus  second  taken  locomotory whether  the  few  minutes  i n working  muscle.  because,  a  to  at  the  time  19  these  experiments  been  exercised  these  animals In  exercising  here  the  impact  was  Chapter  the  cardiac  horses  i s  of  measurements  the  cardiac  output  of  animals  study.  consumption  rates  The  these  regimes  allow  only  resting  man. A  Chapter and  rate  cardiac  major  metabolite  factors  The  impact  rate of  are  f o rthe with  the metabolic  rate  of  on  oxygen  turnover  with  different  of lactate  turnover  known. is quantified  by u s e o f t h e b o l u s of the turnover i n this  regulation  identified  changes  in  t o be a b l e t o  done  analysis  the  the  f o r the horses  i s presented  in  content are  chosen  r a t e s were  lactate  data  In  together  studies  thoroughbreds  involved  turnover  selected  integrated  output  oxygen  necessary  i fmetabolic  An  racehorses.  assessment  comparison  5, p l a s m a  output  e x e r c i s e p r o t o c o l s used  was  valid  lactate  cardiac  of activity  to calculate  other  exercising  technique.  and  in  b e made  the f i r s t  in  determine  plasma  measurements,  animals  used  including  could  analysis.  These  quantitative  injection  The  levels  f o r the d i f f e r e n t  of  In in  values,  on  and  measurements  (5) t o  thoroughbred  the exercise i n t e n s i t i e s  exercise species  study.  of  by use o f t h e  output  chapter  differences  different  response  of resting  determined  changes  presents i n  arterio-venous  turnover  compare  4  output  cardiac  cardiovascular  performed  at  The  horse had  unknown.  i n the following  Chapter  lactate  this  4,  technique.  rate.  measured  and the m e t a b o l i c  work  a r e used  addition,  no t h o r o u g h b r e d  to treadmill  thoroughbred  made  the  conducted,  on a t r e a d m i l l ,  thermodilution  turnover  were  in  in  chapter.  of the  plasma  plasma final lactate  20  concentration oxidizable  and  substrates  Chapter  2  not  important  an  thoroughbred  in  for  tuna,  horses.  cardiac is this  output  on  the turnover  d i s c u s s e d . U n l i k e what last  metabolic  chapter  fuel  for  shows  that  muscle  rate  of  i s found  in  lactate  is  in exercising  21  CHAPTER  2:  LACTATE  2.1  AND  biochemists lactate  have  of  in  muscle  (Hochachka  a l ,  lactate  IN  SKIPJACK  TUNA.  and  1983;  exercise physiologists interest  that  but also  al,  an  1985) .  long  lactate  (Brooks  Eldridge  et  mammals, becomes rate  et  a l ,  fuel  1974;  for aerobic  limiting  lactate (Connett  Donovan  Issekutz  a  an end  muscle  1984;  of  plays  increases with  a_l,  and  study  I t i s not simply  In  turnover  the  compound  important  0^  before  in  this  metabolism.  concentration  Brooks, Okajima  e_t  starts  1984),  renewed  realization  glycolysis  production  few y e a r s ,  shown  the  role  product work  the past  with  double  blood and  e t a_l, 1976;  e t a l , 1981). As  combination can  TURNOVER  INTRODUCTION  Over  et  GLUCOSE  they  elite of  endurance  sustain  distances,  but  swimmers,  (Waters  and  machinery  supporting  tuna  by  this  fluxes  of  fuels  endurance  swimming  and  sprint  locomotion  the 2)  characterized  capabilities. speeds  over  top v e l o c i t i e s  Fierstine,  lifestyle, to  are  swimming  can reach  lengths/s  imposed  and  moderate  they  tuna  and working fast  The  must meet  i t should muscles fluxes  of  Not  only  very  long  of over  1964).  by a  20  body  metabolic  the challenges  i n c l u d e : 1) during  fast  aerobic  anaerobic  end  22  products burst  to  their  generate  During  swimming  lactate  very  wet  weight  umol/g  in  recovery,  tuna  than  concentrations exhausted  smaller  trout  (Black  in  mainly  on  et  a l ,  in  fish.  recovery  1978),  lactate extend  and the  of  species,  2)  from  clearance by  high  lactate  and  Connor,  clearance  of  much  12  faster lactate  recovery  1964).  takes  e x e r c i s e and  of  of  Even h  understanding  and  lactate  goal  of  glucose  in  in  with  a  rainbow  correlation  found  lactate as  during fluxes,  metabolic  been  lactate  i n mammals and  the  to  Lin  investigated  to  measure  tuna  to:  turnover  the fast  much  1)  rate  nonmammalian  could  in a  been  a  recovery  fuels  a  a  rate  assess  only  a  to  high  3)  as  e_t a _ l , 1 9 7 7 ;  in skipjack  between  provide  metabolism  t h e r e f o r e , was  concentrations  i n tuna  not  rely  concentration  r a t e has  (Bever  rates  whether  fuel  turnover  study,  turnover  out  of  salmon  in fish  f l u x e s would  f l u x e s have  this  concentration  recovery  metabolite  metabolic  coho  glucose  occurs  2 h  of  et_ a _ l , 1979) .  of  and  can  1962).  and  blood  (Guppy  than  less  bass  reported  muscle  tuna  concentrations  after  glucose  find  record  clearance  However,  lactate  to  skipjack  blood  load,  the  observed  lactate  range  to  speed,  Minimum  interpretation  in kelp  The  for  during  teleosts.  (Barrett  views  process.  measured  lactate  Estimates  dimension  up  white  reached  a l ,  the  measurements.  dynamic  in  lactate et  high  rapidly,  other  are  Present  and  catabolism  at  blood  skipjacks  much  new  of  exercise. While  90  sites  of be  wider  lactate accounted  importance pelagic  of fish  23  and  compare  and  4)  Cori  cycle  2.2  their  flux  o b t a i n some in  MATERIALS  coast  AND  EXPERIMENTAL  Oahu, back  Fisheries  to  the  holding  seawater.  The  fish or  to  days in  in  were  of  with  and  a  sample  net  acid  use  the  of  in  of  1984.  the  with  capture The  and  same  stores  of  turnover. a  white liquid  previously  The  sharp taken  muscle, N  2  and  by red  of  on  muscle,  extracted  described procedures  and in  4  used stores  for  were  head.  cardiac  five  for  fish  used  the  in  glycogen  kept  the  fish  25^C  their  carbohydrate  control  of  used  group  were  fish  blow  Marine  of  caused  animals  the  were  wells  were  status  control  their  bait  and  c o n d i t i o n s as  therefore,  They  the  to 75,000-liter  captivity  control  the  with  The  in a  off  well-aerated  in captivity  capture.  tuna,  (National  transferred  determined  under  killed  1 g  clamped by  fed  immediately  Approximately freeze  was  lactate  was  August  Facility  supplied  after  experiments,  measurement  to  Research  not  whether  to  May  b a r b l e s s hooks  and  depletion.  similar  with  Skipjack  vessels  were  stores  captivity  turnover  i n mammals,  o p e r a t i o n of  l a b o r a t o r y ) i n the  days  assess  glucose  possible  Honolulu  tanks  fish 4  carbohydrate  measured  ANIMALS.  from  Kewalo  fishing  first  the  caught  Hawaii,  circular  the  were  Service,  commercial  into  values  METHODS  pelamis,  of  brought  insight  with  tuna.  2.2.1 Katsuwonus  rates  the  caught A  blood  puncture. liver  were  perchloric  (Guppy  et a l ,  24  1979).  Glucose,  concentrations  were  Fish vigorously before  (tricaine fish  to  be  i n these  used  their  directed  bag  6-phosphate,  determined  around  being  plastic  glucose  in  to a large  containing  experiments  tanks funnel  (from  1:2,000,  swam  1 t o 10 m i n )  leading  (^-supersaturated  methanesulfonate,  glycogen  tissues.  turnover  holding  and  to a  water  wt/vol):  10-liter  with an  MS-222  effective  anesthetic.  2.2.2  CATHETERIZATION.  stopped  moving,  ventral  side  i t was b r o u g h t  up  on  an  As  into  soon  as the f i s h  the laboratory  operating  table.  The  and  placed  gills  were  0 irrigated  with  containing  MS-222  Catheter  20  g  aerated  24 C  recirculating  (1:15,000).  X  A  catheter  2 i n . , ID 0.80 X 5 1 mm,  seawater  (Surflo  Terumo,  I.V.  Japan)  was  0 inserted  at  pelvic  fins,  cannulation The  a  of  tubing  underside  aorta  of  aorta)  approximately  towards  was  connected  was the was  cannulation  to  animal.  Double  attempted was  done  i n Jones  pressure  to perform,  and s u c c e s s  to the heart.  40-cm  Catheters,  PE  the  e_t a_l ( 1 9 8 6 ) .  tubing, saline  and  was  piece  and s u t u r e d  cannulation  rate  of the  transducer f o r  position. A  through  difficult  heparinized  anterior  mouth This  low  of  to the  ( v e n t r a l and  on a few i n d i v i d u a l s .  described  with  a  i n front  f o r the percutaneous  to the catheter  technique  rinsed  just  of catheter  attached  2 cm  t h e head  the ventral aorta  verification  PE-160  dorsal  angle  directed  catheter  pressure  45  The d o r s a l by use o f a  procedure  was  (under 3 0 % ) .  syringes  were  (10 U/ml) b e f o r e  always  use. Total  25  cannulation double in  time  cannulations,  place,  the  heart  transducer.  Plexiglass  until were  The  .and  then  slowly  anaesthetic  in  showing  were  not  at  this  value  mM  or  more  sampling  bolus  fish  to a  anesthetic 1:30,000  throughout  allowed  without  to  and the  recover  thrashing.  continuously  no  They  adjusting  the  operation, ranged was  from always  assumptions  injection  of less  blood  of stress  value  started  were  several this  of  1  I n some from  hours  of  occurred  the  i n the a n a l y s i s .  for  kinetics  1  was s e t  levels  a l l  ( i . e . a minimum  state met.  limit  than  to decrease  included times  were  surgery.  occasion.  a v a i l a b l e to derive  of steady  technique  a t any  Whenever  sampling 2 to 6 h  The  glucose  after  not  blood  concentration  concentration  with  were  and  after  experiment.  curves  rate  of the animal  concentration  turnover  heart  experiments.  fish  signs  of  glucose  glucose  steady-state  this  the  because  of decay  experiments  and  strapped  The  were  tail by  blood  i n turnover  glucose  in a  ends  After  were m o n i t o r e d v i a  upright,  each  measurements  a blood  showed  blood  sampling  of  state  with  used  original  tail  for  was  concentration.  mM  its  pressure  to approximately  i n d i c a t o r s of the s t a t e  cases,  f o r s i n g l e and  t h e c a t h e t e r (s)  submerged.  their  this  35 m i n  Once  animals  moved  together  Animals  and  turned  reduced  The  Preinjection pressure  was  individually  maintained  valuable  and b l o o d tuna  experiments.  they  20  respectively.  rate  was  adjusted  turnover  exceeded  holder,  concentration was  never  of  a decay required  turnover 2  hours  curve), by t h e  26  2.2.3  INJECTION  SAMPLING.  A  activity  >  mCi/mmol)  [U-  14  100  or  injected  via  the  injection. after  pool.  bolus  was  drawn  about  order  time  40  s  The  never  Mass.)  and  2.2.4 were  was  This  choice  good  this  the of  amount  of  of  from  (Oakville,  METABOLITE  ASSAYS  New  total the were  then was  at  made  specific  volumes  of  0.5  ml  blood saline  throughout  an  blood  volume.  England  Nuclear  Ontario).  AND  immediately spun  the  lactate  with  total  in  and  and  times  drawn  of  min  Samples  5 min  sampling  flushed  10%  purchased  and  first  1  allow  body,  line after  starting  period.  blood  The  equilibrate  excessive  c a t h e t e r was  injected  immediately  entire  was  specimens  recycling.  measurement  drawing  two  s u f f i c i e n t to  Amersham  (8%)  In  to  (4  mCi/mmol)  drawn  the  BLOOD  CJglucose  were  bolus  during  deproteinized  acid  0.  were  after  exceeded  were  ml)  14  (300  carbon  across  mixed  a  The  samples.  perchloric  This  without  Radiochemicals  samples  the  be  obtain  animal.  experiment  (Boston,  allow  intervals.  decay  the  to  [U-  heparinized saline (0.5  AND  C]lactate (specific  uCi  time  glucose  circulated  every  to  activity  between  t o be  assumed  appropriate  at  samples  mixing volume  from  ml  to  blood  in  3  Blood  10  1 4  3 [6- H ] g l u c o s e  estimate  with  [U-  [6- H ] g l u c o s e  and to  METABOLITES  3  uCi  injection  rapidly  25-35 u C i  catheter  C]glucose  flushed  of  LABELED  mCi/mmol),  25-30  simultaneously was  bolus  OF  down.  COUNTING. in The  1-2  Blood  parts  cold  supernatant  was  0 stored  at  determined  -4  C.  Lactate  enzymatically at  and 340  glucose nm  by  use  concentrations of  the  were  procedure  of  27  Bergmeyer  (1974).  determined  with  (Bergmeyer,  at  these  A l l  measurements more  was  than  the  used  after  i n the  were  performed  sampling  the  mean  calculations.  For  each  were  Glucose i t  assays)  values  necessary i n about  activity  method  two  determinations  was  of  found  is  5%  of  never  set  repeat  the  cases. was  in glucose when  of  two  differing  showed  to  lactate  adequate  in  and  first  i f the  activity  This  assays  was  technique  made  specific  subtracting activity.  was  fish  hydrolysis  new  (two  The  7 days  control  concentration, a  but  determinations  the  metabolite  10%.  variability,  of  metabolite  latest  measurements of  glycogen  amyloglucosidase  the  determination  by  the  1974).  duplicate, of  Tissue  such  lactate  estimated  from  total  measuring  by  blood lactate  14 turnover  with  technique never  C-lactate  because  reach  injection  other  the for  with  continuous  infusion  period  turnover  be  method than  can the  lactate  animal  is  several than and  in  of  about  6-8%  1983;  When  have with  However,  is  Okajima  is  of  period in  the  to  high  only,  continuous other  isotopic such  is s t i l l (Davis,  a l , 1981).  The  glucose a  bolus  with  high  compared a  long  measurement  equilibrate  under  in glucose  (in  which a  injection  and  contact  several  activity  et  in  before  using  even  blood found  activities  short  time  bolus  lactate  experiment  activity  glucose  total  very  the  than  necessary  made).  contact  hours).  90%  Brooks,  or  a  is  specific  pools  animal  activities  equilibration  of  specific  isotopic a  use  carbon  significant  experiment,  by  of  infusion  carbon  pools  (because  the  activities  for  conditions,  more  found  in  1983;  Donovan  remaining  lactate, and  activity  28  can  be m e a s u r e d  and  others,  compounds activity bolus  but,  only  and t h e i r injection  lactate  can  activity  found  possible  error  be  be e v e n  a  activity  to  effect  study. measured and new  of  specific  rates.  however,  that  Blood activity.  Blood  5% f o r r e a s o n s  the  negligible. activity  subtracting  of the  secondary  metabolites  %  overestimation ends  of  would  under  of lactate  r e c a l c u l a t e d with for from  explained  cause  (when  these  activity would  new  i t  of alanine,  by  were  5%, the not  "uncorrected"  i s very  represent  the  a l l the  curves;  rate  original  before,  minor  i n the present  decreased  turnover the  a  c u r v e ) , and  curves,  were  This  dividing  the decay  decay  specific  curves.  as n e g l i g i b l e  chosen  unlikely  pyruvate, 5%  of  and total  experiment.  was  perchloric  decay  turnover area  injection  of lactate  the  activity  considered  glucose  as  specific by  explained  ignoring these  compounds  i n a bolus  than  other  The maximal  the specific  secondary  In the  activity.  values  As  cases).  total  total  different  turnover  of  c o n t r i b u t i o n of these  from  lactate  was  pyruvate, secondary  fraction  i n extreme  estimated  activities  rate  significantly  activity  be  randomly  "corrected"  other  by  these  c a n be c o n s i d e r e d  by t h e s u r f a c e  three  turnover  the  specific  has been  In  small  5%  smaller  tail  of  underestimation  this  3  the  dose  of  glucose  caused  overestimation  very  effect  as a l a n i n e ,  together,  experiments,  in  in  injected  a  therefore  2  such  taken  technique,  will  bolus  would  when  maximum  injection  previously,  compounds  represent  ( i . e .a  compounds  In  i n other  separated acid  to  extract  determine (200  ul)  i t s was  29  incubated resin  with  (Sigma  4  ml  1  M  Chemicals).  glucose The  and  mixture  0.6 was  g  Amberlite  shaken  for  MB-3  2 h  at  0 25  C,  allowing  resin  before  a l l  i t was  counted.  After  glucose  was  the  charged  spun  down  separation  recovered  compounds  and  1 ml  90.1+3.2%  as  of  of  to  the  the  determined  bind  to  the  supernatant  was  total  with  radioactive 3  [6-  H]glucose  standards. Lactate perchloric in  acid  glucose.  LS-9000  for  Scintillation  at  least  showed an (dual-label:  counting  12  (ACS  h  for  was  counter  A l l samples  scintillant  measured  correcting  scintillation  correction.  counting  was  e x t r a c t and  liquid  quench  activity  were  counting  40  the  activity  found  performed using  mixed  I I , Amersham)  before  by  on  a  external with  and  10  left  ml  Beckman standard aqueous  i n the  counting.  Single-label 14 efficiency of 94% for C and 42% 73 and 3 5 % , r e s p e c t i v e l y ) . No a t t e m p t  ul  dark  counting 3 for H was made  14 to  measure  no  reliable  trapping the  of  C0  after  a  major  oxidation  (this  Kormanik,  preliminary  in  2  found  the  and  appearance  technique  activity  rapidly that  the  of  is  water.  in blood  fate  and  of  Kobayashi  experiments,  6  dioxide  the  of  like  excreted and  in  in  tuna  in fish:  Wood,  skipjack  tuna  allowed  to  see  1980). were  mammals,  decays  C-lactate,  lactate  because  quantitative  i n other tissues 14  plasma i s not  for  However,  injection  compound 1982;  i n carbon  available  salt  bolus  C  very  showing is  also  Cameron In  injected  some with  14 C-lactate large was  tank  and (1-2  isolated  they body  from  were length  their  per  second)  muscles  and  quietly for  liver  swim  6 hours. to  in a  Glycogen  determine  the  30  activity  in  this  incorporated, extremely  14  from  was  variable  lactate These  and  no  lactate  activity  tissues. to  of  this  i n an  been was  activity glycogen  approach  showed,  unknown  the  quantify  experimental clearly  had  glycogen  Furthermore,  reliably  results  . accumulating  not  Almost  specific  these  too  abandonned. C  the  in  was  synthesis be  and  low  measured  compound.  had  however,  carbon  that  . in  pool  to  . this  species.  2.2.5 The  concept  system  TERMINOLOGY, of  in steady  this  compound  conditions, rate  of  R  and  good flux  does  R^  must are  summary  of  of  no  measurement infusion  major of  (Katz They  assumptions  requires allow  theory study  and of  rate:  e_t  1981;  a_l, to  the  in their  steady-state  bolus  usefulness  turnover  out  steady  metabolite  of  the rate  independently give  a  associated with  but  and  for  a _ l , 1981; differ  various  the  continuous Wolfe, in  their  experimental  bolus  injection  c o n c e n t r a t i o n , and of  of  i_n v i v o .  infusion,  mesurement  a  state,  e_t a_l ( 1 9 8 3 )  et  for  to  called  injection  results  to  these  equal  available  Okajima  continuous  is  terminology  are  applied  Under  measured  Hetenyi  STATISTICS.  concentration  )  metabolism  same  independent  be  and  be  time).  comes  techniques  Unlike  the  equal.  turnover  lead and  situations.  longer  to  only  (R  can  animal  referred  i n the  over  and  AND  plasma  appearance  (R^),  the  can  the  change  I f the  be  measurements Two  not  rate  they  1984).  not  rate.  turnover  ( i . e . when  disappearance  replacement  because  state  the  or a  metabolite  CALCULATIONS  rates of  i t does  appearance  31  and  disappearance.  continuous  infusion  implanting  the  technique  the  An  excellent  isotopes  can  Metabolic  (reviews  and  have  by  stable  they  the  Because purely  of rate  species,  a l ,  et  3.4% the and  Donovan  1983;  a _ l , 1983;  of  to  then  The  calculated  at  used  of  1979;  was  1984).  rate,  of  rate  Several  lactate  1983;  Eldridge,  1984).  experimentally. of  endogenous (Allsop  rate,  and the  rate the  coefficient  about  the  actual  laboratories  have  in different  conditions 1974;  e_t the  between  the  turnover  experimental  blood  developed  calculate  and  been  plasma  common  been  known  to  in  Wolfe,  had  10  1984).  have  turnover  surgically a  last  Wolfe,  5%  plasma  the  stable  investigators  rate  Wolfe,  Brooks,  of  difference  (see  and  over  maximum  calculated  various  the  sources  tracer  under  allow  number  removed  was  in  validated  infused  technique  the  a  a l l  were  Tracers  techniques  Katz,  be  book:  1979;  technique  and  kidney)  the  for  for  and  methods  metabolite  used  radio-  and,  Katz,  infusion  methods  number  tracer  of  i t had  was  modern  large  infusion  appearance. and  a  validated  infusion  variation was  and  Glucose  glucose rate  by  with  v i vo,  the  investigated.  Wolfe's  These  over  difficulties;  by  current  fluxes  radioisotope  been  of  _in  chosen  surgical  species  R.R.  anaesthetized,  1978).  quantified  1983;  et  continuous  (liver  continuous  true  used  (Hetenyi  were  glucose  of  been  theoretically,  Dogs  in  measurement  have  the  of  was  required  the  metabolism  and  to  in  (1984).  Hetenyi  metabolites  al,  of  of  analysis  found  Research  they  applied  difficult  be  injection  catheter  measurement  investigation  Both  second  too  vivo  bolus  because  was  _in_  years,  Here,  (Davis,  Eldridge  et  32  al,  1974;  Issekutz  Freminet  et  Mazzeo  e_t  Chandrasena, tracer has  a l ,  1976;  a_l,  1986;  1977;  bolus  (1984),  Katz  in  to  intracellular  the  the  total  have  lactate  time  has  been  to  infusion  technique  for  rates  measured  identical  1981;  Katz,  techniques  give  equilibrates (Wolfe, by  the  various al,  1981;  K^  the  values  cell  dose  also  1975;  the  et  results  Koch  reported  for  (Dubinsky  present  injected  and  study,  (in  dpm)  a l ,  have  time  and  turnover divided  lactate  to  labeled  be  (Katz,  (Katz  These  et two  lactate  compartments indicated  transporters 1978;  in  Koch  et  1976).  r a t e was by  (in  extra-  found  glucose  Racker,  Lehninger,  not  turnover  e_t a _ l , 1981) , a s  and  of  technique  between  muscle  lactate  may  absent  1981).  because  blood  see  Spencer  seem  continuous  is  were  and  of  fraction  the  including  1979),  Okajima  membranes  Roos,  Katz,  between  a  and  may  injection  techniques  of  use  equilibrium  problem  use  The  not  contains  equilibrates  metabolites  identical  may  and  Freminet  measurements  as  1982;  kinetics  s e v e r a l h o u r s ) . The  two  1974;  lactate  (1984).  results  this  over  1986;  comm.;  same  label  the  quickly  pers.  In as  Dunn,  the  a l ,  Reilly  (1984),  bolus  1984;  specific  of  isotopic the  which  fluids  several  and  (i.e.  to  . The  compound  which  et  1981;  Wolfe  turnover  fluid  the  with  for  Rostami, al,  infusion,  intracellular  and  However,  lead  a_l,  Fahey  labeled  pool  to  continuous and  the  occur).  shown  and  lactate  because  et  Issekutz,  Mazzeo  investigation  Brooks  questionable reach  a_l, 1981;  (1986),  for  1980;  e_t a _ l , 1985)  .the  Katz  injection  et  Okajima  for  reviewed  Minaire  Leclerc,  Stanley  techniques  been  and  the  calculated  surface  area  33  under see  the Katz  decay by  specific e_t  curve use  was  parameters function  first the  Data  determines  5%  a _ l , 1981) .  of  BioMedical  was  a  modified  then  possible  divided  by t h e volume  activity  o f t h e body  metabolite  as  curve  ( i n dpm  regression (BMDP;  specific  rate  concentration  (Katz  Wolfe, of  1984),  which  the  was  mixing  et a l ,  pool  clearance by  function  The  fitted  1981).  when  reached.  The  injected  estimated  rate  the  the  function  0 and the time  activity  divided  area  from  algorithm.  time  min,  P3R  c a l c u l a t e d as the dose  Metabolic  turnover  surface  program  estimates  of the rapidly  volume.  see  Gauss-Newton  was  umol  a multiexponential  i n t e g r a t e d between  possible  calculated  with  least-squares  o f t h e maximum  8%  fitted  nonlinear  maximum  be  decay  To c a l c u l a t e t h i s  Processing  the by  activity  (MCR)  steady  to was  state  34  2.3  RESULTS  Glucose, concentrations are  given  in in  concentration relatively (Tables  glucose tissues Table  and  different  3,  ranged  experiment  blood  a  radioactive  bolus.  preinjection in  Tables  3B).  to  6.8  sample  was  drawn  Lactate  and  glucose  mM.  was  point  blood  was  glucose  In each  before  within  i t  experiments  set  mean  group  glucose  because  the  the  1.2  always  blood  turnover  However, and  glycogen  the c o n t r o l  tuna  the  from  were  and  regulated  throughout  sample  2 and  be  individuals,  concentration  from  Skipjack  to  Fig.  between  of animals 1.  appeared constant  2  6-phosphate,  turnover  injection  of the  concentrations  of the  2%  o f t h e means  given  3.  2.3.1  LACTATE  TURNOVER.  After  injection  of  14 [U-  C]lactate  exceeded lactate the  5%  of  of  the  activity  three  well.  concentration decreased  was  blood  Fish  and  sharply  more  individuals  in  decay  4 had  the lowest over  rates 2.  These  even were  a  fitted  10 m i n  best  never  6 h.  fitted  The with  Specific  after  lactate  are were  values  low b l o o d  the experiment  animals  after  the observed  rate.  MCR  glucose  ( F i g . I A ) . In a l l  relatively  IA). Blood  and  in  functions  turnover  throughout  Table  curves  the f i r s t  (Fig.  stable  Turnover  activity,  functions No.  gradually  relatively  recovered  exponential  calculated  extremely  then  activity  total  specific  sum  cases  the  lactate activity  injection  and  concentration (Fig.  given  for  selected  IB). seven because  35  TABLE  1.  GROUP OF  TISSUE SKIPJACK  METABOLITE  a r e means  umol/g  wet  weight  blood.  Tuna  were  as  TISSUE  IN  THE  CONTROL  TUNA.  Values  conditions  CONCENTRATIONS  +_ SEM  for  for  muscle  handled  animals  5 animals.  and  used  GLUCOSE  and  kept  i n the  Concentrations liver,  in captivity turnover  GLUCOSE  and  given  umol/ml  under  the  in for  same  experiments.  GLYCOGEN  6-PHOSPHATE  (GLUCOSYL UNITS)  +  0.12  4.16  +  0.97  92.54  +  9.17  0.8 4 +  0.17  1.30  +  0.34  24.22  +  5.20  Liver  3.54  +  0.34  4.06  +  0.87  Blood  3.04  +  0.39  White Red  muscle  muscle  0.68  36 TABLE  2.  TURNOVER Values  BLOOD  RATES are  DA  =  bolus  FISH No.  1  from  (g)  number site  Aorta. VA  of  CONCENTRATIONS  AND  LACTATE  TUNA.  SEM,  Dorsal  injection  WEIGHT  +_  Sampling  1  simultaneously by  IN S K I P J A C K  means  parentheses. Aorta,  METABOLITE  of  also Fish  a n d DA.  blood  samples  given:  No.  VA  =  (N) i n Ventral  6 and 7 were  Turnover  rate  was  sampled  determined  14  [U-  C]lactate.  GLUCOSE  LACTATE  mM  mM  (N)  LACTATE  METABOLIC  TURNOVER  CLEARANCE  RATE (umol  . -1  min  kg" ) 1  RATE (ml  . -1  min  kg" ) 1  1 VA 2 VA 3 VA 4 VA 5 VA  1065 1298 1440 1436 1880  4.3 5 +00 8. 12 4.26 + 0. 2.3 0 +00 7. 6.31 + 01 .4 0. 1.8 5 +03  27.5+1.0 (11) 25.0+0.4 (13) 19.1+0.5 (12) 14.6+0.3 (15) 12.0+0.5 (13)  380. 9 296. 0 299. 8 112. 6 199. 9  13 .9 11.8  6 VA 6 DA  1405  11 4.10 + 0 . 41 .2 + 00. 9  11.6+0.3 (ID 10.2+0.4 (ID  180. 8 131. 8  15.6 12.9  7 VA  1412  1.23+0.02 26.5+0.3 (10) 1.2 2 +002. 27.6+0.5 (11)  415. 2 431. 4  15.7 15.6  7 DA  15.7 7.7 16.7  37  FIG.  1  (fish via  Lactate turnover  No. the  4).  Radioactive  ventral  activity  aorta  decay  r a t e measurement i n s k i p j a c k bolus  catheter.  curve  after  i n j e c t e d and b l o o d A: b l o o d  tuna  sampled  lactate specific  injection  of  25  uCi  14 [U-  C]lactate  at  time  exponential  functions.  the  period.  sampling  0.  Curve  B: b l o o d  fitted  with  t h e sum o f 3  lactate concentration  during  SP. ACTIVITY  (DPM/umol)x10 01  _l  _l  L A C T A T E  o  _j  (mM) JO  o  ro. o  CO  o  CD  \\  o  \\ roo  3  3 9  FIG.  2  Relationship  lactate  concentration  single  ventral  6  7)  and  dorsal (slope  sampled  aorta =  aorta  15.1,  (DA). r  2  =  between in  lactate  skipjack  catheter;  0.85).  line  tuna.  was  from  rate  Circles:  triangles: 2  simultaneously The  turnover  by  animals  animals  ventral  fitted  and  aorta  linear  blood with  (fish  No.  (VA)  and  regression  TURNOVER  RATE -1  (y mol min kg ) 1  N> O O  Ofr  4^ O O  41  the  coefficient  concentration  was  stable  enough  steady  state  rejected). fish  the  than  from  in  correlated  from  A  to  with  seven  linear  blood  lactate  highly  were  individual rate  concentration  was  (Fig. 2),  significantly  1 d f / 7 d f , ANOVA).  affected  regression  in  Turnover  was  had  the use of  (3 e x p t s .  concentrations mM.  lactate  individuals  calculations  27.6  not  mean  to j u s t i f y  (F = 40, P < 0.001,  was  concentration.  our  the relationship  zero  MCR  their  15%. These  lactate  10.2  of  of  concentrations  blood  slope  different  less  kinetics  Mean  positively  variation  lactate  ranged  and  of  by  blood  f o r blood  lactate  lactate  v s . MCR  2 (graph is  not  df/7 kg"  not  shown)  had a s l o p e  significantly different  df,  ANOVA).  Mean  MCR  from  was  (r  zero  14.0  = 0.0134),  ( F = 0, + 0.9  P  which  > 0.05,  (SEM) m l m i n  1 -  1  (N = 9 ) .  1  Simultaneous ventral rates 2,  o f 0.044  aorta  was  determined  Fig.  2),  aorta  sufficient  fish rate.  No. The  A  rate  on  these  glucose  specific  the  As was  which  dorsal  for glucose  used and  were n o t  species, than  for  i s given f o r  an average  were b e s t  be  gills.  lower curve  (Table  aorta  curves  by t h e  much  exhibited  Turnover  could  i n mammalian  a c t i v i t y decay  and the  were s i m i l a r  two s i t e s  utilization  aorta  6 a n d 7.  a c t i v i t y decay  TURNOVER.  for  No.  sites  between  lactate  curves  the dorsal  fish  sampling  specific  ( F i g . 3A), decay  from  that  GLUCOSE  typical 9  both  Differences  to quantify  turnover  lactate.  from  lactate  2.3.2 the  performed  indicating  interchangeably. ventral  sampling  fitted  turnover with  the  42  sum  of  two e x p o n e n t i a l  glucose of  are  glucose  and  given  f u n c t i o n s . Turnover  i n Table  concentration  averaged  15.3  3. T u r n o v e r  ( F = 1, P  +  1.2  rate  r a t e was  > 0.25,  (SEM)  a n d MCR f o r independent  1 d f / 5 d f , ANOVA)  umol  min""'*"  kg '*"  as  -  3 determined (SEM)  with  ml  min"  high  blood  not  elevated.  average  [6- HJglucose k g  1  glucose  -  (N  1  =  =  5).  5). Fish  No.  MCR  two  glucose  was  4.7  +  1.0  10 a n d 12 s h o w e d  concentration, but their  Consequently,  f o r these  (N  turnover  MCR  was  rate  lower  a  was than  fish.  3 [6tracer ^0.  H]glucose  because The  reincorporation because  large  of  amount  slows an  down  underestimation study,  turnover .  much  higher  than  that  glucose  with  No.  water  11 a n d 1 2 ,  tritiated  e q u i l i b r a t i o n occurs 14 C]glucose is a  within the  into  rate  activity  CJglucose  metabolic  This  recycling  curve,  of glucose with  reversible  other  to glucose.  rate determined 1 4  recycling  is  glucose i s  the true  [U-  irreversible  into  of the s p e c i f i c  of  carbon  ° *  an  product  labeled  r e c y c l e d back  the decay  16% f o r f i s h  2  end  incorporated  this  and  H  C  c a n be  of  rapid  body 14  because  intermediates  considered  i t s predominant  insignificant  tracer  is  causing  turnover.  3  [6- H]glucose  (Table  is relatively respectively).  3),  high  In was  indicating  i n tuna  (28  43  3.  TABLE RATE  BLOOD  IN S K I P J A C K  Values  are  GLUCOSE  _+  parentheses.  Turnover  injection  [6-  and  12  were  radioactive  FISH  WEIGHT  SEM.  Number  rates  H]glucose  bolus  catheters.  No.  3  injected  aorta  AND  GLUCOSE  TURNOVER  TUNA.  means  of  CONCENTRATION  and  were  or  with  [U-  both  blood  LABEL  of  14  samples  determined C]glucose.  (N) i n  by  bolus  Fish  sampling  mM  were  done  of the  v i a ventral  GLUCOSE  METABOLIC  TURNOVER  CLEARANCE  RATE (umol m i n kg  - 1  )  RATE  -1  (ml  min kg  8  1680  3  H  2.52  + 0.08  (11)  14.8  5.9  9  1497  3  H  2.83  + 0.09  (13)  15.2  5.4  10  1320  3  H  6.77  + 0.17  (13)  11.0  1.6  11  1671  3  H  2.46  + 0.03  (11)  17.3  7.0  12.5  5.1  18. 1  3.5  15.2  2.9  11  12 12  1 4  15 97  3  c  5.19  H  1 4  c  + 0.10  (13)  11  No.  isotopes. Injection  GLUCOSE  (g)  blood  1  -1  )  44  FIG. (fish A:  3  Glucose No.  9).  blood  turnover  Injection  glucose  r a t e measurement and  specific  blood  in skipjack  sampling  activity  same  decay  as  tuna  F i g . 1.  curve  after  0.  curve  3 injection was blood  of  fitted glucose  28.2 with  uCi the  [6- H ] g l u c o s e sum  of  two  concentration during  at  time  exponential  the sampling  The  f u n c t i o n s . B: period.  SP. ACTIVITY  (DPM/umol)xl0  01  o o  o  o  GLUCOSE ro -i  o  6-  ro -j o  3  co 1  (mM) A I  ui I  46  2.4  DISCUSSION  The skipjack These al  tuna  values  (1981)  i  min  1  )  kg  1  Because  )  lactate  Kormanik, transported Racker,  1978;  1976),  The by  without  food.  white  to  the  glycogen  teleosts,  but  There  no  the  is  present  levels  "resting"  only  was in  fish  doubt  other  values  was  500  umol  and i t is  (Dubinsky  and  Spencer  be  - 1  in rats.  used  and  as  an  were n o t o v e r l y  short-term  exhausted  captivity  because  their  b e i n g d e p l e t e d . Red  muscle  30%  lower  90% the  than  two  i n the  Guppy e t a J L  higher.  group (1979);  Glucose  and  types  were  muscle  o f Guppy e t a_l_. S u r p r i s i n g l y , were  low  compared  are a v a i l a b l e  t h a t the e x p e r i m e n t a l  measurements  min  because  can  study  r e p o r t e d by  concentrations no  this  were f a r from  concentration  similar  rate  .  are  (Cameron  1975;  - 1  i_n v i vo.  not  tuna  fish  Roos,  kg  - 1  umol  also  membranes  1981;  were  skipjack  6-phosphate  in  for  O k a j i m a e_t  (up t o  Wood, 1980), and  in  was  min  (200  (1983),  t r a n s p o r t a t i o n , and  concentration  muscle  rest  turnover  used  here  - 1 - 1 kg ) and  min  of e x e r c i s e  cell  a_l,  They  glucose  liver  at  l a c t a t e metabolism  stores  "resting"  and  umol  umol  excreted  lactate  capture,  carbohydrate  of  et  431  Brooks  across  animals  stressed  glycogen  Kobayashi  Koch  of plasma  and not  rapidly  Lehninger, index  is  1982;  (70  levels  Donovan  reported  r a t e s r e p o r t e d by  obtained  different  by  to  the  rats  values  rates  112  than  resting  at 1  from  are h i g h e r  to  and  turnover  range  for  comparable kg  lactate  very  with  f o r tuna  situation  artificial  other liver.  used  for  because  the  47  animals fish  were  restrained  treated  glucose  with  and  (Wells  reduction  in  (Mazeaud  MS-222  lactate  individuals  e_t  carbohydrate  levels  1977) ,  this  type  of  have  been  unsuccessful. (i.e.  metabolism used  in  in  fish  i t  used  experiments was  out  of  on  a  for this  the  1985)  when  present  12  carry  of out  tuna  experimental  fish  artificially to  the  investigate  number  without  experiments  of  tuna  counting  the  and  unsuccessful  plasma  metabolite  concentration  Also,  access  live  Facility where  to  free-swimming  Therefore,  a  catecholamines  difficult  i s extremely  world  untreated  possible depression  the  to  blood  a n e s t h e t i c causes  a l l attempts  limited  state).  live  to  restricted  in  the  fish  possess  bolus  injection  measurement  group  a  under  preliminary  with  in  and  Honolulu  tuna  are  for  costly.  is  kept  tuna  the  in  In  only  captivity  basis.  Because (Vogel,  same  However,  changes  compared  unanesthetized  Even  was  Research  regular  now,  species.  purposes  i n the  any  circulating  technically  steady  Kewalo  laboratory  Until on  ( f o r example  experimental fact,  is  study for  show  . The of  anesthetized.  semi-anaesthetized  this  this  not  suggesting  experiment  ventilated),  do  e_t a _ l , 1984)  metabolism.  conditions  lightly  concentrations  the a^L,  and  of  circulation  animals.  does  injection  in  the  flow  rate  may  be  of  tuna  not  However, seem  blood  extremely  low.  to  The  may  metabolite the  presence  invalidate  recent  through  secondary  technique  plasma  because  of  a  the  half-time  be  inadequate  turnover of  the  the  measurements secondary  circulation  use  rate  secondary of  bolus  indicate  vascular  for mixing  in  that  system  between  the  48  primary  and  and  1.7  the  case  secondary  hours of as  primary  system  a  a  turnover  valid  secondary this  rates  circulation assumption  be  has  into  considered allowing  in tuna  to  In  not  been to  as  to  tuna  detail.  Then such  the  using is  i t  very  metabolite  was and  slow,  the  turnover  factors  comparisons  values. and  high  the  primary  also  be  lactate  study,  critical  mass,  organ  In  experimentally.  that  mammalian  into  measure  was  verified  can  technique  present  i f meaningful  with  any  between  several  account  support  the  realize  on  lactate  injection  blood  e x e r c i s e , body some  role  1.2  comm.).  system  of  approach  skipjack  depend  of  same  between  pers.  secondary  of  particularly  effects  of  important  taken  made,  the  is  generally  should-  mixing  Randall  bolus  trout.  estimated  output)  experimental  the  It  the  The  i n rainbow  that  (D.  (or  i t plays  was  the  input  lactate.  rate  assumed  be  and  trout  trout,  single  producing  therefore  but  i n rainbow rainbow  treated  or  circulations  To  turnover  are  begin  temperature possible  that to  with,  will  be  mechanisms  rates  will  be  shown  to  be  discussed. Lactate positively  turnover  correlated  with  resting  rats  (Okajima  infused  with  different  al,  1974).  This  concentration turnover value  per  rate. is  concentration  is  a  se  et  not is  (both,  a_l,  an not  which  been  lactate  1981)  concentration  and  in  resting  concentrations  used  in  the  activity  is  numerator  and  dogs  lactate  calculation  i s used,  independent  in  ( E l d r i d g e e_t  a u t o c o r r e l a t i o n because  specific  the  has  blood  lactate  Instead, ratio  rate  of  denominator  and  of  this  lactate of  this  49  ratio is  depend  on l a c t a t e  possible  and  to  turnover  negative  rate  (see  of  a  concentration  because  both  increase  as  such Also,  a  ,  in  range  goes  present  correlation  mM.  Measurements  of  not  shown)  before  was  different  steady  Unfortunately, the  with  lactate  positive  indicate of  between  for  rate  the  and  individuals.  correlation  different  exercise.  between  perfusion  Therefore,  the  blood  30  (results  indicate  n o t made  studying  output was  that  showing  throughout may  work  between  have  not c o r r e l a t e d  exercising  and  constancy  than  by  concentrations.  cardiac  rates  covered  individuals  MCR  time  species.  pressure  lactate  MCR  lactate  larger  injections  were  that  i s the f i r s t  to values  However,  c o n c e n t r a t i o n . When  show  a nonmammalian  between  measurements  1983;  i s twofold  data  with  and blood  blood  exercise  concentration  concentrations  bolus  similar  experiments,  lactate  and t h i s  i s extended  state  these  turnover  differed  a  probably  of exercise  correlated  lactate  heart  glucose  and Brooks,  up. The p r e s e n t  made  be  f o r an  plasma  increases with  blood  ( F i g . 2), i s  e t a _ l , 1986,  Donovan  tuna  of plasma  made  also  i s also  the  perfusion  and  can  a  rate) .  rate  demonstration the  rate  i n which  variables  between  but the e f f e c t  rate  turnover  concentration  turnover  perfusion work  two  correlation  concentration  or cases  Jenkins  a _ l , 1984;  e_t  a _ l , 1976)  these  example  turnover  (Brooks ejt  lactate  for  e x p l a i n s why i t  metabolite  correlated,  between  and glucose  Issekutz  i n which  not  negative  Lactate intensity  cases  are  correlation  demonstrated example  find  concentration). This  animals  rate  would  different  levels  of  MCR  over  the  50  observed the  range  of  lactate  r e l a t i o n s h i p shown  effect  of  rate.  lactate  The  and  investigated  2 probably  on  suggests  represents  independent  contributions  rate  also  of  turnover  the  of  lactate  that true  perfusion  concentration  increase  should  be  separately.  The lactate  in Fig.  concentration  respective  perfusion  concentrations  relationship  turnover  few  mammalian  the  turnover  (R ,  in  species  in  t  rates  of  between umol Fig.  body  min 4.  resting  A  - 1  mass  )  is  linear  mammals  and  whole-body  presented regression  (circles)  a  for  across  has  been  2 drawn  (slope  better  =  0.64,  because  conditions" knowing  i t  for  a  that by  measurements  are  of  on  dog,  and  is  man  =  0.85).  difficult  wide  range  lactate  influenced  exercise  r  not  to  of  (triangles  rate in  shapes  and  for  many  is also Fig.  lactate The  illustrated  4).  The  sizes,  rates  species.  not  "resting and  removal  Furthermore,  available  turnover  correlation is  standardize  body  production,  activity.  The  range  R effect  for of  are  rat, values  0 obtained These  for  values  considering  the  skipjack fall  well  e f f e c t of  tuna  in  within  25  C  water  mammalian  temperature.  is  rates  also even  plotted. without  51  FIG.  4  Relationship  turnover tuna. The  (R ) fc  Mammals line  for  was  on  log-log  at  rest  fitted  mammals  between  body plot  (circles)  by l i n e a r  only.  mass  and whole-body  for  mammals  and e x e r c i s i n g  regression  Turnover  and  rates  lactate skipjack  (triangles).  using  resting  were  measured  values with  14 [  C]lactate  Brooks, 1981)/ et  1983;  a l l cases.  Freminet  and  References: Leclerc,  g u i n e a p i g (Freminet and L e c l e r c ,  a l , 1974;  Chandrasena, al,  in  1984).  Issekutz  1 9 7 7 ) / man  et  al^, 1976)/  rat  1980; 1980)/ sheep  (Brooks and Donovan,  (Donovan Okajima dog  and  e_t a l ,  (Eldridge  (Reilly  and  1 9 8 3 ; S t a n l e y e_t  BODY  MASS  53  Ocean-caught  skipjack  tuna  can  have  a  core  such  a  high  0 temperature  10 C  difference Captive  i s  higher  only  animals  than  observed  subjected  ambient, after  to  but  feeding  violent  frenzies  exercise  a ts e a .  d o n o t show  0 more  than  Neill, of  a  1978).  the  more  fish  than  0 at tu r n3o7v eC r.  5 C  excess  It  i s very  used  2  or  rates  W  It lactate  is  tuna  more  h  than  However,  3  h  lactate  the  observations  i s metabolized  et  even kg  can  faster  tuna  concentration diffusion  a  tuna  than can  between  the  load  over  blood  in  k g  1  at  a  -  1  ,  an  lactate take  mmoles.  be a c h i e v e d  i n less  Also,  mM  a  one drop  i n less  but that  a  of the i n blood  than  2 h.  passes v i a significant  muscle.  lactate  a t t h e same  rate  P e r f u s i o n i s lower  in a  of similar  higher  a high  o f 90  of approximately  i n a mammal  with  not a l l lactate  a 3 7 ^ C mammal?  be  12  i n white  turn  output  to  recovery  directly  double  e_t a l _ , 1 9 7 9 ) w o u l d  showed  to  that  during  than  [cardiac  a l ,1978)]  32  suggest  muscle  1964).  study  even -  by  the lactate  min " '  i t s lactate  Connor,  this  that,  white  appears  from  compartment  How  2  in  concentration  portion  or  and  temperature  approximately  umol  (Guppy  recovery  animals  blood  of  umol/g  (Barrett  cannulated  kg  400  to metabolize  complete  2  to notice  and  temperature  o f 2 i s assumed,  of  1  90  water  a t 25 C s h o u l d  rate  (Stevens  t h e body  0  interesting  of  that  exceeded  If a  0  with  tremperature  unlikely study  measured  concentration  These  3 C.  turnover  exhausted  than  i n this  core  90 m l / m i n  size.  tuna,  Blood  allowing  and l a c t a t e - u t i l i z i n g  (Brill lactate faster  tissues.  54  However,  this  diffusional  advantage  cannot  fully  compensate  0 for  the  effect  Therefore, cycle  tuna  lactate  potential (Guppy  et  this  the  and  a  steep  Weber,  B.  fluctuations  red  in  blood  may  high as  lactate  them  muscle  diffusion the  by  blood  i n v o l v e s use  of  exchanger  Hochachka, S.  to  aerobic  red  between  heat  and  their  blood  to  muscle  R.W.  Perry,  Even  kelp  bass  glucose  though  Brill,  T.W.  Moon,  each  is  tuna  set  not  fish  The  clear  (Tables  and  (King  to  ranged  mammalian and  may  Kahn, glucose  steady  from  1.2  significance but  wide  achieve a  2  and  show  Tuna  maintained  points  glucose  e_t a l _ , 1977)  data)  properties  these  the  teleosts  (Bever  levels.  individuals.  differences  other  unpublished  allow  different  blood to  of  represent  6.8  these various  states.  Glucose  Paralabrax  (P.W.  than  similar  mM  fish  such  possibility  regulate  tightly  (Weber,  concentration,  other  very  gradient  Daxboeck,  Cannulated  glucose  nutritional  fast  allowing  lactate-producing white  muscle  to  demonstrate  observed  allow  second  C.  much m o r e  which  in  tissues,  between  appear  trout  homeostasis.  The  countercurrent  Emmett,  F i g . 3).  1981),  do.  temperature.  observations).  concentration  insulins  adaptations  they  could  sink". A  movements  rainbow  other  concentration  lactate-oxidizing  3,  d i f f e r e n c e i n body  as  vascular  Tuna  and  fast  "lactate  unpublished  C  have  1979),  central  J.-M.  10  lactate-utilizing  al,  accelerate  a  must as  of  maintaining and  of  turnover  s p e c i e s . Bever sp.,  has  a  r a t e has e_t a_l  rate  only  (1977)  of  been  showed  about  measured that  2 umol  min  in  kelp - 1  kg  two  bass, - 1  .  A  55  FIG.  5  Relationship  glucose  turnover  skipjack was  tuna.  fitted  rate  between (R )  on l o g - l o g  fc  Same s y m b o l s  for resting  body  mass  and whole-body  plot  f o r mammals a n d  a s i n F i g . 4. A  mammals  only.  linear  The t u r n o v e r  regression rates  were  3 determined  with  [ H]glucose  in  a l l cases  except  for  the  14 horse  (  Freminet al,  C).  References:  and  Leclerc,  1980)/  (Katz-  et  guinea  e_t al,  1980;  pig  a l , 1974)/  (Armstrong  rat  Katz  (Freminet  cat  1979)/  (Brooks  dog  (Trayhurn  et  1975),  man  (Hall  a l , 1979)/  horse  (Evans,  1971).  and L e c l e r c , et  (Issekutz,  pig  Donovan,  1983;  e t a l , 1974; K e t t l e h u t e t  (Kettlehut  1976)/  et  and  a_l, 1981)/  1980)/  rabbit  a l ,1980)/  monkey  1977; I s s e k u t z e t a l , sheep  pony  (Brockman  (Anwer  et a l ,  et a l , 1976)/  BODY  MASS  (9)  57  similar  value  (Lin  et  than  tuna  (Katz  et  was  a_l,  1978)  are  a l ,  found . The  sizes.  Oncorhynchus  1/30  in fish  those  found  kisutch  species  in  other  resting  rats  1974). the  values  The  glucose  salmon,  r a t e s measured  approximately  Although mammalian  f o r coho  data  are  at  i s very  available  relationship  turnover  base  for  between  rest  restricted  a  wide  body  (R ,  range  mass  i n umol  fc  and  min  for  - 1  )  fish,  of  body  whole-body  is  presented 2  in  Fig.  0.99,  5  on  linear  mass  can  be  double  logarithmic scale  regression).  significantly body  a  different  vs.  drawn  for  the  rate  (in  umol  =  0.94).  turnover  Interestingly,  from  metabolic  (slope  the  rate  this  found  mass  vs  kg  - 1  ^;  0.72,  slope  is  = not  classic  same  analogy  mass-specific  glucose  graph  for  r  the  relationship.  body min  slope  =  The  not  shown;  slope  2 =  -0.27,  r  suggest  that  resting  glucose  good  i t i s of  reasons from  animal  athlete).  glucose line.  R  R  t  importance  to  mammals  unless  predict  that  the  species  under  this  line  (extremely  When  corrected  for of  i n F i g . 5)  tuna  falls  exercise i s much  on  less  obtained  directly  in  effect  (triangles  minimal  correlations  rate  found  The  close  turnover  to  depart  The  measure  there study  s l u g g i s h organism  or  for  the  temperature  e x a c t l y on glucose pronounced  the  R  will elite mean  mammalian  in  than  are  mammals  on  lactate  ( F i g . 4) . Under  little  labeled  indicating lactate  that  the  present  lactate the  metabolism  was  role is  not  experimental converted  played  by  important.  conditions  to  the It  blood  Cori  glucose,  cycle  i s not  very  in  clear  tuna why  58  glucose  recycling  glucose  may  have In  can  as  turned  those  probably lactate  as  a  and  high  and  rates are  turnover  metabolize  lactate  of  lactate  plasma  with  study  for  consequence  they  nor  glucose  faster  turnover  mammals,  this  reported  much  high  what  other  compounds.  exchanging.  lactate  over  These  been  so  conclusion,  support  high  was  mammalian tuna  of  their  are  at high in  high  rates.  tuna  as  species. Glucose  is  i n other metabolic values  lactate  indicate  that  to  rate.  Tuna  measured  these  be  teleosts,  in  concentration.  Furthermore,  appears  at  tuna  least  than  with  skipjack  rates  than  higher  correlated  that  turnover  in  rates  shows  animals  the  major  can fate  oxidation like  in  14 mammalian this  species  study,  oxidation and  no  main  because  after  may  rates  the  the  (comparable  humans,  when  such  turnover and  swimming.  These  for  the  suggesting is  high  that  pathway  rates part  in for  of  situ.  reported  fish  may  lactate  Cori  in  probably  for  in  at  high  dogs,  and  body  able  to  and size  achieve  particular  high-performance  produced  clearance  rats,  cannot  cycle  Therefore,  lactate  evolved  clearance  lactate  The  be  they  however,  lactate  the  for  temperature  adaptations  of  is  C-lactate).  because  values,  collected  lactate  o x i d i z e plasma  rates  rates  not  blood decreased rapidly, 14 C c o u l d be m e a s u r e d i n 14  of  These  enzymatic  reported  metabolized  important  applied).  of of  appropriate  are  anatomic  the  to  was  plasma  activity  ability  the  CC^  of  injection  to  correction high  fate  accumulation  bolus  have  though  total  important  tissues tuna  (even  fully  during  recovery,  i n white  i s probably tuna.  account  muscle not  an  59  CHAPTER  3:  ONSET  3.1  OF  SUBMAXIMAL  IN THOROUGHBRED  HORSES.  is  first  dealing  INTRODUCTION  This exercise  chapter  metabolism  characterizes responses  determine statefor  when  because the  plasma  concentration.  selected and later  was  state general  higher  effect  on  selection  lactate exercise  changes lactate  the  turnover  in  rate  of  to  5  steady lactate  the e x e r c i s e p r o t o c o l s the  experiments  rate  can only  using  injection  performed  be  be  measured injection i n steady  As e x p l a i n e d  i n t h e same  i n the  two c h a p t e r s  (Chapter  in  (submaximal)  the bolus  1), the next  rate  of  steady  requires  t o determine  output  a  i n Chapter  behavior  intensities).  cardiac  turnover  used  c o n c e n t r a t i o n cannot  (Chapter  necessary  o f low i n t e n s i t y  c o n d i t i o n s when  introduction  investigate  turnover  t o be a b l e  because  (plasma  at  technique  of the k i n e t i c s  The  made  f o c u s s i n g on t h e e f f e c t  be known d u r i n g  study  steady-state  technique  of lactate  to  times  chapters.  exercise under  had  metabolic  c o n c e n t r a t i o n reaches  injection  with  horses. It  and  c o n c e n t r a t i o n . I t was  Therefore,  for this  sampling  cardiovascular  lactate  the bolus  of three  of thoroughbred  exercise,  lactate  measurement  concentration  basic  treadmill  on p l a s m a  the  and p h y s i o l o g y  their  to  exercise  5) .  EXERCISE  4) a n d  animals  will their  (Chapter  60  A  transient  concentration  has  initiation  of  Stensvold,  1972;  maximum  by  little  commonly  submaximal  a  decrease  the  for  et  has  consequence  metabolism to  back  (Saiki  after  a  new  changes.  of  a  delay  the  relatively  In  addition  after  the  Hermansen  and  et  a l , 1967).  minutes state.  of  A  work,  Remarkably  devoted  to  the  mechanisms  They  usually  interpreted  are  activation  which,  slow  few  steady  i n the  e_t a _ l , 1967)  1936;  Saiki a  lactate  i n humans  (Bang,  a l , 1966;  to  plasma  observed  been  these  in  exercise  Rowell  attention  responsible  due  been  c o n c e n t r a t i o n i s reached  followed  as  increase  onset  in turn, of  the  of is  oxidative presumably  oxygen  transport  system.  adjustments the  to  ability  releasing At  the  system and  to  they  show  (Pan  et  of  heart  a_l,  lactate  the  the  lactate  oxygen  measured  aim  response  performer, a  Pan  et  rate  be  of to  these  this  study  submaximal  transport  simultaneously  state  was  the  was  plasma  not  in  to  rate  transport  occur  and  in  man  horses. characterize in  an  establish  As  major  lactate  (Fregin  overshoot  to  and  1983).  a l , 1984)  lactate  exercise  reached.  heart  et  have  actively  i n humans  does  absent  by  oxygen  Forster  racehorse,  system, with  than  which  or  horses  (Persson,  their  reasons,  reduced  mammals,  spleen  rapidly  a l _ , 1984;  physiological  hematocrit  exercise,  thoroughbred steady  other  their  overshoot  For  i n h u m a n s may  by  from  much m o r e  1984).  ordinary  increase their  submaximal  1983; a  the  shown  cells  activated  The  when  greatly blood  onset  Thomas,  observed  exercise  red  is  to  the  elite i f  and  indices  hematocrit  of  were  c o n c e n t r a t i o n to  61  determine  whether  coincide for  the  The  and  the  to  observed  effect  of has  get  been  lactate  concentration 1972).  from  the  the  glycogenolytic  locomotory established the  lactate  plasma  A  in  this  steady  measurements  to  model  Finally,  pathway  state reflect  in  was  in the  whether  lactate  and  explain  the  fluxes  intermediates  steady  to  state  (Hermansen  lactate  in  biopsies  plasma  muscle  a  steady  to  metabolic measured  investigated  the  of  causes  concentration.  work  terms  responses  possible  also  presented  Muscle in  the  lactate  during  were  assess  tissue.  into  influence  is  'changes  to  cardiovascular  intensity  obtained  plasma.  muscles  changes  shown  concentration  and  and  insights  of  exercise  i t  measured  some  pattern  because  Stensvold,  metabolic  one  to of  of  the  main  state  was  also  were  taken  determine behavior.  during whether  62  3.2  MATERIALS  AND  METHODS  3.2.1 All  EXPERIMENTAL  experiments  exercise Three  were  unit  of  a  field  week  work  or  horses  of  gallop,  and  approximately  this  twice  experimental  set-up.  A  for  values  and  resting  biopsies,o  one month  exercise.  A l l  on  of dry food  a diet  Their  weights  and  just  and above  Vygon tightly added, every  10-15  them  ( I N ) was  only  they  to  were  a  small  area  A  stab  into  2  14  g  the  ml  the min  incision with  vein. to  a  was 17  The  g  of skin  100-cm  t h e neck  extension t o keep  them  line  made X  and  an  of and  patent.  was  the animal.  catheter  needle)  sutured  line  filled  injected 1:200,000  I.V.  8 i n . inner  extension  was  introduction  lignocaine;  c a t h e t e r was  c a p a c i t y ) which  around  of catheter  2%  water.  4.  ml  X  muscle  to  0.5  (3  used  maintained  L o c a l a n a e s t h e t i c was  jugular  the  treadmill  unlimited access  i n Table  with  post-canter  introduced and  i n the  treadmill  vein.  taped but  geldings  are given  with  the  connected  PVC,  and  UK.  an o c c a s i o n a l  at the s i t e  (Becton-Dickinson  and  thoroughbred  been  at the  exercised 6  disinfected  epinephrine).  skin  with  to familiarize  pre-  1985  training  supplemented  catheterization,  subcutaneously  introduced  regular  was  and hay w i t h  ages  of  were  trotting  having  were  JW)  and  for  after  CATHETERIZATION.  T r u s t , Newmarket,  and  Their  a week  fourth  horses  Before shaved  ( K J , SB,  walking  AND  i n t h e summer Health  f o r three months.  consisted  canter  out  the^ Animal  thoroughbred  days  carried  ANIMALS  with No  was  t o the  (Lectroflex saline  and  heparin  was  t h e c a t h e t e r were  flushed  63  3.2.2  EXERCISE  catheterization, heart  rate monitor  ECG  leads.  He  Industrial,  to  an  never  triggered of  experienced  3  pm,  at  walked  i n the  to  outdoor  a  After  safety  the  harness  experiments).  A  and  (Sato, was  mechanism  simulate  harness,  rate meter),  treadmill  switch-off  to  secured  (which  fan  normal  BIAB  was  air  was  placed cooling  locomotion.  experiments 3 h  the where  present  during  with  (EQB-HR7 h e a r t  emergency  animal  least  fitted  Sweden)  the  All  was  electrodes  Ludvika,  him  front  horse  was  above  in  the  PROTOCOLS.  were  after  the  carried  morning  out  feed.  between  10  am  Temperature  and  ranged  0 from  16  to  Different each  horse  min, the  and  relative  before  of  gaits, min,  which  and  for  with  walk  at  1.6  m/s)  followed  a m/s by  3-4  short  a  two  m/s  the  m/s  than  incline  were  50%  of  period  tried  trot  (4  a  m/s)  regimes  for  maximal  exercise  and  for  10-15  speed  bouts  4-min for  and  sustainable  c o n s i s t i n g of  protocol  73%.  trotting  incline  their  A l l  to  exercise  both  6%  53  h o r i z o n t a l canter  warm-up  4-min  at at  incline.  trot  from  submaximal  trot  6.5  less  this  for  and  performances  (ii) a  represents  treadmill  initiated  (i) A  humidity  speed  selecting  comfortable  cantering 40  C  combinations  eliciting  for  20  a  on  were 4-min  walk  (1.6  the  canter  Blood  samples  protoco1.  3.2.3 were ml and  collected  BLOOD AND in  ice-cold  TISSUE 7-ml  ethylenediaminetetraacetic placed  on  i c e . They  were  SAMPLING.  vacutainers  acid  (EDTA)  carefully  containing as  mixed  0.07  anticoagulant before  filling  64  hematocrit  tubes  sedimentation on  to  of  avoid  horse  a microcentrifuge,  problems  red c e l l s .  the r e s t  caused  After  by  the  measuring  of the sample  was  fast  hematocrit  spun  and  the  0 plasma  was  analysis, min  of  separated. and  the  resting  horse  was  brought  blood  was  drawn  and  every  5 min  s).  During  with  between  was  C before  completed  the 4 horses  taking  the  allowed  to  applied  while  time  perform  to a l l  immediately samples  bout.  from  and  further  within  10  sampling  the  The  in  were  frozen  two  The  tissue  every  always  muscle  the canter  5  min  flushed  than  mg  (Snow,  N » 1.5  the  of tissue The  The  2  1983).  specimens  assays.  min  were  the  Before  animal  was  Suction  was  were  pooled  necessary  biopsies  post-canter  after  taken  p r o t o c o l by  f o r 15 m i n .  muscle  200-300  liquid  less  gluteal  procedures  metabolite  frozen  protocol,  i n about  taken  was  the  of exercise  drawn  were  line  in a stall  the  10 m i n  (pre-canter),  and  before  the t r o t  was  samples  after  biopsy  obtain  sample  taken  samples.  described  quietly  was  During  the middle  before  resting stand  (each  successive  previously  (7 m l )  f o r the f i r s t  protocol,  exercise  Biopsies  of  min  thereafter  the canter  saline  sample  the t r e a d m i l l .  every  the  each  a t -20  procedure  blood  on  throughout  use  entire  placed  sampling. A  from  I t was  to  were muscle  the^ c e s s a t i o n o f  exercise.  with  mortar  immediately acid  and  and mixed  samples pestle.  with  homogenized  The  6-7 for  were  fine  parts 2  X  later  15  of  ground  powder  obtained  ice-cold sec  on  in liquid  an  8%  N,, was  perchloric  Ultra-Turrax  65  homogenizer the  (Ika-Werk,  suspension  West  were  determinations.  The  Germany).  frozen  rest  i n  was  Two 1 0 0 - u l  liquid  spun  aliquots of  f o r glycogen  a t 11,000  g f o r 3 min a t  0 4 C  i n  liquid  N  Eppendorf until  2  tubes  METABOLITE  intermediates  were  spectrophotometer NADP)  using  or  the  modified Lactate days  assayed (SP6-500)  procedures  concentration sampling.  determined  with  1974)  corrected  with  and rabbit  Glucose,  (total  NADH  Muscle  glycogen  standards  glucose-6-phosphate,  fructose-1,6-bisphosphate,  lactate  were  also  volume  (1974)  as  0.5-0.7 m l ) . within  three was  technique  (Bergmeyer,  hydrolysis  as measured  (efficiency  = 30.0%).  fructose-6-phosphate, glyceraldehyde-3-phosphate, 3-phosphoglycerate,  phosphoenolpyruvate,  measured  a t 3 4 0 nm,  concentration  dihydroxyacetone-phosphate, 2-phosphoglycerate,  Pye-Unicam  ( o r NADPH)  i n plasma  f o r incomplete glycogen  a  t h e r e d u c t i o n o f NAD  cuvette  the amyloglucosidase  muscle  on  i n Bergmeyer  measured  kept i n  A l l the metabolic  by measuring of  were  performed.  ASSAYS.  described  was  were  i n duplicate  the oxidation  f o r micro-assays  of  the supernatants  the metabolite assays  3.2.4  (or  and  i nthe muscle  pyruvate,  samples.  and  66  3.3  RESULTS.  Resting heart  rate  study  values  and  hematocrit  are presented  i n Table  3.3.1 trot  JW,  TROT  experiments  running  at  4  the older  without  this  are  m/s, horse,  experiencing  relatively  hard  lower  for  plasma  4 with  but a lower could  and  Results in  speed  Fig.  pain  from  was  not  t h e 40-min  a consequence  were  chosen f o r  over  40 m i n  by pounding  of the t r e a d m i l l b e l t .  was  i n this  6. K J a n d SB  4 m/s  caused  used  ages.  o f 3 m/s  not sustain  articular  velocity  weights  PROTOCOL.  surface  concentration,  of the thoroughbreds  summarized  who  lactate  on t h e  The c h o i c e  of  of h i s state of  training. Mean the  end  increased  the  to  to  accumulate  started, t o 2 mM  those  slowly  was  0 on F i g .  after  (KJ and  concentration  2 min o f  after  running,  6 t o 7 m i n , and  15 m i n t h e r e a f t e r .  i n plasma  and reached  during  2-3 mM  At  6), this  elevated  lactate  at rest  0.45 mM.  Lactate  the last  15-20  a t t h e end o f the  trot. Resting  preliminary  was  o f 1.5  bout  (= t i m e  (KJ) o r s l i g h t l y  was  above  walk  and low f o r a b o u t  of the exercise  40-min  that  trot  levels  constant  started  unchanged  t o a maximum  declined  min  was  When  stayed  lactate concentration  o f t h e 4 m i n warm-up  concentration SB).  resting  rate seen  walk (KJ  after  heart was and  rate  sufficient  averaged to double  35.5  beats/min.  (JW) o r e v e n  S B ) . A n a d d i t i o n a l 40 b e a t s / m i n  the f i r s t  2 min of t r o t  before  heart  The  triple  increase  rate  67  TABLE  4.  WEIGHT,  CONCENTRATION, THOROUGHBRED  HORSE  A G E , AND  HEART  RATE  RESTING AND  V A L U E S FOR  HEMATOCRIT  IN  PLASMA  LACTATE  FOUR  TRAINED  HORSES.  WEIGHT  AGE  LACTATE  HEART  RATE  kg  y  mM  KJ  453  4  0.5  41  37  SB  426  5  0.4  44  41  JW  466  13  0.4  32  43  IN  428  3  0.5  25  33  beats/min  HEMATOCRIT %  68  FIG.  6  Plasma  hematocrit trot  at  m/s).  all  6%  Time  from 4  of  a  m/s  3  lactate trained  incline 0  when  3 m/s  graphs,  the  treadmill  represent resting  values.  r a t e , and  speed  ( K J a n d SB: 4 m/s; JW: 3 started  t o be i n c r e a s e d  a t 1.6 m/s. T r a n s i t i o n  f o r JW) was c o m p l e t e d time  heart  t h o r o u g h b r e d h o r s e s d u r i n g a 40-min  on a t r e a d m i l l  4 m i n warm-up w a l k (or  concentration,  scale  from  1.6 t o  i n 20 s . N o t e t h a t  changes a f t e r  10 m i n .  on  Triangles  HCT  %  HR  beats/min  69  LACTATE  mM  70  decreased  to  beats/min  (KJ  15  min.  slowly  a  stable and  During  SB) w h i c h  the  increased  value  last  without  o f 120 b e a t s / m i n was  (JW) a n d 140  sustained f o r approximately  15-20 m i n o f t h e t r o t , reaching  t h e maximum  heart  obtained  rate after  2 min. Mean warm-up 57.7%  walk was  steadily end  increased reached  the  significance  of  6.5  sustain  that  slightly values in  first  observed  for  reached The  concentration 6-7  the  warm-up  about  trot.  necessary was  greater  period  slow  (bottom  Hematocrit  rate  graphs  and  of  until  the  on F i g . 6 ) .  their  statistical  5.  A l l horses (JW) c o u l d  than  10  were  not comfortably  min. Plasma  hematocrit  running  during  lactate  the canter  1  mM)  walk  compared  and t r o t .  o f c a n t e r was  Maximum were to  with  The p a t t e r n  similar  concentrations higher  reach  a  i n the canter  than new  resting  t o what were  i n the trot steady  protocol  seen was also (2-3  lactate  (8-10 min vs  protocol).  rate and  The  F i g . 7. L a c t a t e c o n c e n t r a t i o n was  minutes  min i n the t r o t Heart  horse  and  a t 3-4 m i n b u t t h e y time  bout  the preliminary few  trotting.  at a very  more  i n  (to  of  PROTOCOL.  rate  shown  elevated after  min  i n Table  older  for  heart  are  the  mM).  the  speed  concentration, experiments  CANTER  but  3  animals.  t o 5 2 . 0 % a n d a maximum  decrements  are presented  m/s  value  exercise these  3.3.2 at  this  38.5% i n r e s t i n g  thereafter  40-min  slopes  was  after  decreased  of  The  hematocrit  was  approximately  reached  170 b e a t s / m i n  tripled  d u r i n g the  i n K J a n d SB  after  71  2-3  min  speed  of  as  was  c a n t e r i n g . Even  the  only  135  stabilized after  5-10  other  at  at  The measured value over  61%,  his  lower  6.5  3  which  a l l  running  heart  120  at  the  r a t e he  animals,  between  level  significantly  decreased  seen  140  same  reached  heart  and  in  c a n t e r i n g . KJ  represents  After  (linear  For  values  of  respectively.  exercise  was  highest  hematocrits  min  resting  JW  rates  beats/min  m/s.  highest  after  of  the  beats/min.  some  min  horses,  though  of  a  37%.  more JW  peaking in  at  a l l  regressions  SB  1.5  study  absolute  fold  increase  56  min, until  ANOVAS  are  were  an  reached  3  horses  and  reached  than  and  this  and  59%  hematocrit the  end  given  of  in  Table  CONCENTRATIONS.  The  5) •  3.3.3 levels the  of  glycogen  middle are  who  only  from  the  did  for  (p  <  after  showed  a  min  at  min,  from  before  lactate m/s  (p  =  the  values  were  not  significantly  obtained  t-test,  Even  after  The  for  animals  significant  decrease  and  6.  a l l 4  30%  6.5  glycogenolytic intermediates  Table  10  (paired  0.05). 15  in  cause  concentrations which  the  concentrations  results  not  of  METABOLITE  muscle  given  mean  Therefore,  and  gluteal  protocol ran  MUSCLE  p  were  compared  0.05) with  concentration 0.85).  3  other  in  except  for  horses. Exercise  metabolite for  glycogen  pre-exercise was  JW,  different  pooled.  changes >  canter  obtained  the  in  not  values  increased  72  TABLE  5.  AFTER  3-4  Linear  STATISTICAL MIN  maximum bout. slopes  OF T R E A D M I L L  regressions  relationships  of  hematocrit ANOVA  was  are  ANALYSIS  equal  were  EXERCISE  performed  F i g . 6  and  was  reached  used to  OF T H E D E C L I N E  I N THOROUGHBRED  F i g . 7 between  Refer  HEMATOCRIT HORSES.  on t h e h e m a t o c r i t v s the time  time when  and t h e end of the e x e r c i s e  to determine 0.  IN  the probability  to  methods  for  that the exercise  cond i t i o n s .  0  HORSE  N  SLOPE  R  SLOPE  KJ  0.22  < 0.001  0.61  < 0.001  SB  0.18  < 0.001  0.31  < 0.01  JW  0.06  0.18  <  0.06  0.01  73  FIG. 6.5 to  7  Same  m/s be  for  a l l horses.  increased  Transition  from  a s F i g . 6, b u t d u r i n g  from  Time  a  4 t o 6.5 m/s  4  0 when min  was  a horizontal treadmill  warm-up  completed  canter at  speed  trot i n 20 s .  at  started 4  m/s.  HCT  %  HR  beats/min  LACTATE  mM  75  TABLE  6.  CANTER  METABOLITE (AT  6.5  CONCENTRATIONS  m/s)  IN  THOROUGHBRED HORSES  RUNNING  Values  are  means  _+ SEM  umol/g  wet  weight.  post-exercise * (  indicates  values p  <  were  Fructose Fructose  MIDDLE  A  TREADMILL.  AND  AFTER  GLUTEAL  A  15  MIN  MUSCLE  OF  (n = 4) . C o n c e n t r a t i o n s a r e g i v e n i n  compared  i n glucosyl with  units.  a paired  P r e - and  t-test  0.05)  PRE-EXERCISE  *  131 .7 + 8..7  Glucose Glucose  THE  Glycogen .given  METABOLITE  Glycogen  ON  BEFORE  6-phosphate 6-phosphate 1,6-bisphosphate  POST-EXERCISE  96 .3 + 17 .0  0. 3 1  + 0..082  0. 30  + 0. 106  0. 56  + 0., 093  0. 56  + 0. 089  0. 08  + 0.,014  0. 06  + 0. 0 1 7  0. 25 + 0..050  0. 25 + 0. 023  3-phosphate  0- 03  + 0.. 005  0. 04  + 0. 005  phosphate  0. 06  + 0..005  0. 07  + 0. 006  3-Phosphoglycerate  0. 17  + 0..016  0. 20  + 0. 010  2-Phosphoglycerate  0. 03  + 0..008  0. 03  + 0. 007  Phosphoenolpyruvate  0. 11  + 0..009  0. 11  + 0. 007  Pyruvate  0. 10  + 0.,012  0. 11  + 0. 007  Lactate  2. 73  + 0.. 13  2. 76  + 0. 04  Glyceraldehyde Dihydroxyacetone  76  3.4  DISCUSSION  This short-term  and  animals  course  the  to  here  mobilize  plasma  j a t e  samples  catheterized  presented  the simultaneous  of  exercise  blood  of  in  heart  controlled  multiple  allowed  changes  hematocrit well  study  running  on  time.  cardiovascular  a  marked  plasma  follow  a pattern  similar  t o what  1936;  Hermansen  humans  et  a l ,  1976).  1966;  Saiki  However,  studies careful  the  (Bang,  do  not provide  sampling  of their  which  i n dogs  ability they to  previously  1972;  (Issekutz  frequencies  is  appeared  reported  time  time  rapidly,  Stensvold,  the necessary  use of  thoroughbreds  very  been  and  the  of  of these  Rowell e_t  a l ,  earlier  r e s o l u t i o n t o make  comparisons. The  intensity  patterns  of changes  work  intensity  the  onset  concentration state;  and  steady  state  was  of  concentration,  both  ejt a _ l , 1 9 6 7 )  t h e low  in  l a c t a t e overshoot  and  drawing  by  In s p i t e  had  under  t r e a d m i l l . The  system  showed  in  Rapid  large  response  f o r the f i r s t  racehorses  possible a  of  concentration,  thoroughbred  made  hematocrit  the  lactate  conditions.  was  measurement  elevated.  increased:  heart  the heart  exercise  had  f o r a l l parameters  exercise  and 3)  of  were  rate  heart  rate  took  state  for  reached plasma  hematocrit; longer  effect  lactate  2)  to reach  during  lactate a  steady  lactate concentration  established  on  i n v e s t i g a t e d . When  t h e maxima  higher and  rate  steady  1)  a marked  while  exercising  and were  77  3.4.1 The  ability  oxygen  of  the  of  hematocrit  up  reservoir to  (Lykkeboe  e_t a _ l , 1977) . T h e  to  bring  their  to  52.0%  trot  caused  reached  after  horses et  a l ,  have et  show  Pan  reported  A  true  hematocrit.  After  drift or  to  was  could a  concentration  plasma  et  for  observation i s probably  their  More be  are  4 min.  and  here  values  measured  are  exercise  able  of  38.5%  minutes 60%  of  were  Standardbred  as  after  than  of  were  here  likely  size  training  above  cantering.  horses  adjustments  The  value  hematocrits  thoroughbred  maximal  used  of the  magnitude  additional  and  those  from  1983).  resting  Three  57.7%  third  i n c r e a s e d by  thoroughbreds a mean  one  the  when  striking  liberated  consequently  from  EXERCISE.  most  than  (Persson,  exercise  a _ l , 1984)  (Persson  high  as  racing to  what  (Snow  occur  was  66%  even  observed  work. steady  state  was  r e a c h i n g maximum  to  at fluid  measurements and  of  subsequent  re-sequestering  Preliminary  This  due  and  increases to  measured be  one  locomotion.  to  of  during  f o r submaximal  decrease  min  Hematocrit  rapidly  here  for  increase  similar  a l , 1983).  more  walking  3  1973;  been  hematocrit  an  is  DURING  increase hematocrit  stimulation  response  after  HEMATOCRIT  .erythrocytes can  adrenergic  splenic  IN  drastically  goes  number  via  the  to  for high-speed  total  spleen of  horses  consumption  adaptations the  CHANGES  established  values,  a  slow  but  both  work  intensities.  shift  into  the  of  the  show  hematocrit suggests  not  red  that seem  that  a  plasma  cells total  slow  r e s p o n s i b l e f o r the  decline  This  the  plasma  influx  steady slow  compartment  by  to decrease  for  in of  spleen. protein  parallel. water  into  in hematocrit.  78  At  the end  increase  of  the trot  while  variables  hematocrit  could  catecholamines  response  response large  not  a t that  Humans in  to  was  consequent maximum  maintain  the  heart,  carrying  them  output  rate  low  During observed  simultaneously  in  rapid  the  overshoot)  activation  LACTATE onset  o f the  showed  lactate  i n  i n humans. A t t h e  horses i f  n o tlower  the  the  their  1967).  Horses work o f  when h i g h  CONCENTRATION  o f work,  the  lactate  oxygen  these  overall  variables  system  response animals stages  o f work,  patterns  examined  o f submaximal  equivalent  onset  AT T H E START  concentration and  cardiovascular  the early  overshoot  no  1983). The  50%  t o reduce  viscosity  hematocrit  d i d not prevent  does  and Smith,  t o 3 minutes  (strong  metabolism  reported  2  by  2  same. T h e t h r e e  anaerobic a  the  but  activity.  f o r plasma  after  thoroughbreds  V0 max  a t rest  for  1969)  i nthoroughbred  viscosity  higher  hematocrit  a n d Donovan,  here  augment  hematocrits  PLASMA  were  seen  (see C r o w e l l  i sneeded  changes  The  to  (Brooks  i n blood  3.4.2  heart  rats  capacity  of  bout.  and Kastner,  allowing  EXERCISE.  exercise  both  circulating  (Hollman  only  OF  by  exercise  change  may  that  increase their  i n  started to  showing  regulated  o f the  adjustment  cardiac  rate  slightly  found  allow  decreased, be  stage  heart  can also  hematocrit  should  protocol,  peaked  exercise. found  here  andheart  rate  from  r e l y i n g on  of exercise.  to  what  oxygen  had  They been  t r a n s p o r t by  79  the  blood  metabolism changes  was  probably  of  muscle  in  lactate  not cells  cardiovascular  instance,  oxygen  during  because  could  transfer  the  0^  be  oxidative  pattern  elicited  limited from  for  same  ( i . e . human  be  of  factor  can  responses  supply  the  limiting  concentration  different  level  the  vs at  by  of very  horse). the  capillaries  For  cellular to  muscle  mitochondria. At generation the  the does  working  could  start  be  not  muscles.  the  type  the  different  lactate  of  to  by  a  new  3.4.3 Because high  rates  concentration  of  this  of  appearance  rate  of  removal  A  model  changes terms  is  of  steady  state.  presented  flux  by  the  the  slow  and  utilize 1985),  i s determined  changes  (R  )  ( ^)•  A  R  intensity  can  reported  8 explaining  be in  the  the  of of  THE  flow  to  plasma  PLASMA.  lactate  at  the  plasma  both  by  its  and  by  its  number drawn this  of from  study.  concentration  submaximal  predicts  plasma  sustained,  blood  FROM  circulation  model  in  perfusion is  of  AND  lactate fluxes  in Fig.  This  TO  circulation  about  by  exercise  Brooks,  metabolite  utilization  altered, causing  produce 2;  constant  rates.  be  ATP  recruitment  pattern  FLUXES  concentration  elicited of  from  inferences  pattern  may  oxidative  lactate  the  As  the  types  into  ATP  of  to  fibers.  Chapter  rate  the  or  continuously  (see  total  preferential  fibers  LACTATE  animals  instructive  the  r e c r u i t e d or  fiber  exercise,  accumulation  oxidative  fibers  reach  support  The  glycolytic  lactate-utilizing  submaximal  fully  caused  fast-twitch  of  exercise  in  f l u c t u a t i o n s of  80  R  and  G  during  the  transition  from  rest  organism,  lactate  to  steady  state  exercise. In equal,  a  and  (Hetenyii  resting  plasma et  al  concentration 1983),.  equilibrium  is  the  compartment.  plasma [A]),  (phase  increases 6  and  curves  R  phase  and  overshoot  in  accumulated  steady  rest,  state  equivalent  much  higher  studied  to  than  date The  rest  and  (Figs. plasma  6  the  onset  7).  can  delimited  by  R  scale  is  be  The at  R  G  delimited and  G  in  R^  q  flux  work  R,  and  R  than  A  decreases  part  of  Figs.  there  is of  phase  an the  [B],  a  i s again,  like  rates  however  for  are  at  a l l vertebrates  concentrations  amount beginning  R^  i n phase are  R  end  reported  exercise  net  minutes].  of  the  in  2).  of  and  greater  disappearance  exercise as  in R  the  [B],  where  of  exercise  phase  lactate  the  of  this  concentration  concentration  [A]. At  c a l c u l a t e d by  the  area i f  umoles  state  compartment  [B])  surface  steady  and  half  constant  minutes  [B],  now  which  rest,  Chapter  after  phase  is  of  are  accumulating  R ^ because  and  the  (see  few  [A]  R ^ . The  at  first  min  obtained  to  starts  2-3  i n phase is  exercise,  of  first  first  causing  onset  than  during the  stays  the  R^  and  R^  and  G  therefore  lactate  For  phase  In  R^  and  the  [B]  7). in  lactate  time  seen  the  greater  cross-over  (Fig.6  and  is  G  Between  throughout  new  disturbed  (as  7).  At  R  were  slightly  of  lactate  of  exercise  subtracting curves [A]  given  the  umol  min  to  the  (phases  [A]  surface [B]  quantity 1  at  different  added  i n phase  [this in  measured  from  will and  area  be i f  the in the  81  FIG.  8  Model  appearance rest  to  divided Ra;  (Ra)  and  phase  pool  net  The  (C)].  (Rd)  of  in  where  Ra  The  surface  Rd.  amount phase  of  (A).  lactate  between  to  lactate  Surface  removed  difference  between the  rest  and  Ra  >  in  the  difference  lactate  (B)  to (B)  same  2  where  the  is Rd  in  > (A)  rapidly  i s equal pool  surface  exercise  to  during  areas  i n plasma  state  from  Exercise  indicated  added  these  steady  Rd;  area  of  transition  work.  area  from  rates  the  submaximal (A)  =  the  during  phases:  proportional  concentrations  changes  removal  net  during  amount  (B).  directly  where  the  for  intensity  three  (C)  represents  the  and  constant in  mixing  proposed  is  lactate [phase  Ra  Rd  \  W REST— «  /  [A]  [B]  S U B M A X I M A l  T I M E  [C]  F Y F  R  r | 5  E  83  During plasma  the  lactate  that  a  This  oxidative  imbalance  could  fibers  glycolytic  was  of  the  (Table  the  30%  As  a  to  unit,  mitochondria  or  i t  same  consider be  subsequent  release metabolism  small  number  of  complete  lactate  protocol, indicating was  by  again  fatigue  of  If  the  lactate  to  of  the  by  fast-twitch  most  interesting  for  energy  by  two  a_l, 1 9 8 3 ) . times  the  either  The  ATP an  The  i i i )  have  glycogenolysis metabolism  was in  3  ATP  the  pathway  has  than  the  been  fact  results  glycogenolysis for  its  glycogenolysis fibers  and  fibers  for  glycogenolysis important,  higher  observed  probably the  first  important  oxidative  was  per  in  circulation  aerobic  mechanism would  of  glycolytic high  in  converted  present  i i ) anaerobic  fast-twitch  canter  oxidized  anaerobic the  min  be  second  more  exercise.  adjacent  15  muscle  potential fates  utilized:  i)  gluteal  production  lactate into  first  middle  completely  3 ways:  or  levels  Aerobic  be  elsewhere; of  has  net  glycogen  in  the  can  the  12.3  The  caused  It  sustained  oxidation;  exclusively.  pathway  et  of  interpreted  rapid  exercise.  can  yielding  during  in  glycogen  (Hochachka  amount  muscle  trot  and  g  replaced  in glycogen  l a c t a t e with  the  transfer  now  muscle.  for  a  R  the  increase,  caused  analysis  fuel,  of  in  between been  of  to  METABOLITES.  advantage  with  started  MUSCLE  the  could  min  are  metabolic  anaerobically  to  20  which  skeletal  glucosyl  have  reduction  6).  working  to  fibers.  3.4.4 aspect  15  concentration  slight  present.  last  middle  the  after main  gluteus,  84  particularly  in  fibers.  thoroughbred  In  fast-twitch fibers  view  high  (Snow,  third  only  of  the two  glycolytic  and  oxidative  fish  received  more  The  effect  net  aerobic been  breakdown  min  canter,  umol/g observed  was this  per  min, in  sustained  canter  relative  only  muscle  was  value  and  the  third  both  pathway turning  long  1985).  at  is  could  that  at  a  their  the have  aerobic the  15  of  85  rate  what  in  recently  during  than  operating  ago  mechanisms  ATP  somewhat h i g h e r  between  (Brooks,  utilized  the  cooperative  mechanisms  over  from  i t has  Assuming  57%  oxidative  exchange  and  gluteus.  species  the  in  glycolytic  were  to  the  measured  same  time  in  maintained  after  15  a  state  was  was  rat muscle  ratio that min  This  of  for  were  after  was the  the  has  been  maximum  while  the  plasma  plasma  lactate together  the  Large  exercise  and  Here, after  potential  canter  for  observation,  6).  1986).  before  redox  selected after  submaximal  same  During  a  (Table  (Dobson,  cytosolic  work.  of  apparent  state  freezing  established  interrupted  constant.  concentrations  pre-exercise  course  indicating  steady  the  intermediates  lactate/pyruvate  exercise,  was  the  and  of  differs  proposed  1965)  second  middle  changes  of  exercise  slow  i n e x e r c i s i n g mammals  glycogen  other  number  using  Diaciuc,  the  a  Lactate been  oxidative  level. No  changes  of  11%  requires  has  of  composed  mechanism  types.  the  in  glycogenolysis  the  of  is  and  i t  fibers  and  support  operating  that  fiber  (Wittenberger  i t  second  fact  of  proportion  fibers  The  metabolism  high  horses,  oxidative  1983).  in  its  was  protocol,  lactate  and  concentration with  the  85  measurements true the  of  metabolic end  of  glycolytic steady  state  the e x e r c i s e  bout.  intermediates, was  reached  confirms  and m a i n t a i n e d  that  a  until  86  CHAPTER  4:  CARDIAC  OUTPUT  AND  EXERCISING  4.1  THOROUGHBRED  cardiovascular  usually  increase  simply  OF  HORSES.  oxygen  supply  carbon  potentially  important  augmenting muscles,  the  to  the  dioxide role  provision  than  quantitatively increasing  at  C0  of  the  cardiac rate  of  the  by  oxidative  plasma  way t o  musculature  and t o  the  metabolites  The  fuels  to  contracting  of other  level.  have  lungs.  adjustments i n  has not been  should  exercise  these  the transport heat  by  organism's  into  whole-organism  output  elicited  active  played  and  2  as  release  and i n a c c e l e r a t i n g  products  turnover  adjustments  interpreted  facilitate  end  CONSUMPTION  INTRODUCTION  The are  OXYGEN  an  metabolic  investigated  In p a r t i c u l a r , effect  as suggested  on  the  i n Chapter  2. Lactate species, the as  plasma the  Exercise and  and  turnover  the flux  rates  compartment  activity causes  state  Because  the  selected  for  been  of this  have  been  as  an  thoroughbred i t s aerobic  i n both  measured  metabolite  shown  of the animal  an i n c r e a s e  i t s utilization  has  in  i n and o u t o f  t o vary  changes  fuel  racehorse  has  and a n a e r o b i c  considerably  (see Chapter 2 ) .  the production  oxidative  several  of lactate  (Brooks, been  capacity  1985).  carefully over  three  87  centuries,  i t  investigation In with  the  of  o f plasma  lactate  addition,  horses  by  of  work  rate  standardbred 1983)  and  Manohar,  in  output  on  to  exercise.  high  such  rest  and  1986).  has only  oxygen  Functional  allow  range,  and F r e g i n ,  their  scope  high-intensity  system  a wide  output  aerobic  increase  1981; Manohar,  (Thomas  ponies  them t o  but the effect  been  measured i n  1981; Thomas  (Pan e t a_l, 1984; F o r s t e r  overall  rate  of  oxygen  delivery.  exercise  of  identical To  measurement attempted  of  racehorse.  effects  measurement  goal  of this  to investigate  the  thoroughbred  cardiac  a very  f o r the  e_t a l ,  e t a_l, 1984;  1986).  therefore  under  over  cardiac  horses  have  model  during  cardiovascular  rate on  The was  their  good  fluxes  between  and F r e g i n ,  metabolic  a  ability  36-fold  (Thomas  adaptations alter  provide  impressive  consumption exercise  could  plasma exercise  lactate  output  the  output  in  the  characterizes  the  and on t h e r a t e o f  chapter  present  cardiac  high-intensity  were  i n cardiac  turnover  chapter  turnover  4 a n d 5)  deals  with  i n t h e same  the  animals  conditions.  maximal  during  lactate  following  complete of  plasma  cardiac  The  (Chapters  the e f f e c t o f changes  The p r e s e n t on  study  not obtained  investigation,  output  exercise.  the  and  VC^max  Data  f o r maximal  for technical  was  reasons,  but a  and f o r t h e a e r o b i c  scope  it  lowest  possible  value  of  thoroughbred  horses  and  A-V d i f f e r e n c e s  for  VC^max  could  i n oxygen  be e s t i m a t e d  content.  from  heart  rates  88  4.2 M A T E R I A L S  AND  METHODS  4.2.1 the  ANIMALS.  previous  present state  study  experiments.  of training  was  shaved  and  stab  incision  was  then  punctured  A metal  Before  spring  the catheter  then  catheter,  neck  wave  into  of  observed  whether right  the  on  right  (B) introducer output F,  flow  the  catheter  ventricle,  was  size  placed  catheter directed  introduced  Dacron,  and a  catheter catheter  removing the  closed  e n d , NIH  the right  and connected  atrium  would  (the  clearly  i n the pulmonary  I t was to  pressure indicate artery,  cava). A  jugular  opticath  to a  and sutured  its position  o r vena  dilution  through  of i t s location.  ARTERY.  (Oximetrix,  vein  (16 g X 1.5  percutaneous  t i p was p l a c e d  thermal  200 n e e d l e  ventricle  i n the l e f t  The  3. T h e v e i n  transducer  PULMONARY  and  as i n Chapter  woven  to secure  atrium,  jugular  8 F X 100 cm) w a s p a s s e d  right  into  the animal  the left  the vessel. After  (USCI,  diet,  anaesthesia  forverification  withdrawn  ages,  i n the  local  AV.  in  the  transducer  slowly  the  inserted  used  (A) R I G H T A T R I U M .  above  was  used i n  3.  Monoject  Hemaquet  guide-wire,  introducer  a  guide-wire  (USCI,  cardiovascular  area  performed  with  was  pressure  i n Chapter  horses  also  weights,  catheterization,  were  introducer)  the  body  on a s m a l l  disinfected.  introducer  Their  a n d SB) w e r e  CATHETERIZATIONS.  and  in.).  KJ,  are given  4.2.2 skin  (JW,  The thoroughbred  second vein  model  pulmonary  and a  P7110-E artery  catheter cardiac size  7.5  catheter  89  series  D) was  and  placed  sutured  in  several  position  inches  into  the pulmonary  using  the  technique  artery  described  previously. (C) right  CAROTID  common  been  carotid  performed  experiments. as  ARTERY.  on  artery  A  introducing  a  (Vygon  XRO  intravascular  it  the  neck.  to  cranial  stab  guide-wire,  The  to the a o r t i c The  catheter  sampling  catheters  • (Lectroflex  Vygon  PVC)  neck  and  with  saline.  catheters  was  before was  18 g X 46 cm)  port  was  the  prepared  made  the catheter  were  lines  and  incision  sliding  l o c a t i o n had  months the skin  of the  before  i n position and  located  suturing  about  10  cm  arch.  three  filled  several  to catheterization,  above.  transposition  to a subcutaneous  a l l horses  Prior  described  Surgical  were  which  flushed  No  connected  were  securely  heparin  every  to extension  was  10-15  taped  used  min  to the  but lines  t o keep  them  patent.  4.2.3 carried  out  ranged 71%. was  from The  18  to  3 h  exercise incline,  and  and  measurements  in a stall  brought  protocols  on  m/s  m/s  A l l experiments  the morning relative  were  beside The  were  ( i i ) a 3-4  ( i i i ) a 6.5  PROTOCOLS.  after  20°C  catheterization.  harness  min,  at least  resting  standing  after  EXERCISE  performed  was  the treadmill  trot  (i)  a t 6%  horizontal  humidity  the treadmill  horse  used:  feed.  a  then  while  Temperature from  at least fitted  m/s  sustainable  30 m i n with  a  3 ) . Four  walk  incline sustainable  canter  61 t o  the animal  (see Chapter 1.6  were  a t 6% f o r 40  f o r 10 t o  90  15  min,  for  2  with  and  min. a  for  (iv) a  Trot, canter  warm-up  the trot,  (4  period  for  by  a  min t r o t  m/s  to the galloping  4  m/s,  horse  but (JW)  without  lower  because  treadmill  belt.  having  regular  very the  slow  if  of  the animal  submaximal comfortable, to  presented  Chapter  in  the  could  other  pain  caused  occurred,  over  of  fluxes  Therefore,  40 m i n  by pounding  on t h e  would  to break  stop  into  a  t o change  never  observed  40 m i n . T h e  designed  performances  between  at  to the a r t i c u l a t i o n s ) .  were  lactate  4  over  p a t t e r n was  a t 3 m/s  from  running  (presumably  chosen  to  elicit  s u s t a i n a b l e f o r long lactate  turnover.  The  i n t h e same a n i m a l s  5. I n t h e p r e s e n t  horses.  followed  f o r the older  4 m/s  attempt  applied  trot  i n 45 s .  the animal  occasions  forces  be f o u n d  chosen  not sustain  measurement  o f plasma  was  and he would  state  investigation  in  could  regimes  the  ( 1 . 6 m/s)  K J a n d SB w e r e  o f 3 m/s  was m a i n t a i n e d  allow  differences  protocol,  was  m/s  4 min  achieved  i n the locomotory  steady  by a  o f 1 2 . 5 m/s  on r e p e a t e d  exercise  followed  a t 1.6  The i n c r e a s e  this  gait  o f a 4 min walk  initiated  f o r the gallop.  articular  stress  alteration  enough  he  sustainable  p r o t o c o l s were  ( 1 . 6 m/s)  speed  When  canter  pattern  This  speed  the trot  a  a t 5% i n c l i n e  and a 4 min walk  (4 m/s)  experiencing  a  consisting  the canter,  During  gallop  and g a l l o p  a 4 min walk  m/s) 2  1 2 . 5 m/s  study,  values data  no  is  significant  measured  i n JW a n d  f o r a l l animals  were  pooled.  4.2.4 Cardiac  output  CARDIAC was  measured  OUTPUT  AND  BLOOD  OXYGEN  by t h e t h e r m o d i l u t i o n  CONTENT. technique  91  using  an  Computer  American (9520A)  (OS-1270A). were  and Oximetrix  The  calibrated  The  measured  was  within  of  into  pulmonary  artery  the  cardiac  (D. W h e e l d o n  solution  connected  temperatures  of  and  was  from  activity  at  simultaneously artery  to  Samples  were  cardiac  output  cardiac  output  which  least  accurate with  as  dye  thoracic  at  dextrose  the  t i p  the  with  ranged  was  of  the  temperature a  reference  Volumes from  respectively. f o r each  (5%)  temperature  computer.  boluses  3 times  most  of cold  injection,  the  technique  comm.).  monitored  13.0°C  37°C.  at  24 m l t o 28  Bolus  animal  and  injection  and f o r each  level. Arterial  and  to  bath  such  and blood  located  to  study  compared  pers.  a bolus  was  i n this  I n human s t u d i e s ,  the  when  atrium  the dextrose  4.2°C  performed  study,  catheter. Before  thermistor  ml  gives  techniques  thermistor  dextrose  values.  output  the r i g h t  a  used  the thermodilution  technique  the present  from  System  8% o f t h e t r u e  measurements  injected  Oximeter  and thermostated  using  non-invasive  recorded  of  a  rates  thermodilution  In  Shaw C a t h e t e r  pump  the  impedance  Output  with  accurate  or  Cardiac  and t h e c a t h e t e r  flow  measurements  Laboratories  computer  were  dilution  Edwards  (B). were  and  from  taken  Blood  A-V before  (B).  carotid  content  in  were  oxygen  each  content.  measurement o f  between  to a  given  samples  i n 5 ml h e p a r i n i z e d  and s t o r e d  drawn  the pulmonary  corresponding  a s t h e mean  collected  samples  and from  (A) a n d a f t e r  Oxygen  sealed  blood  differences  calculated  was  tightly  venous  the right  determine  was  mixed  on i c e . Oxygen  (A)  syringes content  92  was  determined  Analyzer  37°C  (Instrument  (Instrument Measurements Hemoglobin  Laboratories  #  were  no  performed  from for  the  pH  should  would  be  such  as  which  were  Oxygen  [0.003  X  spinning  at  was  (in  samples  mm in  cardiac  A-V  (ET)  starting after  after  the  (G).  highest  The  speed  galloping  with  our  the  catheters  to  ml)  X  not  animals  temperature could  successful  caused  too  rest  be  dissociation this  X  values  values.  hemoglobin  saturation]  was  determined  for was  error  exercise,  absolute  %  have  (Prosser,  and  [1.34  10  min  by  on  calculated  +  a  from  content.  2  at  the  rest  5  min  and  7  min  protocol,  7  min  into  the  at  the  1 min trot  ( C ) , and cardiac  because  much  measurements not  shifts  than  (W),  of  back curve  for relative  tubes  protocol  measured  e  hemoglobins  hemoglobin  started  r  sampling.  addition,  Hematocrit  determination  was  In  as  protocol  e  a human  between  in 0  combination.  saturation  2  Bohr  performed  canter  w  Gas  CO-Oximeter  after  H  horse  study  Blood  automatically 0  consumption  had  P  decreased  this  a  in  ^  using  changes  walk  the  by  and  and  3 h  was  minimal.  were  animal  starting  gallop  of  the  a n c  similar  difference  Measurements after  2 '  hematocrit  Oxygen  and  0  than  Human a n d  Hg)].  microcentrifuge. output  C  pH  used  calculated  g/100  (in  2  P  least  or  important  613)  hemoglobin  be  differences  p0  2  display  therefore  concentration  #  later  '  0  introduced  content  Autocal  282)  PCC^.  and  more  p  human  e l i m i n a t e d or A-V  Micro  saturation  and  error  curve  %  a  similar  1975);  a  Laboratories  Hemoglobin  calculated adjusted  on  concentration,  directly.  very  at  (ST)  1 min output  the  neck  mechanical  and  (R),  the  exact  maintained  with  movements  interference position  of  certainty.  93  Therefore, and  heart  only rate  A-V  could  be  4.2.5 output  (CO)  was  -  fa  o  the  pad) Means  variance.  a  post  further  4.3  and  an  were  gallop.  AND  STATISTICS.  T^=temperature the  bolus.  curve  IBM  The  (integral  with  a  of  surface T  dt  from  digitizer  the  bolus  area  under  time  (GTCO  0  to  Corp.  computer.  compared  see  when  was  Cardiac  follows:  with  a  oneway  Student-Newman-Keuls  test  analysis  of  time  comparisons, hoc  hematocrit  dt  determined  The  unplanned  T  vs  was  digitizing  i n the  content,  V  V=volume  temperature  infinity)  *  as  temperature,  b  and  T.)  J  T =blood  injected,  measured  calculated  =  Where  i n oxygen  CALCULATIONS  (T CO  difference  Sokal  the  and  overall  test Rohlf, F  analysis  of  (T-method 1981)  value  was  for  used  indicated  as  that  necessary.  RESULTS  4.3.1 cardiac  CARDIAC  output,  Fig.  9.  trot  protocol  identical,  The  heart  rate  PARAMETERS. and  cardiac outputs (ST)  therefore  and  measured  later  only  stroke  one  i n the value  Mean  values  volume  are  at  beginning  the  same (T)  for  presented  protocol i s given  of  (ET)  in the  were  in Fig.  9.  94  Exercise df,  had  a  F=24.6,  stroke mean  P<0.001),  volume  475  protocol,  ml  min  compared mean  value  -  with  values  have  exercise that  (Joyce canter Mean  exercise  protocol the  (P<0.05). Heart  No  rate  activity  was  level  a  overall  on  stroke  different post  hoc  from  a  heart values  150 t o  at  rest  (P<0.01) b u t  protocols  were n o t  resting  value  protocol  rate  (Fig. 9).  reached  o f 220 t o 2 3 0  o f 49  197+10 beats/min  horses  during  treadmill  unpublished  data),  clearly  indicating  represented was  lower  and  during  higher  the  same  rate  than  mean  i n the canter  the  from  a  other.  from  (P<0.01),  volume  o f 1.58 ANOVA  volume, from  test.  and  was  the t r o t  the  exercise  at rest  i t was  found  for  easy  than  f o r these during  significantly and c a n t e r  between  gallop  trot  than  any  lower  protocols  and  canter.  f o r any  other  (P<0.01).  maximum  the  went  lower  exercise  and c a n t e r  each  and  in  difference  Stroke to  SEM)  protocol  walk  output  t o a change  during  protocol,  heart  (3 d f / 8  P<0.001),  significantly  trot,  from  Harman,  animals.  during  was  went  measured  the  corresponds  beats/min  +_  (F=33.0, Cardiac  measured  gallop  (mean  rate  output  66.5 1/min t o 212.3 1/min d u r i n g  It  rate 144  the  been  .  different  to  beats/min  1  values  Heart  During  of  f o r the walk,  significantly  beats/min  -  on c a r d i a c  P<0.05).  which  k g  1  effect  heart  (F=4.2,  resting  canter  significant  was  1.34  1 during  1 at rest,  t h e walk  p r o t o c o l . Even  indicated a significant no  any other  particular mean  using  and i t i n c r e a s e d  mean  effect was  though  of exercise  found  to  Student-Newman-Keuls  be  as a  95  FIG.  9  volume  (SV)  exercise incline); m/s,  0%  reached for +  SEM  Cardiac  output  i n trained  (CO),  heart  thoroughbred  horses  on  a  treadmill.  R  T  =  trot  m/s,  6%  the  canter  incline). 197  details (N=3).  _+ 10 of  (3-4 During  beats/min  the e x e r c i s e  =  rate  rest;  W  (HR)  and  stroke  at rest  and  during  = walk  incline);  ( n o t shown  on  C  ( 1 . 6 m/s, = canter  protocol  heart  F i g . 9) . S e e  p r o t o c o l s . Values  given  6% (6.5 rate  methods  a r e means  200  \  100  -  o o 150 100  \  DC X  50  1.5 -_  ZPI  1.0  >  0.5  -  -  R  W  97  FIG. at  10 rest  blood; =  Blood and black  start  canter;  of G  m e a n s + SEM  =  oxygen content  during  treadmill  bars:  mixed  trot  protocol;  gallop  (N=3).  i n t r a i n e d thoroughbred e x e r c i s e . Open b a r s :  venous b l o o d . ET  ( 1 2 . 5 m/s,  R = rest;  = end of t r o t 5%  incline).  W  horses  arterial  = w a l k ; . ST  protocol; C =  Values  given are  98  R  W  ST  ET  C  G  99  4.3.2 oxygen in  A-V  contents  Fig.  10  arterial  DIFFERENCES  of a r t e r i a l  for  the  oxygen  t o a maximum  15.8  vol%,  of  venous  30.0  protocol,  and  galloping  thoroughbreds.  content vol%  performed  on  exercise  was  P<0.001).  Post  difference  was  (P<0.05),  ( i i )  protocol higher  i t  (ST)  than  during  the  (P<0.01).  No  significant  at  but  arterial  levels  different  work  greatly during maximum 12.5 highly  m/s.  The  difference  4.7  v o l % at  The  (5  the walk than  (i)  the  walk  i n oxygen  rest  to  23.4  analysis  of  F=27.52,  the  and  was  effect  df,  the beginning  At  vol% in  mean  p r o t o c o l than  (P<0.01),  Mean  v o l % at  5.9  overall  df/12  the walk at  of  statistical  that:  differences  the  of  the canter  between  adjacent  A-V  at  rest  the  trot  (iii)  during  reported  here.  are  from  a  are given  low  resting  protocol  63.4% overall  significant  often was  intensities  of  was  difference  exercise  level  A-V  show  hematocrit  increased the  during  mean  The  given  protocol.  value  higher  gallop  19.8  low  differences.  during  during  of  a  from  are  i t was  protocol  means  were  P<0.05.  Arterial hematocrit,  to  The  was  other  was  The  activity.  highest  tests  higher  of  a minimum  significant  hoc  blood  content  A-V  highly  CONTENT.  the canter  protocol.  t h e mean  venous  levels  from  drastically  the g a l l o p  OXYGEN  v o l % during  decreased  increased  during  went  oxygen  i t  mixed  different  content  rest  and  IN  (5  was  of  reached  effect df/12  of df,  higher  not  than  significant.  Mean  values  i n F i g . 11. value  lowest  venous  of  38.1%  intensity  i n the horses e x e r c i s e on F=7.45,  Only  at  the  Hematocrit to  56.2%  (walk).  galloping  hematocrit  P<0.01).  The  A at  was mean  100  value but  was no  lower  at  rest  significant  various  levels  of  oxygen  mean to  85.1  Whole-body bottom  graph  in  was  highly  hoc  tests  (ST)  compared  different.  be  found  a  (P<0.01),  between  the  walk  higher  the  with  the (ST  -  i t  are  presented  the  statistical  Whole-body  The  level  of  overall df,  than  at  beginning  of  was rest the  walk  (P<0.05).  Mean  and  ET)  canter  and  the  analysis  was  of  1/min  effect  F=12.83,  protocol. in  rate 3.2  The  increased  rates  consumption  the  and  1  rates  graph).  canter  protocol at  (top  the  df/10  oxygen  12  specific  during  resting  (4  Fig.  -  and  protocol.  that  trot  - 1  in  Mass  min "'" kg " ",  values.  from  canter  also  ml  12,  these  show  i t was  the  kg  - 1  significant  that  during  7.2  Fig.  went  during  intensity  could  given  consumption  of  the  work  CONSUMPTION.  are  was  min  on  consumption  higher  rate  oxygen  performed  1/min  OXYGEN  ml  any  exercise.  consumption  resting  at  differences  4.3.3 of  than  of  oxygen to  38.1  exercise  P<0.001).  Post  significantly (P<0.05), trot  protocol  consumption (C)  and  were  rates not  101  FIG.  11  rest  and  10.  Values  Hematocrit during given  (HCT)  treadmill are  means  +  of  trained  exercise. SEM  (N=3).  thoroughbred Same  legend  horses as  at  in Fig.  102  H  40  20  - nr *  i  i  R  W  i  i  S T  E T  i C  i G  103  FIG.  12  rest  and  oxygen  Oxygen during  treadmill  consumption.  consumption. means  consumption  + SEM  Same (N=3).  of trained exercise.  Bottom  legend  as  thoroughbred horses at  Top g r a p h :  graph: in  Fig.  mass  whole-body 10. V a l u e s  specific oxygen given are  104  I CM  CM  50  -  40  -  20  -  R  W  ST  ET  C  105  4.4  DISCUSSION  The  cardiac  output  measured  at  rest  exercise  to  complement  fluxes that  presented  in  thoroughbred  increase 5-fold  their between  maximal  stroke  maximal  A-V  ponies  difference  rest  and  content  oxygen  striking  up  horses  consumption  by  the  more  highest  4.4.1 3-fold  protocol.  The  equivalent not  vary  9).  The  shown may  observed  stroke  only  reported reach  represents  horses able  for to  scope  in  between  the  in  their  increase  the  of  most  performance. their  rest  and  oxygen maximal  mammals.  Thoroughbreds rest  and  directly  rate because  measured  1  aerobic  between was  of  augment  OUTPUT.  change  their  response  one  between  higher  than  This  in standardbred 1.27  higher  to least  and  concentration.  40-fold  volumes  a  50%  in heart  significantly  have  than  be  aerobic  at  v o l % v i a a more  by  than  by  bring  system  shows  ability  can  i n cardiac output  increment  previously values  to  lactate  study  horses,  i s much  Thoroughbreds  CARDIAC  increase  content  1986). 30  This  content  standardbred  i n 0^  transport  Thoroughbred  exercise:  than  plasma  e x e r c i s e . They  was  submaximal  impressive  i n oxygen  maximal  hemoglobin  adaptations  the  of  of  following chapter. have  racehorses  levels  investigation  A-V  difference  thoroughbred  different  our  the  volume  circulating  their  at  horses  (Manohar,  arterial in  and  of  two  stroke  were  horses  in untrained  the  by  volume  an did  states  (Fig.  higher  than  f o r which  animals  a  canter  caused  activity  here  showed  maximum  (Thomas  and  106  Fregin,  1981)  (Thomas  e_t  from  1.34  and  a_l, 1983). 1  at  humans,  maximum  result  of  in  determining  the  stroke  1  rest  to  stroke  heart  volume  s tandardbreds attributed  of to  the  walk  endurance  training,  seem  to  possible Fahey,  et  combination  ranged  protocol.  up  to  20%  but  In  as  role  cardiac  output  a  The  (1983) of  of  higher  compared can  in  given  maximal with  the  therefore  training  a  genetic  important  1984).  a_l  training  p l a y an  thoroughbreds  Thomas  of  thoroughbreds  i n c r e a s e by  in  a  of  can  size  found  short period  1 during  volume  and  a  volumes  1.58  maximal  (Brooks  after  Stroke  intensive^  differences  individual  1.36  and  be  genetic  differences.  true was  The  values  measured  resting  levels  because  10  same  beats/min  animals  under  Chapter  3).  even  under  be  could  not  people  a  during  144  true  kept  the  much  the  the  range  top  maximal canter  speed  submaximal beats/min.  work  heart such  quiet  of  i t  of  could  horses  rate  than  which can  be  measured  presence  on  in  a  rate to  may  several is  can in  no  vary this  galloping  being less  (see  animals  of  reported  from  able  the  horses  horses  represents  were  in  There  measured  achieve  beats/min)  excitable  mean h e a r t  animals  (49  these  were  far  represent  conditions  of  highly  not  catheters.  not  were  intensity, same  rate  thoroughbred  values  values  do  rates  i n the  different  protocol  these  The  minimal  but  output  rest  experimental  resting  perfectly  cardiac  wider  and  than  beats/min,  Unfortunately,  animals,  this  30  be  that  study.  the  The  at  mean h e a r t  different  manipulating  doubt over  higher  here  attained than  half  treadmill. only  At  reached  increase  this  107  rate  to  have  been  220-230  197  beats/min  Thomas  probably an  augment  Endurance-trained  and  that  estimate  maximal  used  the  that,  volume  equal  resting of  1/min. the  225 In  (Brooks  can  also  between  rest  and  4.4.2  their  to  study  i f  lowest With their  above  in ponies 1984),  undergo  eight  1986).  It  value this  8-fold  and  1986) likely  to  between to  horses  their  when  stroke  (i.e. and  would  and  and  conservative  volume  output  calculation,  i t i s very  fold  the  is  Manohar  ability  reported here  cardiac  rest  is possible  VC^max,  stroke  study  support  thoroughbred  make  at  (Manohar,  an  than  we  can  the  and  animals  Recently,  .of t h e  galloping  the  the  Fahey,  horses  show  output  beats/min,  found  and  cardiac  in their  between  have  more  (Manohar,  when  of  by  rest  these  output  ponies  increase in  athletes  1984).  exercise  animals).  view  scope  output  present  assumption  in  untrained  of  human  of  data).  used  scope  cardiac  Fahey,  cardiac  maximal  is  in  the  they  rates  between  intensity  and  heart  6.6-fold  horses  higher.  their  in  h i g h e s t work and  protocol,  maximum  reported a  standardbred  increase  gallop  unpublished  VC^max,  and  rate  Harman,  elicit  demonstrated  1  (Joyce  (Brooks  2  rest  at  the  eight-fold  V0 max  gallop  for  but  not  to  e_t a_l ( 1 9 8 3 )  output  exercise, did  the  observed  beats/min  cardiac  during  a  heart  reach  300  considering  trained  that  1.34  humans  thoroughbred  increase in cardiac  output  V0 max. 2  A-V  that  thoroughbred  A-V  difference  DIFFERENCE horses in  IN  have  oxygen  OXYGEN the  CONTENT.  capability  content  by  at  to  Results increase  least  5-fold  108  between this  rest  scope  and  maximal  with  a  endurance-trained difference Rodahl, even  by  greater  should  be  In  The  than  (Manohar,  in  sustained  for  operating  a  23  in  at  values  attain  and Fahey,  oxygen  Lykkeboe  exercising  e_t  auL with  differences  reasons  able  but  ponies 1986).  i s available (1977) oxygen  No  study]. than  heavy  exercise  was were  beats/min.  horses  can bring  t o an a b s o l u t e  to  reach  than  value  t o p human  17 v o l % when  boost  their  1986).  in  be h i g h e r  1984; Manohar,  because values  found  could  to  capability level  stated  vol% i n this  o f 220-230  and Fahey,  (Manohar,  content  A-V  or i f the animals  to bring arterial  protocol,  animals  only  much h i g h e r  able  i f  content  1984; Manohar,  o f 22.4 v o l %  arterial but  a high  i s probably  F i g . 10). In comparison,  are  the  and  thoroughbred  i n oxygen  have  canter  that  rate  1984; A s t r a n d  o f 3.7% were  4.7  o f time  heart  (Brooks  2  were  period  (see  V0 max  can  protocol  A-V  for  values with  their  horses  here  approach  1986), b u t  alter  resting  differences  shows  ponies  t o such  study the  A-V  gallop  v o l %  and  difference  (Brooks  resting  study  Thoroughbreds  content  lower  difference  exceeding athletes  measured  maximal  Fahey,  true  than  longer  only  of thoroughbred  because  closely  (Manohar,  can  and  1986) c o m p a r e d  at their  A-V  running  5-fold  the  This their  (Brooks  maximum  measured  increase  athletes  scope  [also,  addition,  this  human  lower  previously ponies  4.5-fold  3-fold  1977).  e x e r c i s e . Ponies  1986).  their  arterial  humans  and  oxygen ponies  The thoroughbreds content  can only direct  A-V  of  t o 30.0 v o l % reach  maximal  measurement o f  f o r standardbred  saturated  venous  and showed  that  horses,  blood  of  i t h a d a n 0„  109  capacity the  of  same  reported  30  range here It  oxygen of  vol%. of  from  is  clear  that  elicited  by  about  increased work  from  change 40%  20  transition,  erythrocytes 1983),  hemoglobin trot  a  show  a  exercise  the  (Brooks showed  canter  exercise supply  to  in  A-V  between the  in  0  the  working  increased  cardiac  output  the  consequence  direct as  the  content  the  rest  to  number  of  (see in  changes same  hematocrit  total  spleen  the  arterial  oxygen  During  increase  RATE. more  Persson,  circulating  throughout  horses  have  than  the been  only  represents  This  change  (ET)  the  be  the  by  a  protocol  because (see  in  consumption  trot  the  A-V  Figs.  10  measured  response  between  2  achieved  accompanied  somewhat could  was  in  humans  Thoroughbred  in V0  Oxygen of  12-fold  1984).  musculature  output  Endurance-trained  increase  which  beginning  protocol  a  arterial  of  50%  Fahey,  difference.  2  as  in  ( F i g . 10).  in  of  animals.  in cardiac  content  increase  Indeed,  Hematocrit  12-fold  such  the  same  content  and  a  oxygen  show  3.  protocol,  for  increase  than  increase  2  was  11)  from  METABOLIC V0  large  third  protocols  i n Chapter  already  vol%  one  more  canter  the  (Fig.  released  4.4.3 can  30  concentration.  and  presented  to  therefore  horses.  exercise  60%  may  in  in hematocrit.  about  was  causing  to  horses  differences  thoroughbred  concomitant  went  A-V  for  content  a  Standardbred  between  low  horses rest  and  intensity  rate via  to  of  oxygen  a  3.2-fold  3.8-fold  increase  went (ST)  up and  slightly later  difference and the  12). two  No  in  in 0  2  change  stages  of  110  the  trot  protocol  (ST  Maximal reach  and  oxygen  approximately  an  A-V  difference  of  300  1/min.  70  kg)  can  than  Rowell,  much  of  23.4  60 body  body  mass  an  outstanding  aerobic  two  to  three  times  With trot canter V0  2  was  This  be  measured  difference  recruiting change  gait  at  energy  expenditure  would  the  for  45  V0 max.  Only  low  specific at  trot  because  muscle  body  than  to  given  the  VC^max  and  the the  difference  canter  (see  (see  1/min,  2  been  Hoyt  in  protocols.  switched  have  a  athletes.  a l l o w i n g them  speed  see  support  V0 max  animals They  humans  70  small  and  groups.  of  (more  to have  horses  human  of  6-fold  specific  50%  a  mass  a  rate  mass  output  mass;  With  expected  best  the  velocities any  kg  consumption  represent  body  with  athletes  thoroughbred  than  1/min)  be  a  would  cardiac  in top  1  1984).  with  the  70  (with a  f o r 70  capacity  between  different  -  metabolic  2  was  kg  - 1  Clearly,  55%  (or  1  a maximal  Fahey,  0^  -  thoroughbreds  humans  horses  maximal  would  would  and  higher  a  protocol  min  specific 1979).  kg  - 1  consumption  mass  Schmidt-Nielsen  of  v o l % and  ml  Brooks  in  min  trained  2  whole  lower  ml  V0 max_of  1974;  difference  consumption  156  exceed  41/min  ET).  to  gait,  shown  to  minimize  and  Taylor,  1981). With 5-fold  an  increase  thoroughbred 40-fold represent including  8-fold of  horses  between the  increase  their can rest  their  maximal  aerobic  horses  cardiac  difference  augment and  highest  standardbred  A-V  in  and  i n oxygen  oxygen  ponies.  found An  and  This in  a  content,  consumption  exercise.  scope  output  by  would  mammals,  equivalent  scope  Ill  in  the  delivery  muscles  may  of  changes  how  turnover chapter  be  rate of  this  rate  of  supported in  cardiac  during thesis.  oxidizable by  fuels  thoroughbred  output  exercise  to  the  working  horses.  The  problem  influence is  plasma  addressed  in  metabolite the  last  112  CHAPTER  5:  LACTATE  TURNOVER EFFECT  5.1  OF  exogenous  substrates able if via  to  and  regulate  the  right  the  IN  the  at  the  augmented  via  concentration  THOROUGHBRED  CARDIAC  HORSES:  OUTPUT.  is  lactate),  but  Indeed,  the  Verdonk  a^l,  et  however,  i t  output  have  metabolites these  plasma  (as  the have  of  on  entire an  concentration  of  and  1) by  speed.  To  meet  the  fluxes  can  be  level, 2  the  and  is  rate  i s taken  lactate  of  positively  (Chapter  changes  turnover  the  first  case  Hagenfeldt,  whether  effect,  the  to  been i n v e s t i g a t e d .  a _ l , 1972;  organism  their flow  i n the  concentration  shown  provided  increasing blood  several substrates  et  metabolites  increasing  never  be  be  by  Chapter has  must  i s to  whole-organism in  supply  endogenous  plasma  substrate  plasma  been  adequate  use  their  time  2)  one  Bortz  effect  changes  lactate  rate  never  when  the  second  1981;  an  and  seen  their  has  of  mechanisms:  turnover with  the  oxidizable fuels  plasma,  the  rates  exercise,  At  the  d e p l e t i o n . Organisms  appropriate  of  used  correlated  their  of  muscles.  mechanism  requires  minimize  flux  two in  work  to  mixture  blood  working  muscle  postpone  demands  If  CHANGES  fuels  energetic  the  EXERCISING  INTRODUCTION  Sustained of  IN  1975),  in  cardiac  of  plasma  into  relationship turnover  2;  account, between  rate  would  o  113  also  depend  on  cardiac  ouput.  This  provide  an  effect  has never  been  shown. Lactate control  of  metabolite  wider  range  (see  Chapter  exercise.  of  should lactate  case  output in rate  oxidation during  should  plasma  see  i s equal  et  under  a l l cells  through  muscles  i s not  across  cell  values  found  studied  Therefore,  up w i t h  to  lactate  lactate  exercise),  where  supply  and changes  on t h e r a t e  much  substrates  e t a l , 1981; Roos,  date 1975;  supply cellular  (as i ti s i n cardiac  of lactate  turnover  steady-state conditions,  turnover  of disappearance  and i n t o  a  the  easily  transport  in a l l situations  keep  to the rate  the r a p i d l y  and t o t h e r a t e  mixing  pool  of  of  lactate;  1984). Plasma  substrate  Koch  an e f f e c t  that,  from  Wolfe,  1978;  submaximal  have  (note  appearance  of  over  of other  by t h e h i g h  carrier  1976).  to study  vary  t o working  lactate  limited  can  model  they  the fluxes  lactate  Lehninger,  perfusion  because  indicated  Racker,  and be  as  lactate  and  Spencer  of  ideal  c a n be m a n i p u l a t e d  because  rapid  a l l the  (Dubinsky  the  supply  is  than  and they  limited  membranes  turnover  values  2),  The  diffusion  for  fluxes  in  lactate  some,  a l , 1986),  and  can  animals  i t srole  emphasized  by  Brooks  exercising  organisms  be  (Donovan during  (1985). gain  an  is  not  performance  transporting  lactate  at  compartment.  If  do, s p e c i e s g e n e t i c a l l y  performance,  like  they  the  high  and Brooks,  oxidizable 1983;  sustained exercise It  some  important  rates  thoroughbred  through  horse,  clear  Mazzeo  has  whether  advantage their geared  would  be  been  by  plasma for high expected  114  to and  have  the  ability  training  albeit  a  has  no  Lactate  lactate  cardiac from  output  the  athlete  of  and  other,  to  whether  throughout  a  5.2  bout  i f  the  metabolism  MATERIALS  AND  studies  ages  given  regular  turnover  fat  flow  in  data  assess  trained  values  addition,  measure  changes  to  the  animal  measured  in  I attempted  to  rate  exercise,  of  Brooks,  exercising  of  2)  in a  with  lactate  submaximal  decreases  as  would  oxidation  to  be  total  increased.  the  The  AND  CATHETERIZATIONS.  the  four  (Chapter  3  i n Table  training  previously.  and  In  of  and  using^blood  fuel  rates  and  in horses.  effect  4),  metabolic  contribution  on  previous  experiments,  rate  rats,  prowess,  therefore to  species.  ANIMALS  performed  are  measured  resting  (Chapter a  (Donovan  the  rates,  exercising  its athletic  was  in  turnover  METHODS  5.2.1 were  study  i t s flux  sedentary  investigate  predicted  as  In  rate  been  turnover  study  compare  for  to determine  lactate  lactate  more  energy  on  never  lactate  ability.  turnover  rates  1)  high  noted  this  flux  previous  importance  on  of  horses:  this  means  effect  goal  thoroughbred  no  turnover^ has  The plasma  sustain  enhance  s p e c i e s by  training 1983).  should  to  4  horses was four  thoroughbred  and  (see were  Chapter Chapter  kept  identical animals  on to had  horses  4). 3).  the what  Measurements  Their During  same has  used  in  weights the  diet  the and  present  and  their  been d e s c r i b e d  undergone  a  surgical  115  transposition  of  subcutaneous to  measurement  the  of  vessel  system  surgical  allowed  whenever  a  a  right  and a  placed  in  pressure  transducer  connected  to  were  keep  described  and  patent. i n Chapter  5.2.2 carried  (18  out  easy  had  X  The  46  cm)  lines the  was  using  neck  experiments for  to the  a  the  arterial  size a  8F  catheters  were  Detailed  catheterization  XRO  i n the 125  cm)  Medical  catheters  were  capacity)  which  filled  flushed  X  Kontron  2-ml  and  Vygon  introduced  Both  ( 1 0 0 cm,  a  collected.  (USCI,  108).  to  t r a n s p o s i t i o n of  access  t o be  atrium  (Model  to  the  measurement,  g  right  taped  lines  them  blood  extension  securely  Extension  relatively  artery  performed  rate.  cardiac catheter  the  before  procedures  turnover  catheter  carotid  months  turnover  arterial  intravascular carotid  common  several  lactate  Before  was  right  position  facilitate  this  the  with  every  saline.  10-15  min  procedures  to are  4.  EXERCISE  at least  3 h  PROTOCOLS. after  Experiments  the morning  feed.  were  Temperature  0 ranged 71%.  from No  earlier fitted of  fluxes and above  to  20 C  measurement than  30  with  resting  quietly  17  a  min  turnover  during  work,  the harness A  was fan  and  tied  turnover  a heart  stall. the  humidity  catheterization.  r a t e was  in a  relative  lactate  after  harness  standing  him.  of  and  rate The  was  while  was  brought  t o an emergency  simulating  a i r  started were  the animal of  was  lactate  the  treadmill  switch-off  mechanism  cooling  on  to  Measurement  For the determination  horse  53  animals  rate monitor.  performed  from  during  normal  116  locomotion  was p l a c e d Two  trot  at  and  exercise  6%  horizontal  incline canter  canter  protocols  lower  trotting  horse  (JW)  speed  of  trot  at  because  latter  for  JW  measurements  the (4  m/s)  every  30  longer  identical  lactate injection  not sustain  chosen  before  s during intervals  was  h e was a b l e t o to a canter at  from the  horses  a l l animals  of  were  of  was u s e d  over  were  Heart  been  continuous  before trot  and a t  metabolic  and  subjected to i n Chapter  TURNOVER.  and  short  recorded  experiment  horses  to determine  a  4 min  r a t e was  reported  OF L A C T A T E  1,  by a  basic  same  with  i nthe  ( 1 . 6 m/s)  followed  The  the  pooled  initiated  10 m i n o f e a c h  Chapter  at the respective  a 4 min walk  protocol.  MEASUREMENT  selected  cantering  different  the f i r s t  (see  40 m i n  significantly  e x e r c i s e p r o t o c o l s have  turnover  over  measured  thereafter.  technique  A  f o r the older  a higher  switching  and a 4 min walk  responses  horses.  the values  for  the canter  cases,  2 cases,  on t h e o t h e r  consisting  I n two  4 m/s  f o r IN b e c a u s e  these  not  and  m/s  to the trot  for individual  details),  In  study.  h a d t o be u s e d  A l l e x e r c i s e bouts  5.2.3 injection  was  data  protocol  cardiovascular  could  performed  period  trot  3 m/s  for  were  Therefore,  warm-up  he  identical  previous  and he h a d problems  IN  calculations.  the  of  velocity.  and  gaits.  m/s  s e l e c t e d : 1) a 4 m/s.  were  t o be a d j u s t e d  study  6.5 m/s  the  f o r 15 m i n . T h e y  speed  8.3  were  s u s t a i n a b l e f o r 40 m i n , a n d 2) a 6.5  had  previous  of the animal.  protocols  p r o t o c o l s ... o f  these  (see  i n front  The  the rate Wolfe, infusion  3.  bolus  o f plasma  1984).  Bolus  because the  117  infusion and  technique  i t  would  expensive  in  injection  (as  measurement of  have  such  much  made  a  larger  the  large  animal.  done  here),  placed  some  important  rates  that  could  because  the  done  the  to  present  quantify  the  when u s i n g  high  cost  infusion  the q u a n t i f i c a t i o n of l a c t a t e experiments.  contribution  of  isotope  Even  be m e a s u r e d  continuous  of  prohibitively  constraints  perform, in  amounts  experiments  was  turnover  addition,  requires  of a  single  the  number  on  i n each  was  bolus  horse.  In  too expensive  to  oxidation  could  not  be  Indeed,  i t i s not  possible  lactate  oxidation  to  total 14  turnover when  rate  (by  the bolus  rest  at  each  (R),  at  during  the  i n j e c t i o n technique  Separate horse  following  experiments  activity  the t r o t  rate  of  out  for  C 0  2^  i s used.  were  level.  the beginning  production  carried  Measurements  of the trot  protocol  ( E T ) , and  exercising  animals,  were  performed  protocol  during  each at  (ST), later  the canter  protocol  (C) . For injected 7 the  min  1 min into  canter  after  the beginning  t h e same protocol  measurement  of  protocol (C).  cardiac  the r a d i o a c t i v e of the trot  ( E T ) , and  The  output  same  protocol  7 min  timing  bolus  after  was  i n the previous  was  (ST),  starting  used  f o r the  study  (Chapter  14 4).  [U-  C]lactate  purchased (rest), injected  from  Amersham  140-220 into  uCi the  administered  in  was  with  flushed  (specific  a  (UK),  (trot) right  13-20 50  ml  activity and  and  atrium. ml  saline  =  doses  230-260 The  total  was  of  120-150  uCi  uCi  (canter)  were  labeled  solution,  s a l i n e . The  150 m C i / m m o l )  metabolite  and  the  was  catheter  procedure  (bolus  118  injection of  the  and  and bolus  after  was  the  determine  after  loss  At  cardiac  The  0.1-0.6%  of  activity  i n 6 s . The e x a c t  by w e i g h i n g  the  end  size  the syringe  before  o f t h r e e randomly  chosen  c a t h e t e r was w i t h d r a w n and c o u n t e d  w h e t h e r ... p a r t  flushing.  represented  was c o m p l e t e d  determined  injection.  experiments, to  flushing)  o f the b o l u s remained  activity  measured  of  total  the  was  not  i n the c a t h e t e r s only  doses  taken  i n the l i n e  injected,  and t h i s  account  i n the  into  calculations. Blood artery  samples  starting  approximately intervals during  10  every  s  collected  in  and  s  on  2  ice-cold  injection.  h  sampling in  7-ml  tubes  They  time  resting  acid  (10  (EDTA) was  min  were  taken  was 6 t o 20 m i n  a n i m a l s . Samples containing  were  0.07 ml  a s a n t i c o a g u l a n t and  measured spin).  the c a r o t i d  3 m i n and a t l o n g e r  vacutainers  i c e . Hematocrit  micro-hematocrit  were drawn f r o m  f o r the f i r s t  Total  ethylenediaminetetraacetic placed  ml)  after  10  thereafter.  exercise  (5  immediately  in  P l a s m a was s e p a r a t e d 0  from  the  counting  rest  of  Pye-Unicam  reduction All  sample  stored  a t -20 C b e f o r e  and g l u c o s e c o n c e n t r a t i o n s were m e a s u r e d on  spectrophotometer  of  NAD  +  or  NADP  +  t h e a s s a y s were p e r f o r m e d  details)  and  and m e t a b o l i t e a s s a y s . Lactate  a  the  within 1  3  volume  of  ml.  Isocap  300  quench  correction.  days  of  (SP6-500) at  nm  i n duplicate sampling  Scintillation  scintillation  340  by  f o l l o w i n g the  (Bergmeyer (see Chapter  with  a total  of lactate  2 for  cuvette  c o u n t i n g was p e r f o r m e d  c o u n t e r by u s e o f i n t e r n a l  The a c t i v i t y  1974).  on an  standard  was c a l c u l a t e d as  119  total  plasma  glucose.  activity  Glucose  described  activity  procedures  samples  (0.5  minus  ml)  the a c t i v i t y  was  determined  (see  Methods  mixed  with  measured  i n plasma  by use o f p r e v i o u s l y  in 10  Chapter ml  2).  aqueous  Plasma counting 0  scintillant for  (ACS  at least  ranged  resting were  65  even  always  after  to  2 h  activity  were  counted  No  i n the dark  f o r 20 m i n .  activity  injection  could  at 4 C  Efficiency  be m e a s u r e d i n  of the r a d i o a c t i v e bolus  experiments  by a minimum  could  left  on  t h e same  of 4 days  be m e a s u r e d  even  i n plasma  in  horse  though  no  or urine  24 h  Turnover  rate  injection. C A L C U L A T I O N S AND  calculated under  this  surface  as  the  2  not  improve  the  the  sum  only  function the  was  activity  by  the  total  of  blood  calculated  t h e sum  was  curve.  fitted  two  exponentials between  To  was  kg  calculated volume  body  horses].  specific  weight Metabolic  turnover  rate  used  t h e sum o f  described i n functions d i d  here),  and  0 and t h e time  activity  as the dose  [using  calculate  functions, therefore,  was  time  the surface  with  exponential  f i t of the calculated  blood  as  curve  d i v i d e d by  decay  of three  possible  maximum  per  injected  activity  the decay  integrated  maximum  thoroughbred  dose  STATISTICS.  f u n c t i o n by u s e o f t h e p r o c e d u r e  (using  of  the  specific  area  exponential  Chapter  of  82%.  separated  area  two  being  Successive  5.2.4 was  Amersham)  after  animals.  residual  a  12 h b e f o r e  from  glucose,  II,  t h e mean  measured  by  clearance divided  by  was  when  reached.  injected value  5% The  divided  o f 142.1 ml  Persson rate  this  (1968) i n (MCR)  plasma  was  lactate  120  concentration output  (Wolfe,  was  determined  interpolation  of  relationship.  This  (linear  whose  study to  output  a  overall  value  F  necessary. estimate  A  the  and  and  hoc and  and  to  Rohlf,  output  using  r e s u l t s of  the  from  JW,  each  KJ,  and  for  IN  equation  a  oneway  test  (T-Method 1981)  that  horse  SB  the were  (r=0.98)  output 7).  the  of  the  ANOVA  slopes  the  for  was  analysis  to  ANOVA,  to  calculated  multiple  in  to  in  determine by  regression  the  lactate  variability  used  the  was  performed  changes  was  when  analysis  was  total  and  unplanned  used  further  contributions  analyze  cardiac for  Rohlf  (Table  of  linear  with  regression  cardiac rate  vs  by  measured.  indicated  significance  Sokal  5.3  Sokal  turnover  regression  post  rate  cardiac  calculated  Data  compared  respective  concentration lactate  not  multiple  the  heart  regression  was  Student-Newman-Keuls see  4).  experiment,  rate  r=0.98-0.99)  were  comparisons,  mean  heart  (Chapter  Means  each  r e l a t i o n s h i p was  calculate  cardiac  For  from  the  regressions;  previous pooled  1984).  linear  model  (see  1981).  RESULTS  The concentration  lactate of  specific  lactate  activity  in  plasma  in  Fig.  decay  after  curves  bolus  and  the  i n j e c t i o n of  14 [U-  C]lactate  thoroughbreds experiments,  are  given  (KJ),  at  the  rest  calculated  and  13  to  during  multiexponential  15  for  one  exercise. functions  of  the  In a l l fitted  121  the  measured  activity at  specific  decreased  rest  (Fig.  activities  much  14),  more  extremely  sharply  particularly  well.  during  when  the  Specific  canter  considering  than  that  the  14 dose  of  [U-  less  than  lactate  half  canter  amount  11.2  Fig.  min  kg  trot  protocol  - 1  and  Plasma  lactate  levels  of  animal,  of  the  study. values  clearance  four  horses  of  the  protocol  protocol  at  - 1  min  same  was  rest kg  - 1  Values  the  was  canter.  The  13  25%  of  fitted  ( F i g . 13  and  during  the  - 1  51.3  and  45.2  beginning  of  the  protocol  steady  Fig.  the  animal  i n t e g r a t i n g the  the  was  a  was  trot  +_  lower  to  (Fig.  at  the  15)  and,  15).  different for  this  higher  during  exercise  each  animal  and  +  2.7%  to  a  for  rate,  147.5  at  (ST),  rate  a  than  animals) of  summarizes  cardiac  and  7  the also  plasma  output  and  heart  rate  average 132.7  +_ 9.0  at  the  130.0  _+  later  in  the  8.0  beats/min given the  increased 54.7  Table  hematocrit  The  each  rest,  +_ 9.6  N = 4) . F o r  which  as  lactate.  +_ 2.1  maximum  7,  experiment,  well  protocol  heart 4  each  as  and  for  Table  for heart  37.9  SEM,  (for the  in For  rate  (ET) ,  (means  hematocrit 36.2  during  at  rates  given  concentration,  beginning  of  during  (insets:  are  mean  metabolic  had  14).  turnover  this  the  lactate  JW  Fig.  concentration  state  results  same  umol  resting  rest.  activity  of  kg  - 1  42.3  concentration  Lactate  shows  the  after  measured  later  activity  mean  at  in  were  - 1  min  and  graph  in  administered  umol  14)  (bottom  umol  injected  r a t e s measured  were  graph  than  the  turnover  functions top  C]lactate  +  level other  from  0.8%  a  in of  the  exercise,  horses. resting  during  canter  the  Mean value canter  122  FIG.  13  Lactate  concentration horse  (KJ)  time the  0  injected sampled with  a  (inset) after  (experiment  first  5 into  from double  specific  min the the  in  plasma  injection No.  11).  after  activity  of See  decay  of  a  122.14 Fig.2  injection.  curve  and  resting uCi  for a  [U-  thoroughbred 1 4  C ] l a c t a t e at  detailed  Radioactive  right  atrium  at  time  0  carotid  artery.  The  decay  curve  exponential  function.  lactate  and  view  bolus b l o o d  was  of was was  fitted  fr  0MpOIAIr//IAIdd]  A11AIJL0V dS  124  FIG.  14  lactate horse  AND  15  Lactate  concentration (KJ)  at  rest  specific  (insets)  a c t i v i t y decay  in  and e x e r c i s i n g  plasma on a  of a  curves  and  thoroughbred  treadmill  during  the  14 first of uCi at  5  for  after  bolus  122.14  uCi  (rest:  (end  trot:  ET)  time  injection were  min  0  R ) , 169.14 and  251.02  (experiments and  fitted exercise  sampling with  No. sites  double  protocols  injection  and  uCi uCi  11 as  of  [U-  (start (canter:  to  14  in Fig.  exponential the timing  of  C]lactate. trot: C)  S T ) , 144.27  were  injected  respectively). 13. A l l d e c a y  functions.  Doses  Same curves  See methods  injections.  126  START  CO  TROT  O  ZT  1.0  10-  o  i  r  CL  i  r  4  V  >  • •  4  > O <  10-i  END  CL if)  TROT  1.0  5-  \  1  V.  r2  r  -i  4  MIN  127  TABLE  7.  LACTATE  CARDIAC  OUTPUT  EXERCISE  (CONT'D ON  EXPT  HORSE  OF  ACTIVITY STATE  No.  TURNOVER  RATE, LACTATE  THOROUGHBRED NEXT  HORSES  CLEARANCE AT  RATE,  R E S T AND  AND  DURING  PAGE).  SPEED  INC-  HEART  m/s  LINE  RATE  %  HCT  %  PLASMA [LACTATE] mM  b/min  -  -  38.8  44.0  0.80+0.02  (ST)  4.0  6  118.8  59.0  2.07+0.03  (ST)  3.0  6  118.0  55.3  1.47+0.03  JW  TROT ( E T )  3.0  6  108.1  57.6  0.74+0.02  5  JW  CANTER  6.5  0  122.3  53.5  1.89+0.08  6  SB  REST  -  -  43.3  35.1  0 . 8 3 + 0 . 02  7  SB  TROT  (ST)  4. 0  6  157.5  58.0  1.99+0. 09  8  SB  TROT  (ET)  4. 0  6  138.4  57.9  0 . 9 8 + 0 . 02  9  SB  CANTER  6. 5  0  146.3  56.6  1.2 5+0. 02  10  SB  CANTER  4. 0  6  175.3  58.2  3 . 5 4 + 0 . 07  11  KJ  REST  —  —  36.2  32.9  0.6 2 + 0.02  12  KJ  TROT  (ST)  4. 0  6  134.2  54.1  0 . 8 4 + 0 . 02  13  KJ  TROT  (ET)  4. 0  6  144.4  54.0  0 . 8 0 + 0 . 03  14  KJ  CANTER  6. 5  0  168.2  55.4  0 . 8 1 + 0 . 02  15  IN  REST  —  —  33.3  32.8  0 . 5 6 + 0 . 02  16  IN  TROT  (ST)  4. 0  6  121.2  49.0  0 . 7 2 + 0 . 02  17  IN  TROT  (ET)  4. 0  6  129.0  48.8  0.7 2 + 0.02  18  IN  CANTER  8. 3  0  153.1  53 .3  0 . 9 8 + 0 . 02  REST  1  JW  2  JW  TROT  3  JW  TROT  4  128  TABLE  7.  N  CARDIAC ml  (CONT'D).  OUTPUT  min-1 kg-1  TURNOVER RATE umol  (Rt) min-1  kg-1  METABOLIC RATE m  CLEARANCE (MCR)  l min-1 kg-1  20  116.5  12.2  15.3  15  367.2  127.8  61.7  13  364.8  115.4  78.5  19  333.7  34.9  47.2  17  378.1  71.7  37.9  23  153.5  7.3  8.8  11  542.3  85.5  42.9  18  477.2  70.4  71.9  17  504.2  95.2  76.2  276.2  78.0  14  —  25  106.0  11.2  18.1  14  451.2  51.3  61.1  19  487.2  45.2  56.5  19  571.1  42.3  52.2  23  107.0  6.5  11.6  19  417.3  51.3  71.2  17  444.9  50.7  70.4  19  529.7  55.1  56.3  Turnover rate was measured by bolus injection of [UC]lactate. ST: start of trot protocol; ET: l a t e r i n trot protocol ( s e e M e t h o d s ) . HCT = m e a n h e m a t o c r i t . L a c t a t e concentration given as mean + SEM; N = number o f b l o o d samples. Note that i n c a n t e r p r o t o c o l , s p e e d was h i g h e r f o r IN than f o r the other horses ( e x p t . No. 1 8 ) . I n e x p e r i m e n t No. 10, SB was cantering at abnormally low speed and struggling. Cardiac output was calculated by linear interpolation using data from p r e v i o u s study ( C h a p t e r 4; s e e Methods f o r d e t a i l s ) .  129  protocol. all  Plasma  the  experiments  reported  in  assumption  only  beginning  slightly  reached  about  the  2  highest  with  for  as  435.8 + 35.2  _+  2.0  61.5  +_  5.9  the  canter  ml  min  -  1  lactate  states  the  trot  (KJ  the  beginning  i n t h e same  animals.  levels and  1  at  second  part  of that  same p r o t o c o l  was  of  measured.  ranged  from  the trot  -  1  of the t r o t  the  cardiac k g  -  1  at  protocol  ( E T ) , and 495.8  63.4  protocol,  During 0.81 t o  Average  protocol  the  showing  +_ 11.2 m l m i n  rest,  were  IN) a n d  ( m e a n s +_ SEM,' N = 4) . M e a n -  lactate  (JW a n d S B ) . L a c t a t e  protocol.  120.8  k g  lactate  (JW a n d SB)  was  turnover  are given  at  beginning  F=8.1;  the  Mean  +  and  MCR  was  7.7  (ST) and  55.7  + 7.9 i n  protocol.  value  exercise  two  concentrations  canter  (ET) d u r i n g  resting the  the other  errors  injection  i n resting  animals  individuals  at  later  the  Mean activity  in  the bolus  protocol,  two  throughout  13 t o 1 5 . T h e  experiment.  a t the beginning  same  37.3  during  +  in Fig.  t o 0.83 mM  during  a l l animals  (ST),  13.5  for  the  443.9  41.6  for  lactate  rest,  +  0.56  lower  mean  values  output  i n each  steady  low s t a n d a r d  f o r IN w h e r e no d i f f e r e n c e  canter, mM,  mM  the  r e q u i r e d by  the trot  (ET) t h a n  except  1.89  of  was  trotprotocol  from  elevated  concentration  (ST),  state  ranged  by  the insets  t h e r e f o r e met  concentration the  shown  7 and by  steady  was  c o n c e n t r a t i o n was  as  Table  of  technique  At  lactate  of  9.3  P<0.005).  in Fig.  umol  of the trot  on t u r n o v e r  r a t e was  Post  hoc  rates  min  -  for  16. T h e y 1  k g  -  protocol.  1  the  ranged  show  from  t o a maximum The o v e r a l l  highly significant tests  different  that  a low  o f 75.9  effect  of  (3 d f / 1 2 d f ;  lactate  turnover  130  FIG.  16  Lactate  thoroughbred rest;  ST:  protocol; details.  turnover  horses. start  C:  Values  of  trot  during  the  rate given  in resting are  protocol; canter  means  ET:  +  later  protocol.  and SEM  exercising (N  during See  =  4).  the  methods  R:  trot for  131  I  I  80 60 40 20 -  R  ST  ET  1  C  13 2  FIG.  17  plasma  Relationship lactate  horses.  =  =  horses: and  r  squares  triangles  lactate  concentration  thoroughbred 59.02,  between  Line  fitted  0.80). D i f f e r e n t (JW);  (IN).  solid  in by  turnover  resting linear  symbols  circles  rate  and  and  exercising  regression  represent  (SB); open  mean  (slope  individual  circles  (KJ);  133  150 H  2 LACTATE  mM  134  TABLE  8.  OUTPUT  ON  EFFECTS THE  RATE  OF  PLASMA  LACTATE  OF  LACTATE  TURNOVER  REGRESSION  %  MODEL  CONCENTRATION  OF  AND  IN THOROUGHBRED  CARDIAC HORSES  THE  VARIABILITY IN  R  EXPLAINED BY  MODEL  R  fc  = f ( [LAC] )  0.80  64  26.5  <  0.001  R  fc  = f(CO)  0.58  34  7.6  <  0.05  R  t  = f([LAC],  0.87  76  21.7  <  0.0001  Linear 17; rate; ANOVA  CO)  regressions  experiment  No.  [LAC] = p l a s m a was  equations  used were  probabilities  were  performed  10 was  not  lactate  to determine  the data  included).  R  concentration;  different  above].  from =  CO  whether the slopes  significantly  (P) a r e g i v e n  on  from  Table  lactate = cardiac of the 0  7  (N =  turnover output.  regression  [F v a l u e s  and  135  rate  was  significantly  exercise  protocols  different  E T ) . Mean  the  trot  (ET),  velocity  than  gait  placed  much  higher  than  and  he  umol  3.5  conditions, min  -  k g  1  -  1  line  effects cardiac Table  and  was  slope=59.0,  fitted  34%  was  lactate multiple  output of  throughout  protocol  normally  against rate  a t 6.5  plasma  a  was m/s,  lactate  experiment.  turnover  low  trying to  pushing  the  of  a t P=0.05. I n  h e was  steady  of lactate  least  Under  reached  highly  276.2  the  also  concentration regression,  and  rate  in  cardiac  their  regression:  analysis  of the and  i s summarized  in  plasma  and c o u l d  in  lactate  explain  64% o f  The e f f e c t o f changes i n  significant  variability  17.  concentration  changes  rate.  lactate in Fig.  (linear  lactate  significant  turnover  i s given  regression  turnover of  plasma  squares  plasma  lactate  was  rate  complete  in  in  between  turnover  by  effect  variability  cardiac for  on  The  concentration the  but  (ST  a t an u n n a t u r a l l y  cantering  mM  A  changes  output 8.  t h e same  o f h i m . H i s mean h e a r t  high  lactate  r=0.80).  of  during  a  not  a t the beginning  by c o n s t a n t l y  horses  h i s rate  was  protocols  not s i g n i f i c a n t  relationship  concentration  higher  cantering  front  rate  .  The  The  in for  of  turnover  later  was was  f o r the d i f f e r e n t  (4 m / s ) . I n a d d i t i o n ,  maintained  concentration  was  than  the treadmill  rail  these  (ST)  than  (C) a n d t h e t r o t  turnover  difference  for this  Mean  canter  10, t h e a n i m a l  faster  metal  lactate  the  experiment  go  the  protocol  but  at rest  (P<0.05).  between  and  lower  but could  turnover output,  combined  only  rate. were  effect  account  When  both,  used was  in a  highly  136  significant lactate  and  could  turnover  explain  rate  (Table  76%  8).  of  The  the  variability  coefficient  of  in  multiple  2 determination addition to  (R  of  the  simpler  shows  regression  5.4  Table  single  see  Sokal  that  a  the  the  second model  and  Rohlf  1981,  in  lactate  (1 d f / 1 4 p.  cardiac  df;  634).  output  increase  lactate  the  variable  using  variable  significant  variability  by  independent only  i n c l u s i o n of a  increased  This  in  the  in  the  turnover  rate  8).  DISCUSSION.  the  study  rate  of  measurements racehorses  lactate  of and  shows  concentration  reported  for  particularly for  invasive  carried  out  of  isotope  the  turnover turnover  on  rate rate  the  and  horses  because  four  could  correlated  in  the  thoroughbred  correlation  rate  of  first  between  plasma  lactate  2. very  experiments, animals  the  the  the total  be  expensive  racehorses  only.  for  only  is  provides  fluxes  turnover  are  required  output  also  positive  thoroughbred  limited  It  lactate  in Chapter  Because  cardiac  turnover.  confirms  tuna  that  plasma  lactate  used  as  independent  caused  of  This with  output  a  model  determination  significantly  regression  as  P<0.025;  analysis  (see  was  cardiac  concentration F=6.8;  )  In  to  are  present  measurement  measured  not  study  addition,  number  keep,  of  four  the  and  commonly had high  of  to  be  cost  lactate  experiments; times  in  each  137  animal  under  large  animal  carried to  different  out  treadmills in this  maintain  time  and  available  AS  7-fold  lower  than  50  (15  is  found  (45-50  umol  in  min  1  e_t  a_l,  (see  closely their  (Issekutz Lactate  min by  min  ;  the  2)  and  OF  of  PLASMA  a  5 to  the  mean  caused  rate  over  kg  1  This  "*") ,  value  but  considering  and  is  horses  min  are  range  of  et  turnover  compared  with  mammalian  mass  rates kg"  1  similar  a_l,  rates  other  1  to  intensity 1985;  on  a  6-fold  turnover  f o r t h e same w o r k Stanley  such  the  umol  a g a i n s t body  standard  ROLE  2  kg  1  running  see  amount  V0 max  66  1  expensive  horses,  (trot)  -  studies  In thoroughbred  kg  humans  are  total  AND  2 ) . The  in  of  few  limiting.  (see Chapter  1  very  S t a n l e y e t a_l ( 1 9 8 5 ) f o r  when .  i s presented  the  also  mass  kg  - 1  Chapter  a  and found  log-log  species,  pattern expected  i t for  size. At  is  umol  1 9 8 6 ) . When  matches  body  reported  the  RATE  55%  umol  in exercising min  was  turnover  9.3  here  thoroughbreds  plot  over  body  treadmills  Therefore,  to  expected  measured  values  Mazzeo  of  humans  in  up  Finally,  f o r the type  FUEL.  lactate  rate  umol  (canter)  in  the  difference of  of  rate  discrepancy  such  TURNOVER  OXIDATIVE  exercise  flux  resting  operate.  LACTATE  increase  resting  and  f o r t h e ^ p r e s e n t work  AN  submaximal  conditions.  are available  thesis,  to  5.4.1 LACTATE  exercise  rest,  oxidized et  aj^,  oxidation  about i n rats 1976)  fifty  percent  (Donovan and  and  of  the  Brooks,  i n humans  i s r e s p o n s i b l e f o r 13  (Mazzeo to  20%  lactate 1983),  turned i n dogs  e_t a _ l , 1986) . of  the  oxygen  138  consumption  of  (1985)  Mazzeo  V0  in  2  a  and  a resting  rats  similar  et  al  thoroughbred for  by  lactate  rate  only  7%  lactate  of  5  ml  of  lactate  min  oxidation be  of  total  value  than  use  striking  during  Brooks,  1983)  from use  the  in  Stanley an  (from  e_t  a_l,  Donovan to  study  (continuous  and  quantify because  infusion  50.%  is  is  resting  a resting  100% o f  f o r humans,  V0 max,  the  in  rats  lactate  to  the  bolus  If  necessary  80%  of and  the  same  same  12%  to  exercise (calculated  1986)  and  lactate  Unfortunately,  injection  the  decreases  2  oxidize  oxidation  in  thoroughbreds,  V0  humans u s e  1983).  rate  (Donovan  in  to  For  2  2  e v e n more  to  1986).  oxidized  V0  V0  b u t a much  are  75  2  and Mazzeo e_t a_l,  lactate  c a n be  2  i n t h o r o u g h b r e d s would  oxidation  their  the  V0  fuel  2  Brooks,  in  an o x i d i z a b l e  V0 max),  65% o f  oxidized  differences  horse.  1985,  If  Interspecific  flux  lactate  50-60%  if  (Mazzeo e_t a_l,  cantering  astounding  impossible present  of  a  (i.e.  lactate  1983).  c o n t r i b u t i o n of  oxidized  and i n humans  of  the  found  At  is  resting  a mean  and  even  consumption  as  is  e t aJL  -1  that  estimate  lactate  contribution  intensity  oxygen  rate  the  resting  kg  oxidized,  exercise.  turnover  4.5%  Note  rate  (using  -1  min  in rats).  of  lactate  only  ).  lowest  relative  the  - 1  Stanley  39% of  their  oxidation  umol  t u r n o v e r was  (the  percentage  9.3 kg  - 1  to  14%  lower  of  and f o r  turnover  . turnover  from  from Donovan and B r o o k s ,  of  horses,  [calculated  (1986)]  (calculated  fraction  accounted  human  alone  it  directly technique  rats  was  in was  when o x i d a t i o n has  the used  to  be  14  quantified  by  collection  previously,  infusion  would  of have  C 0  2'  been  b  far  u  t  '  too  a  s  explained  costly  in  such  139  large  animals).  measured  here  metabolism  was  would  cantering plasma  However,  to oxidation, this  only  account  lactate  as  the  above  substrate  only  compared  with  necessary  to  i f 100% o f t h e l a c t a t e  going  thoroughbred  horses,  even  horse.  an  Even  though  oxidizable  fuel  calculations  plays  a minor  other have  f o r less  than  role  during  of  lactate  6% o f VO^  in a  the contribution  of  i s  in  clearly  mammalian  direct  pathway  turnover  significant show  that  submaximal  species,  and  exercise  i t  o x i d a t i o n measurements  this  is  t o draw  not this  conclusion. Resting kg  -  have  1  (Anwer umol  been  -  k g  1  available  maximally  to  80%  -  (1971)  flux  the  for the -  in  exercise,  1  25%  of  canter :  3  i t  carbohydrates  [assuming  times  trained is  at  the  clear  o_r_ e n d o g e n o u s  turnover mammals  pattern  rest a  rate  a n d 50  kinetics  turnover  value  rest  of  a n d a t 50% of  supplies can only  and f o r about  glucose  on  ( i . e . 50% and  contributions  glucose  12  no d a t a a r e  the glucose  combined  At  that  glucose  1  horses  can reach  i s oxidized at rest  resting  horses].  and  min  i s o x i d i z e d depending  If  exogenous  VC^  umol  but  i n other  mammalian  the  and  7  horses  1971),  of glucose  rate  of ponies  Trained  (Evans,  standard  turnover  lactate  k g  1971).  1985).  respectively),  account  untrained  E x e r c i s e causes  (Brooks,  glucose  exogenous  1  work.  rates  i n c r e a s e by 2 t o 3 - f o l d  follow  VC^max,  min ' '  in  rest  of the total  of  during  at  1  intensity  horses  -  measured  during  to  80%  turnover  e_t a ^ l , 1 9 7 6 ; E v a n s , min  work  glucose  s u b s t r a t e s must  o f 36  reported  and d u r i n g  exogenous  1 0 % o f VC>2  fuels play  by  umol Evans  submaximal other  than  a major  role  140  in  oxidative  amino  ATP  acids  probably  is  use  muscle  fat  that,  from  in  as  a  resting  the  important  suppressed  training  by  could  may very  be  an  observed (Snow could  increase  during  a_l_, 1 9 8 5 ) ,  be  very  intensities turnover unusual  on  than rate  indicates  that  much  protocols. measured umol  min  able  to  higher  in 1  kg reach  in 276  this et  a l , 1983),  energy  min  the  fat  rates  Stanley  trained min  at  10  horses.  to  during of  ejt aJL  kg  - 1  has  (1985)  at  a  under section)  and  flux  canter  disappearance  only  Here,  lactate  lactate  trot  lactate  horses  exercise  Results  the  been  increase  high  boost  A  utilization  measured  - 1  A  oxidation  may  The  that  during  higher  (see  subjects. - 1  Horses  kg  ability  observed  umol  that  study. 1  was  thoroughbred  animals.  umol  R^  horses.  triglyceride  present  same  fuel  in exercising  in  the  indicating  standardbred  suggests  becomes  in  oxidizable  oxidation  the  have  by  increase  exercise  highest  1  However,  experiment  than  humans  is elevated.  these  in  suggesting  glycerol concentration  lactate  in  they  The  in  during  oxidation  i n d i c a t i n g that  276.2  conditions  of  1981)  for  horses  0.98  carbohydrate  also  after  used of  Fregin,  trained  i n plasma  high  reliance  in  source  and  and  substrate  to  of  horses  standardbred 0.83  important  evidence  e_t  their  rates  of  important  large  an  oxidizable  of  that  (Thomas  exercise  kind  rate  shown  remain  high-intensity different  state,  when work have  value  contribution  thoroughbred  untrained  (Thomas  untrained  the  minor,  major  of  exercise  Because  be  their  investigators  fat  to  The  high-intensity  more  likely  work.  increases  production.  SB  reached was  230  already  relatively  low  141  plasma  lactate  highest 11  concentration  human  values  were  of  3.5  measured  mM  at  (Expt.  10)  while  concentrations  of  the 9  to  mM. The  rate  decreases  exercise to  present  throughout  is sustained,  progressively  substrate Plasma down  for  free  carbohydrate prolonged  exercise  function  showed  - 1  et  largest  A  and  lactate  turnover  submaximal humans  reliance  have upon  (Holloszy  e_t  concomitant therefore  work.  shown  fat  as  a  1986)  .  and  decrease  be  As  been  a_l,  increases  The  about  during MCR  goes  in  plasma  expected  rate  concentration  during  the  in  rats,  thereby  has  the  trot  protocol  i n man  (Stanley  therefore  plasma  found  Endurance  i n c r e a s i n g MCR  in  70%  lower  training  for  but  a  (Donovan  given and  higher 55.7  ml  as  to  of rate  than  the  Exercising support  plasma has  a  humans  the  higher  ability  a  the  r e s t i n g MCR  a_l, 1 9 8 5 ) .  the  with  concentration  observed  i n humans,  et  to MCR  . The  and a  in  was  have  turnover  humans.  changes  a l , 1985)  value  At  -  decreased  been  the  than  lower  rate  clearance  rest  kg ''').  -  of  et  between  min ''"  half  lactate  to  pattern  Stanley  horses of  ml this  intensity  Metabolic  increase  63.4  (canter),  reported  thoroughbred  4.5-fold  same  work  CLEARANCE,RATE.  to  a l _ , 1986;  was  measured  given  a  (13.5  .  of  (Mazzeo  of  concentration  would  LACTATE  intensity kg  horses  acid  that  exercise.  protocol  -  dogs,  metabolism  turnover  (MCR)  min "'"  bout  their  exercise.  5.4.2  trot  rats,  energy fatty  suggests a  increase  throughout  rates  study  lactate  been  turnover Brooks,  a  shown rate 1983).  142  The  higher  reflect  MCR  shown  the h i g h l y  5.4.3 TURNOVER  horses.  of animals  and  Issekutz  e t a_l, 1976),  1986),  glucose and  and  shown  of  goes could  to  rate  a_l_  disappearance  is  relationship  showed  (1985)  between  reported that  influences  concentration.  mass  by  to  working  directly  i n humans. glucose  has  and  their  override  (Jenkins an  muscles  mass  plasma  of  these  in  the  should  f o r any  muscles.  Indeed,  rate  of lactate by  contradictory  on  where  the  suggest action  be  plasma  an rate  e_t a_l_, 1 9 8 6 ) . T h e s e  results the  their  effect  and t u r n o v e r  effect  1972)  r e l a t i o n s h i p s . The  however,  concentration  of  Hagenfeldt,  controlled  Some  rates  et a l ,  as  i n these  that  1974;  (Mazzeo e t  1967;  action  in  observed  a_l,  flux  (Bortz  concentration  be  e_t  The  observed  observed  insulin  can  2).  plasma  e_t a _ l , 1 9 8 1 ;  humans  Issekutz,  metabolism  recently  relationship,  the  substrate  for  1983),  to .increase  uptake  concentration  available  been  explain  seems  and  A simple  of oxidative  e_t  (Okajima  a _ l , 1981) , g l y c e r o l  up.  cellular  proportional  lactate  (Chapter  been  also  metabolites  Stanley  tuna  (Paul  the  ON  correlated  (Eldridge  (Davis,  acids  and  r e l a t i o n s h i p has been  seals  fatty  concentration  given  even  CONCENTRATION  positively  dogs  et  have  rate  1983),  simply  animals.  rate  including rats  (Verdonk  free  1975)-  Brooks  therefore  METABOLITE  are  T h e same  may  of these  turnover  lactate  Donovan  al,  PLASMA  The  of  number  condition  OF  RATE. '  thoroughbred a  trained  EFFECT  concentration  in  by t h o r o u g h b r e d s  slope that  effect  plasma evidence inverse has  also  authors of the hormonal  of  glucose  143  Most on  substrate  et  a l ,  of  that  Issekutz's  data  the  his  1984).  suggest  of  by  total  whole  organism  is  turnover  results  agree  Issekutz well  et  known  rate  not  rate  in  It  the  exactly  rates  (Fig. 2  to  IN  in large  OUTPUT.  that  the  the  and  lactate  other  effect  of  changes  increase  in  the  output  is  8).  of  of  at  These  studies in  (in  output  (see  cardiac  particular  lactate turnover). cardiac  this  concentration  data  case  played  that  Table  investigated  This  role  cardiac  (see  i f  understood.  shows  of  by  thoroughly  turnover  fluxes,  caused  Issekutz,  substrate  kinetics  the  CARDIAC  in  plasma  relationship  which  more  fully  flux  matched  the  lactate  the  be  lactate  i n v e s t i g a t i o n of  specifically  a _ l , 1976 that  on  plasma  with  paragraph) was  first  is  blockade.  changes  is  CHANGES  independent  versus  ouput  OF  elicited  concentration.  concentration  be.studied  the  (1984)  rate  lactate  the  on  Issekutz  affects  is  that  beta-adrenergic  flux  fluxes  level.  with  correlation  next  the  perfusion  correlated  in must  EFFECT  represents  of  Hetenyi  depends  l a c t a t e turnover  protocol  metabolite  and  i n plasma  pattern  (see  showed  rat hindlimb  by  effects  information  (1986)  epinephrine  changes  effects  5.4.4  a_l  plasma,  in  that  metabolism limited  et  the  in  fluctuations  control  study  via  complex  Hormonal  but  abolished  experimental  concomitant  by  increase  was  glucose  Challiss  insulin  the  indirectly  Indeed,  the  of  i n v e s t i g a t i n g hormonal  review)  lactate.  exercise  by  a  with  lactate production  reported  rates  studies  deal  for  for  concentration  by  the  fluxes  1983  available rate  of  It  is  elicited  144  by  exercise  goes  1984).  Therefore,  effect  on  fact, also  the  the be  Challiss  et  utilization  turnover  by  in  flux  increase the of  in  1983;  cardiac  oxidizable  must have  an  l a c t a t e to these muscles.  In  probably that  with  be  d e p e n d s on  blood  recent glucose.  of  glucose  flow at  Furthermore, i n the  e_t a _ l , 1 9 8 6 ) , and by  only  absence of  this  perfusion provides  rest  glucose  glucose concentration  o u t p u t not  substrates  for  rate  mediated  muscles,  true  exercise  plasma  should  o u t p u t , and  the  contractions.  Jenkins  could  contracting  is  rat hindlimb  change  in  output  Fahey,  a l l plasma m e t a b o l i t e s  showed  increases  rate  of  this  isometric  Donovan,  cardiac  ( B r o o k s and  by c h a n g e s i n c a r d i a c  (1986)  the  rate  significant and  rates  that  a_l  during  in  d e l i v e r y r a t e of  influenced shows  the working muscles  changes  turnover  evidence  and  to  a  (Brooks  adjustment changes.  An  more o x y g e n  to  but  i t also accelerates  the  supply  to  meet  the  energetic  demands o f  for  the  r e l a t i o n s h i p between  exercise. The lactate range  concentration depending  conditions.  This  interspecific the  in  Issekutz  e_t  the  exercise in  on  reported and  turnover  the  animal  variability  differences  e f f e c t of c a r d i a c  ignored  when  slopes  but  kinetics  lactate  t h a n when v a r y i n g  resting  dogs  (Fig.  4  on  over a very the  be p a r t l y a c c o u n t e d f o r more i m p o r t a n t l y ,  studies. the  slope  concentrations  For was  Issekutz  by by  been  instance, much  higher  were e l i c i t e d  amounts o f N a - l a c t a t e in  wide  experimental  l a c t a t e f l u x e s which has  (1976) showed t h a t  different  and  a l s o , and  o u t p u t on  metabolite a_l  can  rate vary  were  by  infused  e_t a _ l , 1 9 7 6 ) .  Their  145  results rate  can  be e x p l a i n e d  on t u r n o v e r Why  lactate  but  and  to  a  Racker,  would  i t  Lehninger, on  intracellular these  occurs-by  Koch  muscle  that  The  of  (mainly  transfer  diffusion:  s e e Dubinsky and  1975; a n d S p e n c e r a n d  rate  of  lactate  local  During  may  occur  A  high  i f lactate  than  i t  blood  flow  are maintained,  i s  i n these  therefore  extra-  and  dissipation  i s oxidized  supplied  thereby  membranes i s  carrier-mediated,  exercise,  CONTROL  by  of  faster i n surrounding  vessels  would  maximizing  probably  cardiac control  metabolite others.  do to  not  Because equally  ensure  the rate of  plasma allow  Augmenting  increase  oxygen.  Changes  allow  the  cardiac  plasma a  SUPPLY.  finer,  influence the  dependent  on  can  be  flux  turnover  of  affecting output  metabolite  perfusion  viewed  as the  rates.  These  an  individual  the fluxes  therefore  of oxidative  specific  Both  of a l l plasma  metabolite  i n the supply in  FUEL  the fluxes  adjustments  be a l t e r e d w i t h o u t  overall  hand,  output for  EXOGENOUS  lactate concentration  turnover.  are  adjustments  OF  and plasma  lactate  changes,  other  by s i m p l e  cell  fluid.  output  substrates  the  diffusion  across  influence  translocation.  cardiac  coarse  transport  between  5.4.5  rate  of perfusion  output  gradients  gradients  lactate  cardiac  e t a_l, 1981; Roos,  cells  capillaries.  in  concentration  gradients  the  Lactate  1975).  depends  changes  lesser extent  1978;  when t h e e f f e c t  i s considered.  turnover?  rapid,  easily  of a l l  causes  an  f u e l s as w e l l  as  concentration,  adjustment  on t h e  f o r the flux  146  rate  of  each  individual  concentration metabolite each  therefore  flux  rates  oxidative  contribution production supply  fuel  of can  finely  glucose  free  rates  would  during  fatty be  endurance  performers  turnover  rates  when  mammals,  increased  ability  skipjack rates species at  a  lactate  that  from  with  higher  of equivalent much  lower  turnover of  size,  several  mechanism  this  other  the skipjack  lactate exercise  rates  to  Chapter lactate  of 2,  flux  operates  10°C).  and because  t o be a c c o u n t e d  tuna  an  their  sites  teleost  species  than  f o r a mammalian  (approximately  i s known  "good"  across  In  be e x p e c t e d  as  turnover  d o n o t show  o f plasma  are high,  some  such  high  turnover  mammals.  to  time.  sustainable  production  though  energy  shows t h a t  compound  a range  of tuna  conditions,  of  even  respective  lactate  horses  this  would  turnover in  at  of  f o r endurance  support  higher  other  temperature  this  oxidation  experimental  than  rates  thesis  thoroughbred  i s shown t o h a v e  is  high  not n e c e s s a r i l y  sites  rate  fuels  adapted  of  for  provided  oxidizable  work. T h i s  have  this  lactate  animals  transfer  compared  tuna  proportion lactate  to  The  at the r i g h t  to support  tuna  but  compartment  utilization  other  operating  skipjack  sedentary  plasma  do  control  the supply  via  If  acids,  steady-state  intensities:  of fuels  expected  fine  separately.  regulated  over  The adjustment  to overall oxidative  CONCLUSIONS.  advantage  the  i t allows  t o be a l t e r e d  performance  exercise  because  combination  5.4.6  fuel.  represents  individual fuels be  the right  or  exogenous  under  i s very  Because a  large f o r by  different likely  to  147  be  able  and  to  support  lactate  i s probably  species.  Therefore,  provide  evidence  athletes"  could  In  contrast,  of  thoroughbred  for  high  prefer  mammalian  minor in  of role  as an o x i d i z a b l e  represents  less  submaximal substrate lactate higher  than  work, in  as  that,  differences  a  fuel  by  in  kinetics  ability  to  exercise.  in  on t h i s  fuel  fat  horses.  oxidizable  be  rats.  fuel  measurements  major  low  other  large  lactate  required  f o r the " e l i t e "  Chapter at  a  during  oxidative  contrast  results  plasma  plays  utilization  These  oxidize  only  last  metabolite  by  of  rates  i n the  consumption  preference  not  this  shown  mammals,  do  metabolism  the  This  values  energy  of  i s i n sharp  substrate  among  lactate  oxygen  rates  turnover  i t i s shown  oxidation  horses  exercise  f o r muscle  could  fuels.  the metabolic  lactate  plasma  of t o t a l  exercising  even  lactate  necessarily  5%  and  that  not  animal  the expected  for  higher  do  turnover  Therefore,  horses  in this  oxidizable  within  The  exercising  reliance  particularly fact  horses.  "elite  other  In a d d i t i o n , work  that  well  species.  mammals.  thoroughbred  over  fuel  study  the l a c t a t e  sustain  the present  idea  oxidation,  tuna  that  thoroughbred  sedentary  chapter  fall  lactate  oxidizable  the  the  lactate  horses  include than  from  5 shows  of  of plasma  important  against  adaptations the  an  results  Chapter  sedentary  rates  of  with  the  species,  but  emphasize  the  interspecific are present.  The  5  the  high  performance  show  that  rates of  i s not  endurance  148  A  positive  concentration  and  both  studied  species  correlation system, wider  and  of  show  lactate  have effect  an  than  o f more  slopes  and  and  turnover on  the slope  not been  recognized  relationship  in can  output  changes  output  and  for  the  earlier be  explained  is  taken  metabolite turnover  in  adjustments  i n cardiac  output  represent plasma  the  coarse  metabolite  and  i f the e f f e c t  turnover.  and  influence i t  is  i n metabolite  controls  with is  output  Differences versus  4  lactate  in cardiac  this  i n the turnover  of lactate kinetics  plasma,  fine  plasma  Because  much  Chapters  correlation  account.  this  reported for  r e l a t i o n s h i p , but  concentration  metabolite  a  this  concentration  into  covers  correlated  Changes  in  non-mammalian  from  between  easily  2,  also  previously.  studies  in a  Results  of this  lactate  Chapter  previously  that  rate.  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