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Histamine receptors in rabbit atria Polanin, Alicia 1979

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HISTAMINE  RECEPTORS I N RABBIT  ATRIA  by  B.Sc.  (Pharm.),  A THESIS OF THE  A L I C I A POLANIN University of B r i t i s h  Columbia,  SUBMITTED I N P A R T I A L F U L F I L L M E N T R E Q U I R E M E N T S FOR THE DEGREE OF MASTER OF S C I E N C E in  THE F A C U L T Y OF GRADUATE S T U D I E S D i v i s i o n o f Pharmacology and T o x i c o l o g y of the F a c u l t y of Pharmaceutical Sciences  We  accept t h i s t h e s i s as conforming to the required standard  THE  U N I V E R S I T Y OF B R I T I S H D e c e m b e r , 197 9  ©  Alicia  COLUMBIA  P o l a n i n , 1979  1976  In p r e s e n t i n g t h i s  thesis  an a d v a n c e d d e g r e e a t the L i b r a r y I further for  agree  the U n i v e r s i t y  make  it  freely  thesis for  written  It  of  J  for  I agree  r e f e r e n c e and copying of  that  not  copying or  this  ~^LJ  for  that  study. thesis or  publication  be a l l o w e d w i t h o u t  2k  A .fs 1  requirements  t h e Head o f my D e p a r t m e n t  is understood  The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook P l a c e Vancouver, Canada V 6 T 1W5  the  B r i t i s h Columbia,  by  financial gain shall  of  permission.  Department  Date  of  that permission for extensive  representatives.  this  fulfilment  available  s c h o l a r l y p u r p o s e s may be g r a n t e d  by h i s of  shall  in p a r t i a l  my  ABSTRACT  In (H^  order  o r  i n  exposed i n  t h e  t o  t o  r a b b i t  r a t e  (H^  and  o f  o f  h i s t a m i n e  i s o l a t e d  H2)  »  t h e  r i g h t  h i s t a m i n e  a t r i a  C i m e t i d i n e  H^)  antagonized  of  4 - m e t h y l h i s t a m i n e ,  h i s t a m i n e ,  a z i n e  pretreatment  t i v e l y  b l o c k e d  had  e f f e c t  no  on  The  a l l  a g o n i s t s .  b l o c k e d and  t h e  f o r c e  r e s p o n s e s  o f  i s o l a t e d  C i m e t i d i n e  i n o t r o p i c  i m p r o m i d i n e ,  and  and  e f f e c t s had  no  t o  pretreatment  r e s p o n s e s  t o  h i s t a m i n e  r e s p o n s e s  t o  4 - m e t h y l h i s t a m i n e  t o  r e c e p t o r  was  e f f e c t s Promethc o m p e t i -  and  o r  o r  impro-  i n c r e a s e d  by  4 - m e t h y l h i s t a m i n e ,  response  b l o c k e d had  but  c o m p e t i t i v e l y  h i s t a m i n e , t h e  a t r i a l  blockade)  h i s t a m i n e ,  pretreatment  PEA,  on  b l o c k a d e )  a t r i a  on  (H^) .  e f f e c t  2  o f  c o m p e t i t i v e l y  and  h i s t a m i n e  4 - m e t h y l h i s t a m i n e  l e f t  o f  by  i m p r o m i d i n e .  e f f e c t s  and  a n t a g o n i s t s .  c h r o n o t r o p i c  r e c e p t o r  e f f e c t  Promethazine  H  were  alone  impromidine  l i t t l e  p o s i t i v e  c h r o n o t r o p i c  the  m i d i n e . f o u r  v e r y  ( s e l e c t i v e  t h e  r e c e p t o r  and  r e c e p t o r s  p r e p a r a t i o n s  a g o n i s t s ,  ( s e l e c t i v e  c o m p e t i t i v e l y  h i s t a m i n e  i n c r e a s e d  ( I ^ ) ,  pretreatment t h e  was  had  o f  a t r i a l  r e c e p t o r  4 - m e t h y l h i s t a m i n e (PEA,  types  i s o l a t e d  s e l e c t i v e  2 - P y r i d y l e t h y l a m i n e r a t e .  a t r i a ,  s e l e c t i v e  presence  The  c h a r a c t e r i z e  no  t o  t h e  i n o t r o p i c  e f f e c t  i m p r o m i d i n e .  PEA.  The  on  t h e  phospho-  -4 d i e s t e r a s e i n o t r o p i c (1  x  1 0  i n h i b i t o r but  - 4  M ) ,  Histamine  (1  not  the  t h e o p h y l l i n e  (3  c h r o n o t r o p i c  impromidine  (1  x  10  _ 8  x  10  M)  e f f e c t s M)  and  p o t e n t i a t e d  of  PEA  t h e  4 - m e t h y l h i s t a m i n e . (1  x  10"'4M) .  _5 x  10  M)  exposure  f o r  20  seconds  d i d  not  a l t e r  the We are  cyclic  AMP  levels  of isolated  r e p o r t t h a t both types present  cannot  histamine cyclic  reports  receptor  AMP.  (H^ and E^)  i n rabbit right  confirm  rabbit right  and l e f t  of histamine atria.  atria.  receptors  However,  (Hughes,1978) t h a t b o t h  agonists  and l e f t  I  and  act through the generation  of  iv  TABLE.OF  CONTENTS Page  ABSTRACT LIST  i  OF T A B L E S  i v i  L I S T OF F I G U R E S  v i  INTRODUCTION  1  1.  History  1  2.  Discovery of histamine receptor a g o n i s t s and a n t a g o n i s t s  3  METHODS  10  1.  Preparation  of tissues  2.  Rate and f o r c e r e c o r d i n g  10  3.  Depletion  11  4.  Studies  of catecholamines  of responses  receptor  10  agonists  5.  Measurement  6.  Studies  7.  Cyclic  8.  Analyses  9.  Preparation  histamine  and a n t a g o n i s t s  11  o f pA2  with AMP  to  12  theophylline.  13  assay  '  and s t a t i s t i c s  15  of drugs  16  RESULTS 1.  17 Chronotropic right  2.  responses  of rabbit  atria  17  a.  Cumulative dose-response  b.  Effect  of histamine  Inotropic responses to  histamine  Cumulative  b.  Effect  curves  receptor  17  antagonists  of rabbit l e f t  receptor  a.  agonists......  dose-response  of histamine  curves  receptor  20  atria  antagonists  c. pA studies The e f f e c t o f t h e o p h y l l i n e on t h e c h r o n o t r o p i c and i n o t r o p i c r e s p o n s e s to histamine r e c e p t o r a g o n i s t s 2  3.  13  37 37 4-9 58  .....63  V  Page a.  4.  E f f e c t s o f t h e o p h y l l i n e on a t r i a l r a t e and f o r c e development  63  b.  E f f e c t of t h e o p h y l l i n e (3xlO M) on t h e c h r o n o t r o p i c r e s p o n s e s t o histamine receptor agonist i n the r i g h t a t r i a  63  c.  E f f e c t o f t h e o p h y l l i n e (3xlO~ M) on t h e i n o t r o p i c r e s p o n s e s t o histamine receptor agonists i n t h e l e f t a t r i a . ....... ... •  68  - l 4  4  The e f f e c t  of histamine  cyclic  concentrations.  AMP  on  atrial 68  DISCUSSION  84  BIBLIOGRAPHY  95  vi  LIST  OF  TABLES Page  Table  I.  The on  effect cyclic  of AMP  histamine concentrations  83  vii  L I S T . OF  FIGURES Page  Figure  1.  The  effects  agonists Figure  2.  The  on. a t r i a l  effects  pranolol  3.  The  effects  pranolol  Figure  4.  The  effects  pretreatment response Figure  5.  The  pretreatment  Figure  6.  The  7.  The  effects  azine  Figure  8.  The  of reserpine  the  or  propranolol  25  on  the  or  propranolol  chronotropic 27  o f c i m e t i d i n e and  response  on  the  to histamine  of cimetidine on  pro-  the  and  of cimetidine  pretreatment  chronotropic  response  on to  .29  p r o m e t h - ."  chronotropic  to 4-methylhistamine  effects  methazine  pro-  chronotropic  of reserpine  pretreatment  response  on  or  21  t o 4 - m e t h y l h i s t a m i n e . . . . 23  pretreatment  chronotropic Figure  response  the  the  to histamine  of reserpine  on  pro-  t o PEA  effects  methazine  response  on  or  to impromidine  effects  response  18  of reserpine  pretreatment  chronotropic  .  rate  pretreatment  chronotropic Figure  of histamine receptor  and  31 pro-  the impromidine..  33  v i i i  Page Figure  9.  The  effect  of promethazine  treatment response Figure  10.  The  Figure  11.  The  the  on  rabbit  effects  Figure  12.  The  Figure  13.  The  effects  Figure  14.  The  Figure  15.  The  effects  The  of  atria...  38  of reserpine on  the  or  propranolol  inotropic  response 41  of reserpine on  the  or  propranolol  inotropic  response  on  43  reserpine the  or  propranolol  inotropic  response 45  of reserpine on  the  or  propranolol  inotropic  response  PEA  47  effects  prometh-  inotropic 50  o f c i m e t i d i n e and  p r e t r e a t m e n t on  response  the  and  to histamine  effects  azine  of cimetidine  p r e t r e a t m e n t on  response 16.  force  impromidine  azine  Figure  contraction  effects.of  pretreatment to  the  4-methylhistamine  pretreatment to  receptor  histamine  pretreatment to  35  of histamine  left  pretreatment to  chronotropic  t o PEA  effects  agonists of  on  pre-  the  prometh-  inotropic  to 4-methylhistamine  52  ix  Page Figure  17.  The  effects  azine  p r e t r e a t m e n t on  response Figure  18.  The  of cimetidine  to  effect  19.  The  pA  right Figure  20.  The  Figure  21.  The on  inotropic 54  o f p r o m e t h a z i n e • and on  cimetidine  the response  to-PEA  value f o r cimetidine  i n the  atria  pA  left  2  prometh-  impromidine.  pretreatment Figure  the  and  2  59  value f o r cimetidine  i n the  atria  61  effect  of reserpine  the chronotropic  pretreatment  response  to  theophylline... . Figure  22.  The on  effects the  64  of reserpine  inotropic  response  pretreatment to  theophylline Figure  23.  The  effect  24.  The  effect  25.  The  effect  26.  The  effect  inotropic  response  response  the  to impromidine  72  the  t o PEA  o f t h e o p h y l l i n e on response  the  t o 4 - m e t h y l h i s t a m i n e . . . . 70  o f t h e o p h y l l i n e on  chronotropic Figure  response  o f t h e o p h y l l i n e on  chronotropic Figure  66  o f t h e o p h y l l i n e on  chronotropic Figure  56  74 the  to 4-methylhistamine  76  X  Page Figure  27.  The  effect  inotropic Figure  28.  The  effect  inotropic  of theophylline response  the  to impromidine  of t h e o p h y l l i n e response  on  t o PEA.  on  78  the 80  xi  TO MY MOTHER who h e l p e d  make t h i s  day  possible  xii  ACKNOWLEDGEMENTS I  am v e r y  grateful  t o Dr. J.H. M c N e i l l  advice  and encouragement throughout  thanks  t o D r . R.L. R o d g e r s  writing expert  of this technical  thesis,  this  for his  study.  f o r h i s guidance  special  during the  and t o B e v e r l y Wenkstern  contributions.  I owe  valuable  for her  1  INTRODUCTION  1;  History Histamine  thesized to  [5-(2-aminoethyl)-imidazole]  i n 1907  by Windaus  be a n a t u r a l c o n s t i t u e n t  amine  has been  most,  i f n o t a l l , mammalian 100  shown t o be  than  lung  and dog g a s t r i c mucosa Its  first They  discovered  some  that  species.  (Best  t o over  reported  et a l . ) .  Hist-  amounts  ranging  in  from  50 y g / g i n g u i n e a p i g  (Vugman a n d R o c h a  e Silva,  e f f e c t s on t h e mammalian  the overall  syn-  i t was  t i s s u e s i n amounts  i n blood  pharmacological  (1910,  1966).  tissue  1911,  were  1919).  e f f e c t s of histamine  varied  In the guinea p i g bronchiolar c o n s t r i c t i o n  the main e f f e c t • but i n other  vascular have  o f o u r body  i n v e s t i g a t e d by D a l e and L a i d l a w  between was  ng/ml  I n 1927  first  distributed i n varying  less  system predominated.  a direct stimulatory  species  t h e e f f e c t on t h e  H i s t a m i n e was  a c t i o n on c a r d i a c  also  found  to  contraction i n  species. The  between  peripheral vascular  species.  arterioles and  and Vogt.  was  capillaries  important  i n d o g , m o n k e y a n d man  species  The  Histamine produced  a strong  i n r a t and r a b b i t , a s l i g h t  dilation  I n most  effects of histamine  histamine  caused  i n the peripheral  vascular aspect  varied  contraction  contraction  (Dale  also  and  i n the c a t ,  Laidlaw,  a generalized  of  1929).  dilation  of  organs.  effects of histamine  of the " t r i p l e  were  response"  found  first  t o be  an  reported  by  2  Lewis  i n 1927.  Lewis  tions  of histamine  of  small blood  to  a direct  blood  caused  that  a red  local  spot,  v e s s e l s , f o l l o w e d by  a c t i o n of  v e s s e l s , and  spread  observed  dilation  the  drug  succeeded  on  neighbouring  was  a l s o found  due  to  a wheal  the  finally  of  cutaneous local  the  a flush  arterioles  dilation  formation  w a l l s of by  injec-  fine  due  through  due  to an  wideaxon  reflex. Histamine in  the  dog  and  cat  considered  t o be  production  and  acidity. with  Rosengren, In pheral  the  acid  ( I v y and  guinea  on  Trendelenburg positive  p i g , cat  altered  by  1920).  Today h i s t a m i n e  stimulus to  gastric  gastric  of pepsin Bachrach,  secretion is  acid  juice  of  high  i s also increased 1966;  Kahlson  along  and  1968).  of histamine  direct  stimulate gastric  s e c r e t i o n of  output  c o n t r a s t to the  recently.  effects  and  competitive  the  heart  and  systems, the  have been  studied  peridirect relatively  as  the  effects  had on  were  not  norepinephrine stores with reserpine,  norepinephrine  and  the  chronotropic effect  atria,  with dichloroisoproterenol,  g a n g l i o n i c blockade  chronotropic  organ  on  (1960) showed t h a t h i s t a m i n e  rabbit  h a n d , L a h e r and  of histamine  other  inotropic  depletion of  antagonism of  other  i t evokes  potent  v a s c u l a r s y s t e m and  effects  a  a very  I n man  that of  (Popielski,  to  w i t h hexamethonium.  M c N e i l l (1979) were a b l e  inotropic  effects  on  cat a t r i a  or  On  the  to block  the  with  large  _3 concentrations antagonist  of histamine  p r o p r a n o l o l (1 x  ( 1 x 10 _7 10 M).  M)  by  the  3-adrenoceptor  3  2,  • D i s c o v e r y • o L h i s t a m i n e - r e c e p t o r a g o n i s t s , and a n t a g o n i s t s :  Bovet  Histamine  blocking activity  was f i r s t  and Staub  i n 19 37  selectively  amine t o x i c i t y  when t h e y  i n guinea This  pigs  demonstrated by  by a p h e n o l i c  observation  started  blocked  ether  (compound  929F).  histamine  s y n t h e s i s and t h e two a n t i h i s t a m i n i c  hist-  derivative  the era of anticompounds  phenbenzamine and p y r i l a m i n e m a l e a t e were i n t r o d u c e d f o r clinical highly 1946) in  use (Halpren,  effective  associated  d i d not prevent  lactic or  the inotropic heart  and  Muschek, In  by  i n asthma  i n anaphy-  (Yonkman e t a l , 1946) of histamine  1960; A s h and S c h i l d ,  of histamine  f o r t h e observed  suggested  on  1966; M c N e i l l  that  of receptor.  which  proposed  t h e name  by t h e known a n t i h i s t a m i n i c  actions of histamine  and g a s t r i c  acid  may  discrepancies i n the antihist-  I n 1966, Ash and S c h i l d  receptors blocked  that there  receptor present  secretion,  on i s o l a t e d  compounds. atria,  w h i c h were n o t b l o c k e d  t h e known a n t i h i s t a m i n e s , were m e d i a t e d  type  symptoms  or u r t i c a r i a but  pressure  and c h r o n o t r o p i c e f f e c t s  one t y p e  activity.  uterus  hayfever  i n blood  1948, Folkow e t a l . f i r s t  They c o n c l u d e d rat  developed  1972).  would account  for  the f a l l  (Trendelenburg,  more t h a n  aminic  rhinitis,  other  (Loew e t a l ,  antihistamines alleviated  shock, t h e bronchospasm  the  be  allergic  Later  (Yonkman e t a l , 1 9 4 6 ) were  I n man t h e s e  with  e t a l , 1944).  antagonists, diphenhydramine  and t r i p e l e n n a m i n e  t h e U.S.A.  they  1942; Bovet  through  a  second  In  1972  Black  e_t a l . d i s c o v e r e d  pounds t h a t b l o c k e d mediated name E^ the by  through  the  f o r these  and  gonists  Schild  to  be  cimetidine,  second type  receptors.  clinical  amide and E^  of  and and  the  (Wood a n d  et  F  a c t i v e as  be  This  a very new  be  be  too  receptor  activa2  new  2-Methyl-  agonist  and  receptor  agonist receptors. Durant  2-(2-pyridyl)ethylamine  (PEA)  receptor  was  s t i m u l a t i o n and receptors.  have r e p o r t e d and  c o m p o u n d was  specific found  to  be  13%  Very  impromidine histamine  is  receptors.  were d i s c o v e r e d .  in stimulating  potent  that  i n s t i m u l a t i n g E^  agonists  that  E^  meti-  competitive  in stimulating  histamine  Later  Burimamide,  4-methylhistamine.  histamine  anta-  toxic  d i s t i n g u i s h e d by  specific  for  histamine  to  also demonstrated  could  Owen e_t a l . ( 1 9 7 9)  92676) t o  agonist.  1973).  and  receptor  some s p e c i f i c i t y  recently  Simkins,  i s a highly selective  a l . (1975) r e p o r t e d  had as  other  inhibit  synthesized  1973).  as  Later  a n t a g o n i s t , was  Simkins,  about  a c t i v e as  the  metiamide.  (Wood a n d  is a relatively  as  be  receptor  and  histamine  i s 43%  E^  specific  2-methylhistamine  4-Methylhistamine  first  proved  receptors  a c t i v e as  gave  be  compounds  16%  and  to  drugs d i d not  latter  his colleagues E^  The  receptor  antagonists  Black  and  .  c i m e t i d i n e appear to  receptor  tion  use  receptor  were b u r i m a m i d e and  r e p l a c e m e t i a m i d e , as  for  thought  com-  w h i c h were p r e v i o u s l y c h a r a c t e r i z e d  discovered E^  of  T h e s e new  (1966) as  a l s o an  s e r i e s of  actions of histamine  actions of histamine Ash  to  the  a new  E^  e v e n more  (SK  £  receptor potent  5  than histamine  in stimulating  receptors  (Durant  et a l ,  1978). Recently to  contain  a number o f  either  parations  contain  histamine  receptor  specific actions  H-^ of  receptor large the of  or  H  or  H  tissue preparations receptors,  2  both types has  histamine  agonists  s t i m u l a t i o n because of  fact  that  receptor  the  pharmacological  classical  activities.  adrenergic  and  anaesthetic  local  1974c; Douglas, There all  m e c h a n i s m and type.  There  involved McNeill  and  which are  of  1960;  preof  reputedly  antagonists. ascribed  Some  to  by  This  fairly  may  be  due  to  exhibit a variety their  anti-  anticholinergic,  activity  Trendelenburg,  enough  information  of H  2  are  (Dews and  M c N e i l l and  AMP)  levels  1 9 7 5 , 1976 ; 0 y e ,  2  by  one  mediated  anti-  Graham, Verma,  ( K u k o v e t z and  receptor  that  state type  by  nucleotides  It i s believed  through H  increased  are  cyclic  response mechanism  Verma, 1978).  available to  mediated  receptors  i s evidence that  (cyclic  McNeill,  that  with  use  blockade  also possess  receptors  mediated  associated phate  of  i n the  type  shown  1975).  i s not  responses  their  other  The  In a d d i t i o n to  they  1949;  and  antihistamines  activity,  Dutta,  the  antagonist.  histaminic  1946;  by  have been m i s t a k e n l y  amounts o f  s t i l l  of receptors.  been r e v e a l e d  receptor  2  and  have been  may  that  of  another be  Poch,  1972;  responses  stimulation  are  cyclic  adenosine-3',5'-monophos-  (Klein  and  Levy,  1975 ; T e n n e r a n d  1971;  Verma  McNeill,  and  1978a).  6  These  effects include cardiac  1974;  Verma  and M c N e i l l , 1 9 7 7 a ) ,  contraction (McNeill of  histamine  induced  and  cytolysis  antagonists  of the heart.  found  t o vary  histamine  with  rabbit  histamine left type.  H^  types  5  increased On pairs,  suggested  types  have  of the heart  been  being  characterized p i g heart  o f t h e New.  1978).  and p a p i l l a r y  as  Zealand  They f o u n d  that  m u s c l e , w e r e o f t h e H-^  s t i m u l a t i o n also produced i n the right  , receptor AMP  the other  the  tissues including  i n the guinea those  agonists  regulating the inotropic action i n the  response  cyclic  cell-  receptor  2  (1977a) having  ( M c N e i l l and Verma,  i n the right  and n o t  of T  of cardiac receptors  began t o d e f i n e  a positive chronotropic H2  and H  and t h e p a r t  and M c N e i l l  receptor  only  (Lich-  in. various  types  species  ventricle  chronotropic found  The  receptors  atria,  secretion  f r o m human l e u k o c y t e s  i n v e s t i g a t o r s t o study  present  receptor  predominantly  acid  of  inhibition  of specific  receptors  Verma  force  and W o l l i n , 1977),  1975), and i n h i b i t i o n  has enabled  those  white  cardiac  eta l ,  ( P l a u t e t a l , 1975).  availability  examined.  Soil  a n d SRS-A r e l e a s e  of histamine  the  1974b;  and G i l l e s p i e ,  The  increased  (Verma and M c N e i l l , 1 9 7 7 a ) , g a s t r i c  and Verma,  tenstein  a c c e l e r a t i o n (Reinhardt  atria,  and they  effect.  receptors  were  were a s s o c i a t e d  with  They a l s o  s t i m u l a t i o n was  showed  that  associated  only  with  levels.  h a n d , Hughes  that  atria.  a positive  b o t h H,  (1978),  and H  using  receptor  rabbit  atrial  activation  "7 7  lead  to  increased  measure  cyclic  conclusion with  the  H£  AMP  was  papaverine  the  the  et  concluded mediated  the  through  force  Langendorff  These  phosphodiesterase cardiac  the  of  the  guinea  in  calcium  e f f e c t s of  both  H^  pig  influx  correlate  well  an  et  rat  rat  cyclic  left  inhibition by  may  that  be  with  be  (1974)  in  hearts  cardiac the  perfused and  increase  with  They  elevating  by  McNeill produced  reserpine  mechanisms o t h e r  responsible  for  the  in  the  prethan  theophylline. calcium  theophylline.  atrium,  from the  AMP  atria  suggest  in  not  al.  increase  a without and  may  Furthermore, Martinez  findings  left  direct effects  theophylline  McNeill  can' p r o d u c e  a b o l i s h the  of  the  methylxanthines  i n guinea pig  i n the  action  the  p o s i t i v e i n o t r o p i c e f f e c t of  in  and  phosphodiesterase.  Later,  i s evidence that  mechanism of that  to  not  phosphorylase  e f f e c t s produced  There  Her  pretreatment  theophylline  that  inhibit  technique..  theophylline  treatment.  and AMP  (1977) were a b l e with  not  hypothesis.  s u c h as  did  AMP.  contractile  the  to  action  cyclic  cyclic  found  pig heart  theophylline  of  however, d i d  that  chronotropic  methylxanthines  showed t h a t  levels  observation inhibitors  the  abilities  that  support her  a l . (1972)  and  relative  She  agonists.  i s o l a t e d guinea  their  on  potentiated  receptor  levels.  levels to  based  McNeill, of  AMP  phosphodiesterase  papaverine and  cyclic  was  i s involved Scholz  (1971)  theophylline,  mainly  due  e x t r a c e l l u l a r space  to  an  concluded as  seen  increase  during  excitation  caused  by an enhancement  o f membrane  permeability 2+  to  calcium.  ion  that  displaces  phylline  mcrease  studies  m  uptake  likely  that  Mn  , an  the e f f e c t s of theo-  Kukovetz and Poch  (197 2)  guinea p i g a t r i a ,  across  the c e l l  concluded,  that  an  membrane i s t h e  of the positive inotropic action of and M c N e i l l  to calcium  a c o r r e l a t i o n between  (1977) a l s o  involvement  postulated  on t h e r a t l e f t since  they  atria  could not  t h e c o n t r a c t i l e and t h e c y c l i c  effects of theophylline. Hughes  zole  and  o f Ca  showed  , inhibits  the effect of the methylxanthines  find  as  Ca  on i s o l a t e d 2+  Martinez  may b e a s c r i b e d  AMP  bound  mechanism  theophylline. that  and Scholz(1969) 2+  on peak t e n s i o n .  from t h e i r  most  Meinertz  (1978),  i n h e r study  a s t h e E^ r e c e p t o r  t h e H-^ r e c e p t o r Black  analogs  agonist  agonist.  used  and 3-(2-aminoethyl ) t r i a z o l e  However,  e t a l . (1972) suggested  are not very  selective.  H^ a n d E^ r e c e p t o r  agonist  increase  rate  i n atrial  that  Durant these  e_t a l . ( 1 9 7 5 ) two  histamine  B o t h compounds have  properties.  that  2-(2-aminoethyl)pyra-  Hughes  Therefore,  some  the  ( 1 9 7 8) a t t r i b u t e d t o  H-^ r e c e p t o r  s t i m u l a t i o n may h a v e b e e n  E^ r e c e p t o r  stimulation.  , i n part,  also  due t o  Because o f t h e d i s c r e p a n c i e s , i n r e s u l t s d i s c u s s e d we d e c i d e d present study  t o r e - i n v e s t i g a t e the type  i n the isolated  right  and l e f t  the i n t e r a c t i o n of histamine  theophylline.  Finally,  biochemical  of histamine rabbit atria,  receptor studies  agonists  above  receptors and t o with  t o determine the  9  involvement  of c y c l i c  r e s p o n s e s were c a r r i e d  AMP  in  out.  and  receptor induced  10  METHODS 1.  Preparation of White  (+  0.5)  Purina  kg  used  minutes  on  the  and  were q u i c k l y  2.1  2  C.K.  solution  oxygen and atria  the  in a  C.K.  Rate  A  resting  the  were  the  by  a  sharp  carotid  performed  (i.p.) blow  and  and  the  placed i n Chenoweth-Koelle 1946)  5.6  of the  mM;  mM;  2  and  left  volume t i s s u e  cut  gas  right  atria  away.  bath  10  The  of  by  95% tube.  the  were atria  containing  com-  mM.  glass  ventricles  (C.K.)  mM;  mixture  sintered  the  and  was  a  2.2  2  d-glucose,  with a  away f r o m  following  CaCl 2H 0,  through  tissue  at  animals  the  separated, were oxy-  35° C.  force recording  widest  fine on  dioxide  The  2.5  They r e c e i v e d The  cutting  oxygenated  excess  buffer  and  The  placed  KC1,  dissected  2 0 ml  libitum.  by  NaHCOg, 19.2  carbon  f a t and  genated  mM;  was  study.  weighing  They were k i l l e d  Koelle,  Levey(1971).  suspended  through  5% were  method o f  2.  mM;  the  sex  8 mg/kg i n t r a - p e r i t o n e a l l y  e x c i s e d and  120  of either  T h o r a c o t o m y was  (Chenoweth and  MgCl 6H 0,  and  ad  sacrifice.  blood vessels.  NaCl,  The  water  exsanguinated  position:  The  throughout  Chow a n d  before  head  solution  2  rabbits  w i t h h e p a r i n sodium  30  jugular  Zealand  were  Rabbit  injected  hearts  New  tissues  portions  of  individual  atria  hooks t o a p l a t i n u m e l e c t r o d e . o p p o s i t e end  tension of  1.0  gm  of each was  of the  applied  A  atria  t o each  were  attached  Palmer  clip  was  for recording. of  the  11  preparations  and kept  equilibration electrically frequency double atria  period.  driven with  the threshold  3.  and f o r c e  Depletion In  catecholamine  before  atria  were  stimulated  left  atria  beating  was u s e d  right  were a l l o w e d  to  t o use o f drugs.  s o l u t i o n was c h a n g e d e v e r y  at  During  5 minutes.  f o rrecording  the atrial  of contraction.  of  catecholamines  an a t t e m p t  reserpine;  The s p o n t a n e o u s l y  a t 35°C f o r o n e h o u r p r i o r  the bathing  the left  5 m i l l i s e c o n d s q u a r e wave p u l s e s  A G r a s s M o d e l 7 9D p o l y g r a p h rate  later  a G r a s s M o d e l S6 s t i m u l a t o r a t a  voltage.  and e l e c t r i c a l l y  time  by r e a d j u s t i n g d u r i n g t h e  Ten minutes  o f 1.0 H z . w i t h  equilibrate this  constant  t o minimize  release  the indirect  some r a b b i t s w e r e p r e t r e a t e d  1.5 m g / k g i . p . 2 7 h o u r s ,  sacrifice.  effects of  Some  atria  were  with  a n d 0.7 5 m g / k g i . p . 3 h o u r s challenged  with  tyramine  -4 ( 1 x 10 4.  M) t o c h e c k  Studies  f o r completeness  of responses  t o histamine  of catecholamine receptor  depletion.  agonists  and  antagonists When t h e p r e p a r a t i o n s amine and i t sa n a l o g s curves  were o b t a i n e d  response described was u s e d  curves  were  were  studied.  i n the right  i n the left  stable the effects of  atria  Chronotropic  one c o m p l e t e  r e s p o n s e s were assumed  dose-response  atria  and i n o t r o p i c dose-  using  the cumulative  b y Van Rossum a n d Van Den B r i n k f o ronly  hist-  (1963).  dose-response  t o have o c c u r r e d  curve.  method  Each t i s s u e Maximal  when a t h r e e - f o l d  12  higher  dose t h a n the  increase they  i n the  preceding  response.  were added t o  the  a d d i t i o n of  5.  Measurement of  the  the  employed  receptor  to  vitro.  The  molar  dose of  dose  of  pA  Arunlakshana would a  be  molar -1  pA  to  and  log  cimetidine that  of  that  to  study  left  of  the  10  2  a  the' n e g a t i v e  same p A  e f f e c t s of  10  carried receptor The of  out  1 x  Schild,  to  for  types of  effect  a  of  similar  against  can  a in  logarithm  values.  2  1959)  According  the double  to receptors  Furthermore, the  negative  which y i e l d s  compare  i n the  agonist  the  right  a  log  slope  of  affinity  of  u s e d was  atria  with  histamine.  c i m e t i d i n e were used  and  1 x  10  M.  release  M.  Sequential  were p e r f o r m e d  In  s e r i e s i n c r e a s i n g doses  In the  .  curves one  used,  i n each  The atrium,'  —5 M,  catecholamine  10  to  site  -7 propranolol  -1)  antagonist  —6 3 x  further  antagonism.  concentrations  M,  the  s i n g l e dose.  the  the  was H  as  dose r a t i o  atria.  —6 x  a  prior  antagonists  (1959) t i s s u e s w i t h  give  (agonist  of  and  characterize receptor  of  Schild  f o r the  the  following  2  affinity  which reduces  indicates competitive pA  s o l u t i o n 30 minutes  (Arunlakshana  2  also to  concentration  A  1  of  antagonist  expected  p l o t of  bathing  i s defined  agonist  produce  pA2  and 2  to  When b l o c k i n g a g e n t s w e r e  q u a n t i f y the  site,  failed  agonist.  Measurements be  one  .  C.K.  the  to  minimize  buffer  contained  .  histamine  i n each t i s s u e with of  order  dose-response  washing  in  blocking agent,  between. cimetidine,  13  were added. carried  A parallel  series with  out t o c o n t r o l f o r t i m e - r e l a t e d changes  sensitivity antagonist tissue.  of the tissues.  T h e pA^  mean + S.E.  6.  Studies  with  Separate  values  and combined  had reached  returned  to a basal  level  study  was a g a i n  due  level,  was a d d e d  state  were  done by  o f a histamine  C.K.  right  level,  buffer.  the i n i t i a l  and l e f t  When t h e  t h e t i s s u e was  After the atrium  a sub-maximal  concentration  dose o f t h e h i s t a m i n e  administered.  hist  administering  analog.  a n d when t h e r e s p o n s e  The a d d e d  reached analog  change  a  of steady  under  i n response,  t o e a c h o f t h e a g o n i s t s , was p l o t t e d a n d s t a t i s t i c a l l y  compared t o t h e combined 7 .  on i s o l a t e d  a steady-state  the oxygenated  theophylline  as  e f f e c t s o f t h e o p h y l l i n e and  studied  submaximal c o n c e n t r a t i o n  washed w i t h  p l o t t e d and expressed  theophylline  A series of experiments  response  i nthe  a t each dose o f  r r  were t h e n  amine a n a l o g s were a l s o atria.  The ED , v a l u e s 50  a g e n t was a l s  w e r e p l o t t e d a n d t h e ~pA^ w a s c a l c u l a t e d f o r e a c h  the  a  no b l o c k i n g  Cyclic  AMP  Tissues tongs  assay were  (Wollenberger  nitrogen, maximal  effects of the agonists.  frozen  with  Wollenberger  et a l , 1960), p r e v i o u s l y c h i l l e d  2 0 seconds  i n liqui  following the administration o f a sub-  concentration  were r a p i d l y r e m o v e d  by c l a m p i n g  of histamine  ( 1 x 10 ^ M ) .  from t h e t i s s u e bath  The  and dropped  atria into  14  liquid  nitrogen.  -80°C u n t i l was  A l l samples were  assayed  measured  f o r cAMP.  using the  Becton  subsequently  Cyclic  AMP  stored  content  Dickinson Cyclic  at  of the  AMP  atria  radio-  125 immunoassay k i t  I.  is  for cyclic  highly  the  specific  This  k i t c o n t a i n s an AMP.  ^ +  . Hapten  Tissues body  T  were  of  sample.  hapten sites  hours  f o r the  f o r the thereby  The  sample o r  standard.  Following  Cyclic The  the  to the  the  supernatant  was  which  available  hour  an  by  i s present  The  in  labeled binding  hapten  bound  bound w i l l  c e n t r i f u g e d and  tissue  bound  the  the  to  be  i n the  precipitating Next  anti-  equal  i n c u b a t i o n p e r i o d the  c o m p l e x was off.  the  antibody  labeled  w i t h ammonium s u l p h a t e .  decanted  has  c o n c e n t r a t i o n of hapten  18-20  hapten-antibody  I and  competes w i t h  radioactivity  f r a c t i o n s were s e p a r a t e d  molecules  AMP  antibody  amount o f  of  I-Antibody  hapten  number o f  level  related  pitated  and  reducing the  inversely  hapten  + 4°C.  Hapten  u n l a b e l l e d hapten  limited  antibody.  free  at  standard  The  Hapten-Antibody  ^  incubated w i t h the  f o r 18-20  affinity  and  general principle  Antibody  125 I  T J  the  which  assay i s : Hapten  the  The  antibody  bound  precithe  bound r a d i o a c t i v i t y  of  15  the  labeled hapten-antibody  scintilation  counter.  Concentration  the  s a m p l e s was d e t e r m i n e d  9•  Analyses Left  developed Right  and  atrial  preparations  preparations  atrial  more t h a n  160 b e a t s  curve.  were d i s c a r d e d  were  i ft h e b a s a l  0.15 gm o r m o r e t h a n discarded  r a t e was l e s s t h a n  0.7  gm.  i fthe basal  80 b e a t s  per minute o r  per minute. by g r a p h i c a l l y c a l c u l a t i n g  concentration  o f an agonist  producing  presence Schild  The c a l c u l a t e d E D ^ v a l u e s and absence  plot  intersects pA  2  the study,  of the antagonist, at a point  f o reach t i s s u e ,  i nthe  to construct  yields  -1)  against  a line  corresponding  a  which  t o the pA . 2  as w e l l as a l l other  values  w e r e p l o t t e d a s t h e mean + S . E .  Statistical  s i g n i f i c a n c e was d e t e r m i n e d  the  Student's  and  theophylline studies  values.  f o rhistamine  A p l o t o f l o g (dose r a t i o  the x axis  values  5 0% o f i t s m a x i m u m  o f c i m e t i d i n e were used  (1957).  - l o g concentration  for  AMP i n  were o b t a i n e d  response.  in  a  values  EDJ-Q  The  of the cyclic  from a standard  t e n s i o n was l e s s t h a n  atrial  using  statistics  developed  the  c o m p l e x was c o u n t e d  t-test.  Differences  a two-tailed  The p a i r e d  were  test.  test  was u s e d  and t h e unpaired considered  by t h e use o f  test  i n the pA  2  f o ra l l other  significant  i f p < 0.05  16  10.  Preparations The  water  drugs  freshly  reconstituted with  and F r e n c h  dl-isoproterenol reserpine, Sigma  Poulenc;  The  drugs  impromidine, 4-methylhistamine  2-pyridylethylamine  Kline  the  were  drugs  on t h e day o f t h e e x p e r i m e n t .  cimetidine, and  of  used  L t d . ; histamine  hydrochloride,  dl-propranolol  tyramine hydrochloride  and h e p a r i n ,  Company; p r o m e t h a z i n e  and t h e o p h y l l i n e from  B.D.H.  were:  dihydrochloride  dihydrochloride, obtained  Laboratories  Chemical  distilled  from  Smith  dihydrochlorid hydrochloride obtained  hydrochloride  from from  17  RESULTS  1.  Chronotropic responses receptor  a.  atria  dose-response  effect  histamine,  right  atria  to histamine  agonists  Cumulative The  of rabbit  curves  of increasing  impromidine  a n d PEA o n r a t e  i s shown i n f i g u r e  increased  atrial  histamine _5  w a s 1 x 10  doses o f h i s t a m i n e ,  rate.  1.  of isolated  A l l four agonists  The t h r e s h o l d  4-methylrabbit  significantly  concentration f o r  -7  1 x 10  M, a c o n c e n t r a t i o n 2 00 t i m e s  for  histamine.  was  3 x 10~" ' M, w h i c h  for  histamine.  1  which  histamine, 1 x 10~ M 6  0  h i g h e r t h a n was  c o n c e n t r a t i o n f o r impromidine  was s i g n i f i c a n t l y  The m o l a r  necessary  lower  than, that  c o n c e n t r a t i o n s o f each  needed  agonist  t h e maximum c h a n g e i n r a t e w e r e a s f o l l o w s : -4 1 x 10 M (228 ± 7 b e a t s p e r m i n u t e ) ; 4-methyl-4 3 x 10  M  (210 ± 6 b e a t s  (188 ± 5 b e a t s  ± 5 beats  appeared for  The t h r e s h o l d  a n d PEA  caused  Histamine,  (208  M and f o r 4 - m e t h y l h i s t a m m e  per minute).  The p o t e n c y  of  Colebatch,1970). o f these  release  T h e r e f o r e we o b s e r v e d  3  was l o w e r  The d i f f e r e n c e s  be due t o c a t e c h o l a m i n e  10~ M  impromidine  t o be h i g h e r , b u t t h e maximum r e s p o n s e  may p a r t i a l l y  impromidine,  p e r m i n u t e ) ; and PEA, 1 x  the other histamine agonists.  effects  per minute);  i n responses  (Broadley,1978;  the chronotropic  agonists i n the presence _7  of the beta  adren-  ergic  a n t a g o n i s t p r o p r a n o l o l ( 1 x 10  M), and i n animals  which  were d e p l e t e d o f c a t e c h o l a m i n e s  through reserpine  pretreatment.  than  18  Figure The  1  effects o f histamine  receptor  The e f f e c t s o f h i s t a m i n e , impromidine four  on r a t e were  agonists  increased  studied right  agonists  i n rabbit right  atrial  t h e mean r a t e  (beats  of  a r e shown  parentheses.  i n  rate.  PEA, 4 - m e t h y l h i s t a m i n e and  represents animals  on a t r i a l  rate.  Each  atria.  A l l  point  p e r m i n u t e ) +_ S.E.M.  Number  19  Dose  of  Agonist  (-log  M)  20  The  effects  pretreatment  of reserpine  or propranolol  on t h e c h r o n o t r o p i c  4-methylhistamine,  responses  impromidine,  (1 x  10  M)  - /  to histamine,  a n d PEA a r e shown i n f i g u r e s _7  2-5.  Neither  ment  reserpine nor propranolol  significantly  methylhistamine slightly  not  depressed  ( 1 x 10  t h e maximum r e s p o n s e  M) p r e t r e a t m e n t  catecholamine  the  chronotropic  studies agents  release response  i n atria  Effect The  methazine  accounted t o PEA.  the catecholamine of histamine  effects  impromidine,  responses  i nthe  suggest  f o ra large portion of  2  subsequent  receptor  t o these  blocking  agonists  were  pretreated rabbits i n order  release.  of the specific  the chronotropic  decrease  These r e s u l t s  and H  receptor  and o f t h e s p e c i f i c  or propranolol  Therefore,  responses  4-  was, however,  reserpine  t o PEA.  of reserpine  to histamine,  a significant  of the  on t h e c h r o n o t r o p i c  to minimize  on  response  of the effects  performed  b.  caused  4-  pretreatments  The e f f e c t  In contrast either  maximum c h r o n o t r o p i c that  However, both  and impromidine..  significant. _7  M) p r e t r e a t -  affected the threshold of histamine,  o r impromidine.  methylhistamine,  ( 1 x 10  antagonists H^ r e c e p t o r  H^ r e c e p t o r  antagonist  to histamine,  a n d PEA i n t h e r i g h t  atria  antagonist  pro-  cimetidine  4-methylhistamine,  a r e shown i n f i g u r e s —6  6-9.  Both  antagonists  (promethazine  2 x 10  M and c i m e t i d i n e  —6 1  x 10  curve  M), s i g n i f i c a n t l y to the right  shifted  ( f i g .6).  the histamine  dose-response  An even f u r t h e r s h i f t  to the  21  Figure The  2  effects  of  chronotropic  reserpine  response  Histamine right  atria  to  or  propranolol  on  the  histamine.  dose-response  pretreated  pretreatment  with  curves  were performed  reserpine  or  in  rabbit  propranolol  -7 1 x  10  M  as  significantly Each p o i n t +  S.E.M.  described (P  >  0.05)  represents Number o f  m  the  the  methods.  a f f e c t e d the  Neither response  mean r a t e ( b e a t s  animals  are  shown i n  per  pretreatment to  histamine.  minute)  parentheses.  22  Dose of Histamine (-log M)  Figure  The  3  effects  chronotropic  of r e s e r p i n e or p r o p r a n o l o l pretreatment response  to  4-Methylhistamine in  rabbit  right  atria  1 x  pretreatment to  10  dose-response  as  (beats  described m  significantly  4-methylhistamine.  were  performed pro-  • the methods.  ( P > 0.05)  affected  Neither the  response  E a c h p o i n t r e p r e s e n t s t h e mean  p e r m i n u t e ) + S.E.M.  parentheses.  curves  pretreated with reserpine or .  M  the  4-methylhistamine.  -7 pranolol  on  Number o f a n i m a l s  are  rate  shown i n  24  25  Figure The  4  effects  of reserpine  chronotropic  response  Impromidine rabbit  right  atria  or propranolol,pretreatment  on t h e  t o impromidine.  dose-response pretreated  c u r v e s were, p e r f o r m e d i n  with  reserpine  or propranolol  -7 1 x 10  M as d e s c r i b e d  significantly Each p o i n t + S.E.M.  m  t h e methods.'  Neither. pretreatment  (P > 0.05) a f f e c t e d t h e r e s p o n s e  represents  t h e mean r a t e  Number o f a n i m a l s  (beats  per  t o impromidine. minute)  a r e shown i n p a r e n t h e s e s .  26  C  9  8  Dose of Impromidine  7  6  (-log M)  27  Figure The  5  e f f e c t s of reserpine  chronotropic PEA  response  to  dose-response  or propranolol.pretreatment  on  the  PEA. c u r v e s were performed  in rabbit  right  -7 atria  pretreated  as d e s c r i b e d significant PEA. +  with  reserpine  i n the methods. (P <  Each point  0.05)  Both  decrease  represents  or propranolol  1 x  10  M  pretreatments caused  i n t h e maximum r e s p o n s e  t h e mean r a t e  (beats  per  a to  minute)  S.E.M.  "Significantly animals  are  different  from  c o n t r o l a t P < 0.05.  shown i n p a r e n t h e s e s .  Number  of  28  • Control  4  Dose of PEA  3  (-log M)  Figure  6  The  e f f e c t s o f c i m e t i d i n e . and p r o m e t h a z i n e . p r e t r e a t m e n t  the  chronotropic Histamine  atria  from  represents  to  dose-response  rabbits pretreated t h e mean r a t e  "Significantly animals  response  different  a r e shown  histamine. c u r v e s were performed  i n right  with  point  (beats from  on  reserpine.  p e r minute)  Each  +_ S.E.M.  c o n t r o l a t P < 0.05.  i n parentheses.  Number o f  30  Dose of Histamine (-log M)  31  Figure  7  The  effects  of cimetidine  the  chronotropic response 4-Methylhistamine  in  right  point  atria  from  and, p r o m e t h a z i n e to  animals  different  a r e shown  curves  were  performed  pretreated with .reserpine.  r e p r e s e n t s t h e mean r a t e  "Significantly  from  on  4-methylhistamine.  dose-response  rabbits  pretreatment  (beats per minute) control  i n parentheses.  a t P < 0.05.  Each  +_ S.E.M. Number o f  32  • Control O Cimetidine 10" M • Cimetidine 3x10" M 6  6  200 H  A Promethazine 2X10" M 6  (3)  £ \ (D -Q  S  150  QC  100 H I  5  1  3  Dose of 4-Methylhistamine (-logM)  33  Figure  8  The  effects  of cimetidine  the  chronotropic Impromidine  response  and,promethazine t o impromidine.  dose-response  from r a b b i t s  right  atria  point  r e p r e s e n t s t h e mean r a t e  "Significantly animals  different  a r e shown  p r e t r e a t m e n t on  c u r v e s were performed i n  pretreated  from  with  reserpine.  (beats per minute) control  i n parentheses.  a t P < 0.05.  Each  +_ S.E.M. Number o f  • Control O Cimetidine 10' M • Cimetidine 10~ M A Promethazine 6  5  2X10" M 6  Dose of Impromidine  (-log M)  Figure The  9  effect  response  of promethazine  p r e t r e a t m e n t on t h e c h r o n o t r o p i c  t o PEA.  PEA  dose-response  c u r v e s were performed  from r a b b i t s p r e t r e a t e d w i t h r e s e r p i n e . represents  t h e mean r a t e  Promethazine response  in  terms  h a d no s i g n i f i c a n t  t o PEA.  significant)  (beats  o f change  per minute)  i fthe chronotropic  i n rate  shown i n p a r e n t h e s e s .  (although  ( f i g . 9a).  atria  point  +_ S.E.M.  (P > 0 . 0 5 ) - e f f e c t  A larger effect  i s seen  Each  i n right  still  response  on t h e not i s plotted  Number o f a n i m a l s a r e  36  •  Control  Fig 9 a §30-  A Promethazine 2 X 1 0 "  6  (0  M  £ ^£15-  <o  oc  <l  A  4 3 Dose of P E A (-tog)  150  H  c  E  \  V)  to  n £  100  cc  C  4  Dose of PEA  (-log M)  37  right  of the dose-response  cimetidine  1 x  10  significantly  M.  c u r v e was  Cimetidine  shifted  the  noted  (1 x  i n the presence  10  M  and  4-methylhistamine  3 x 10~  of  M)  dose-response —6  curve had  to the r i g h t  no  significant  ( f i g . 7). effect  However, promethazine  on  the chronotropic  (2 x  response  10  M)  to  —6 10~ M  4-methylhistamine ( f i g . 7). C i m e t i d i n e (1 x and _5 1 x 10 M) a l s o c a u s e d a s i g n i f i c a n t s h i f t t o t h e r i g h t  of  the —6 i m p r o m i d i n e d o s e - r e s p o n s e c u r v e , w h i l e p r o m e t h a z i n e ( 2 x 10 M) did not s i g n i f i c a n t l y a l t e r the c h r o n o t r o p i c response t o —6 impromidine ficant the  ( f i g . 8).  effect  on  chronotropic  Promethazine  t h e PEA effect  dose-response o f PEA  was  difficult  to detect  a  (although  still  significant)  tropic (fig. in 2.  response 9a).  the r i g h t  significant  atria  (3 x  10  effect  no  signi-  ( f i g . 9).  Since  l a r g e r change  seen  no  i f the  chrono-  i n rate  effect  on  rabbit  (not  atria  be  to  PEA  response  shown).  histamine  curves  of i n c r e a s i n g doses  impromidine  rabbit left  agonists  significantly The  A  o f change  had  had  agonists  isolated  traction.  be  of rabbit l e f t  Cumulative dose-response  histamine,  change. can  M)  s m a l l , i t may  of a non-reserpinized  Inotropic responses  The  M)  10~  curve  very  i s p l o t t e d i n terms —6  Cimetidine  receptor a.  not  (2 x  and  atria,  PEA  on  of histamine,  force of contraction, i n  i s shown i n f i g u r e  increased  4-methyl-  the a t r i a l  threshold concentration  10.  force  A l l four of  f o r histamine  conwas  38  Figure The  10  e f f e c t s of histamine  contraction The  point  of rabbit left  atria.  on f o r c e A l l four  represents  animals  on t h e f o r c e o f  PEA, 4 - m e t h y l h i s t a m i n e and  o f c o n t r a c t i o n were agonists  increased  t h e mean t e n s i o n  are"shown i n  agonists  atria.  effects of histamine,  impromidine left  receptor  parentheses.  studied atrial  (gm) +_ S.E.M.  i n rabbit tension. Number o f  Each  39  Dose of Agonist (-log M)  40  1 x 10~'M a n d f o r 4 - m e t h y l h i s t a m i n e threshold  concentration  concentration The  molar  maximum (1.0  concentrations  o f each  impromidine (2.0  3 x 10~ M,  was l o w e r t h a n differences  effects  t o be g r e a t e r ,  M)  The  3 x 10  _ 3  M  release.  may We,  and r e s e r p i n e  the potency  b u t t h e maximum  partially  studied  i n t h e presence  of  and r e s e r p i n e  reserpine  t o histamine,  decrease (1.0 1.0  ± 0.07 g m ) .  through  response  of response  These  4-methylhistamine Neither  pretreatment  o f , o r t h e maximum r e s p o n s e  (figs.  i n t h e maximum  ± 0.09 gm;  tropic  M) n o r r e s e r p i n e  or propranolol  3  pretreatment  ( 1 x 10  o r impromidine  10~ M  pretreatment.  propranolol  amine  gm);  propranolol  a n d PEA a r e shown i n f i g u r e s 11-14. _7  the threshold  10  the inotropic  impromidine  affected  a  have been due t o  therefore,  effects of propranolol  on t h e i n o t r o p i c r e s p o n s e  a  ( 2 . 1 ± 0.12  f o rthe other histamine agonists.  of these agonists _7  ( 1 x 10  caused  Histamine, 3 x  As i n t h e right, a t r i a ,  i n responses  catecholamine  which  ( 0 . 7 3 ± 0.05 gm) a n d P E A , 1 x  ?  appeared  3 x 1 0 "^M,  needed f o r histamine.  i n r a t e were as f o l l o w s :  ± 0.14 g m ) .  impromidine  was  agonist  ± 0.06 g m ) ; 4 - m e t h y l h i s t a m i n e ,  The  b  f o r impromidine  much l o w e r t h a n t h a t  change  and PEA, 3 x 10~ M.  11 and 1 3 ) .  i n o t r o p i c response a n d t o PEA  These r e s u l t s suggest  a  to  that  either  significant 4-methylhistamine  ( 1 . 0 ± 0.1  o f PEA a n d 4 - m e t h y l h i s t a m i n e  catecholamine release.  to, hist-  In contrast,  pretreatment caused  1 . 0 5 ± 0.08 gm)  significantly  gm)  some o f t h e i n o i s mediated  Therefore, subsequent  studies  41  Figure  The  11  effects  inotropic  of reserpine  response  Histamine rabbit  left  1 x 10  pretreated. with  reserpine  or  propranolol  .  M as. d e s c r i b e d  m  t h e methods.  Neither  pretreatment  ( P > 0 . 0 5 ) a f f e c t e d t h e r e s p o n s e .to h i s t a m i n e .  Each p o i n t  represents  of  a r e shown  animals  on t h e  histamine.  .  significantly  pretreatment  d o s e - r e s p o n s e . c u r v e s were performed i n  atria  -7  to  or propranolol  t h e mean t e n s i o n i n parentheses.  (gm) +_ S.E.M.  Number  42  Dose of  Histamine  (-log M)  43  Figure The  12  effects  inotropic  of reserpine  response  to  rabbit  left  atria  -7 1 x  10  as  (P <  methyIhistamine. (gm)  + S.E.M.  "Significantly  on  the  with  curves  were  reserpine  performed  or  propranolol  .  described  significantly  dose-response  pretreated  . M  pretreatment  4-methylhistamine.  4-MethyIhistamine in  or propranolol  m  0.05)  the methods. decreased  Each point  from  the response  represents  Number o f a n i m a l s different  Both.pretreatments  are  control  t h e mean  to  4-  tension  shown i n p a r e n t h e s e s . at  P.<  0.05.  Dose of 4-Methylhistamine (-logM)  Figure The  13  effects  inotropic  of reserpine  response  to  or propranolol  left -7  1 x 10  atria  . m  reserpine  t h e methods.  or  Neither  (P > 0.05) a f f e c t e d t h e r e s p o n s e  Each p o i n t  represents  of  a r e shown  animals  c u r v e s were performed  pretreated.with  . M as d e s c r i b e d  significantly  on t h e  impromidine.  Impromidine dose-response rabbit  pretreatment  t h e mean t e n s i o n i n parentheses.  i n  propranolol pretreatment t o .impromidine.  (gm) +_ S.E.M.  Number  46  • Control • Reserpine • Propranolol 10~ M 7  C  8  7  Dose of Impromidine  6  (-log M)  47  Figure The  14  effects  inotropic PEA  of.reserpine  response  or propranolol  pretreatment  on t h e  t o PEA.  dose-response  c u r v e s were performed  i n rabbit  left  -7 atria as  pretreated  described  significant PEA.  reserpine  i n t h e methods.  or propranolol  1 x 10  Both.pretreatments  caused  ( P < 0.05) d e c r e a s e , i n t h e maximum r e s p o n s e  Each p o i n t  *Significantly animals  with  represents  different  t h e mean t e n s i o n  from  control  a r e shown i n p a r e n t h e s e s .  M a to  (gm). +_ S.E.M.  a t P < 0.05.  Number o f  48  4  Dose of PEA  3  (-log M)  49  of  the e f f e c t s  the in  inotropic atria  Effect  PEA  pretreated  blocking  agents,  effects  of the  receptor  rabbits  i n order  out  to  antagonists  receptor  antagonist,  antagonist cimetidine  on  promethazine the  inotropic  to histamine, 4-methylhistamine, impromidine,  i n the l e f t  atria  are  shown i n f i g u r e s  and  cimetidine  15-18.  —6 methazine  (2 x  competitive  10  on  release.  of histamine receptor  of the  responses  receptor  responses t o t h e s e a g o n i s t s , were c a r r i e d  the catecholamine  The and  and  from reserpine  minimize b.  of the  and  Both  pro-  —6 M)  block of the  inotropic  ( 1 x 10  response  M)  produced  a  to histamine  (fig. 1 x  15). Increasing the concentration of cimetidine to _5 10 M caused an even f u r t h e r d i s p l a c e m e n t o f t h e h i s t a m i n e  dose-response  curve to the r i g h t  —6 1 x  10  (fig.  15).  Cimetidine,  —6 M and  response  3 x  10  M,  shifted  curve to the r i g h t ;  the  4-methylhistamine  however, only  the  of cimetidine  was  shift  dose-  produced  —6 with  3 x  10  significant effect  on  M  concentration  (fig.  the  16).  Promethazine  (2 x  10  statistically M)  had  little  i n o t r o p i c response of 4-methylhistamine ( f i g . 16). -6 -5 C i m e t i d i n e , 1 x 10 M a n d 1 x 10 M, p r o d u c e d a p a r a l l e l shift of the impromidine dose-response curve, but only the h i g h e r _5 c o n c e n t r a t i o n ( 1 x 10 M) c a u s e d a s t a t i s t i c a l l y significant displacement of the dose-response curve to the r i g h t ( f i g . 17). —6 P r o m e t h a z i n e (2 x 10 M) d i d n o t s i g n i f i c a n t l y a l t e r t h e —6 impromidine response ( f i g . 17). P r o m e t h a z i n e (2 x 10 M) d i d  50  Figure  15  The  e f f e c t s ..of c i m e t i d i n e  the  i n o t r o p i c response Histamine  atria  and promethazine  to  histamine.  dose-response  from r a b b i t s pretreated  represents  t h e mean t e n s i o n  "Significantly animals  c u r v e s were performed  i n left  with  point  reserpine.  Each  (gm) +_.S.E.M.  d i f f e r e n t from  a r e shown  p r e t r e a t m e n t on  control, at P <  i n parentheses.  0.05.  Number o f  51  1.5  -I  Dose of Histamine  (-log M)  52  Figure  16  The  effects of cimetidine  the  i n o t r o p i c response 4-MethyIhistamine  in  left  point  atria  from  represents  "Significantly animals  to  and promethazine  on  4-methylhistamine.  dose-response  rabbits pretreated  t h e mean t e n s i o n  d i f f e r e n t from  a r e shown  pretreatment  c u r v e s were with  reserpine.  Each  (gm). +_ S.E.M.  c o n t r o l a t . P < 0.05.  i n parentheses.  performed  Number o f  ,53  A Control O Cimetidine 1 0 " M • Cimetidine 3 X 1 0 " A Promethazine 6  6  M  Dose of 4-Methylhistamine (-logAA)  54  Figure  17  The  effects of cimetidine  the  i n o t r o p i c response  and promethazine .pretreatment on  to' i m p r o m i d i n e .  Impromidine dose-response left point  c u r v e s were performed i n  a t r i a from r a b b i t s pretreated represents  "Significantly animals  t h e mean t e n s i o n  with  reserpine.  (gnr) +_ S.E.M.  d i f f e r e n t . f r o m c o n t r o l a t P. < 0 . 0 5 .  a r e shown  i n parentheses.  Each  Number o f  55  A Control O Cimetidine  10~ M  • Cimetidine  10 M  6  _5  A Promethazine 2X10" M 6  *T**—\ 1 C  8  7  Dose of Impromidine  I  6  (-log  Figure  18  •The e f f e c t o f p r o m e t h a z i n e response  rabbits pretreated  t h e mean t e n s i o n "Significantly animals  pretreatment  on t h e  t o PEA. .  PEA d o s e - r e s p o n s e from  and c i m e t i d i n e  c u r v e s were performed with  reserpine.  i n left  Each p o i n t  atria represents  (gm) +_ S.E.M.  d i f f e r e n t from  c o n t r o l a t P < 0.05.  a r e shown i n p a r e n t h e s e s .  Number o f  57  Dose of PEA  (-log M)  58  cause  a s i g n i f i c a n t decrease  to  PEA  ( f i g . 18).  no  effect  i n t h e maximum  In contrast, cimetidine  on t h e PEA r e s p o n s e  ( f i g . 18).  inotropic  response  ( 1 x 1 0 ~ M) h a d A higher  concentra-  .-5 tion  of cimetidine  dose-response (not c.  curve  ( T x 10  i n a t r i a of non-reserpinized  pA2  studies  receptors Verma  above r e s u l t s are present  (1978 ) r e p o r t e d  receptors  i n rabbit  (Arunlakshana was c a r r i e d  value  tion the of  2  ferent  pA  than  2  of  receptors  1959) u s i n g  histamine  However, M c N e i l l and  Therefore  H-^, a n d n o t a pA  right  to confirm  (figs.  value  and l e f t  atria  our results.  Hist-  was t h e a n t a g o n i s t . a  a correlation  The  correlaatria  coefficient  19 a n d 2 0 ) .  i n the'left  i n the right  a t r i a was s t a t i s t i c a l l y  atria.  According  a c t o n t h e same r e c e p t o r s  study,  ,  study  2  7.2 7 +_ 0.12 w i t h  +_ 0.09 w i t h  r i s e t o t h e same p A  the present  b o t h H^ a n d  o f 0 . 9 7 1 +_ 0.008 , b u t i n t h e l e f t  (1957) drugs which give  atria.  a t r i a was  was 6.68  that  atria.  and c i m e t i d i n e  i n the right  0.984 + 0.004  that  t h e p'resence o f o n l y  o u t i n an a t t e m p t  value  The  i n left  and S c h i l d ,  coefficient pA  suggest  left  a m i n e was t h e a g o n i s t 2  rabbits  shown).  The  pA  M) a l s o d i d n o t a l t e r t h e P E A  2  value.  Therefore,  one c a n s p e c u l a t e  may b e i n v o l v e d  that  to  dif-  Schild  are expected t o from the r e s u l t s different  i n t h e two r e s p o n s e s  studied.  A  59  Figure  The  19  pA2 v a l u e  f o r cimetidine  i n the right  H i s t a m i n e was t h e a g o n i s t . log  (dr-1)  The  pA  2  value  correlation -1.09  calculated  from  coefficient  + 0.06.  Each p o i n t  t h e mean E D  was c a l c u l a t e d  atria.  5 Q  of 5  represents  the  observations.  t o b e 7 . 2 7 + _ 0.12 w i t h  o f 0 . 9 7 1 +_ 0.008 a n d a s l o p e  a of  60  3.0 H  —\ 7  Dose of  1 6  r  5  Cimetidine (-log M)  61  Figure  The  20  pAg, v a l u e , f o r c i m e t i d i n e  Histamine log  (dr-1)  The  pA  2  correlation -0.97  was t h e a g o n i s t .  calculated  value  atria  Each p o i n t  represents  f r o m t h e m e a n ED^g o f 5  was c a l c u l a t e d  coefficient  + 0.04.  i n the. .left,  t o b e 6.68  the  observations.  +_ 0.09 w i t h  o f 0.984 +_ 0.004 a n d a s l o p e  a of  62  3.0  H  i 7  Dose of  1 6  I 5  Cimetidine '(-log M )  63  study  by  guinea  3.  Parsons  pig atrium,  The  effect  tropic a.  of  •isolated  atrial  t h e o p h y l l i n e on  reserpine  and  and  of  6.1  the  to histamine  and  22.  tension.  pretreatment.  rate the  atria,  Theophylline These  cimetidine.  chronotropic  atrial  left  s t i m u l a t i o n of  for  receptor  t h e o p h y l l i n e on  rabbit right  rate  a pA~  t h e o p h y l l i n e on  e f f e c t s of  f i g u r e s 21  involving histamine  revealed  responses  E f f e c t s of The  in  (1977),  ino-  agonists and  rate  force and  development  force  of  r e s p e c t i v e l y , are  significantly  e f f e c t s were not  From the  and  dose-response  shown  increased altered  curves  by  in -4  figures was  21  and  chosen  studied  b.  a  i n order  pretreatment histamine  22  on  the  receptor  submaximal dose of  theophylline  to  e f f e c t s of  i n v e s t i g a t e the  chronotropic agonists.  in reserpine  and  theophylline  (3 x  responses  to histamine  receptor  response  to  (1 x  M),  10  - l 4  pretreatment  10  M)  (1 x  responses  on  increased of  10~ M) , and 8  the  agonists  submaximal c o n c e n t r a t i o n s impromidine  M)  of  were  animals. -4  E f f e c t of  Theophylline  the  10  theophylline  inotropic effects  A l l of  pretreated  (3 x  the  chronotropic i n the  right  chronotropic  4-methylhistamine PEA  (1 x  lO'^M),  atria  64  Figure  The  21  effect  response The  of.reserpine.pretreatment  to theophylline. change  i n right  atrial  phylline,  was n o t s i g n i f i c a n t l y  reserpine  pretreatment.  change are  on t h e c h r o n o t r o p i c  in. r a t e  shown i n  (beats  rate,  theo-  ( P > 0.05) a f f e c t e d b y  Each p o i n t r e p r e s e n t s  per minute)  parentheses.  produced by  +_ S.E.M.  t h e mean  Number o f  animals  65  Figure  The  22  effects of reserpine  response The  pretreatment  to theophylline. change  i n left  atrial  phylline,  was n o t s i g n i f i c a n t l y  reserpine  pretreatment.  change in  on t h e i n o t r o p i c  i n tension  parentheses.  tension,  by  theo-  (P > 0.05) a f f e c t e d b y  Each.point  (gm) +_ S.E.M.  produced  r e p r e s e n t s t h e mean  Number o f a n i m a l s  a r e shown  67  Control • Reserpine  5  4  3  Dose of Theophylline Hog  M)  68  as  shown i n f i g u r e s 2 3-25.  The  combined  effect  of  theo-  -4 phylline was  greater  ever, the  ( 3 x 10  M)  any  than the response  the combined  sum  and  one  to either agonist  e f f e c t s were  of the i n d i v i d u a l  of the histamine  not  alone.  statistically  responses.  Therefore,  tropic  effect  o f t h e o p h y l l i n e was  additive with  tropic  effect  o f any one  histamine  of these  agonists How-  greater the  the  than  chronochrono-  agonists.  Theo-  phylline c.  d i d not p o t e n t i a t e t h e response ( f i g s . 2 3-25). -4 E f f e c t o f t h e o p h y l l i n e ( 3 x 10 M) o n t h e i n o t r o p i c  responses In  to histamine  contrast  receptor  to the r e s u l t s  agonists  i n the l e f t  i n the right  atria,  the  atria com-  -4 bmed  effect  histamine response greater  (H^ o r H  2  ) agonists  to either agonist than  Therefore, the  of theophylline  t h e sum  ( 3 x 10 was  alone,  b u t was  of the i n d i v i d u a l  —6  M,  not  shown).  This  any one  greater also  of the  than  the  statistically  responses  (figs.  26-28).  the i n o t r o p i c e f f e c t s of  p o t e n t i a t i o n r o f the i n o t r o p i c -4 r e s p o n s e t o 4 - m e t h y l h i s t a m i n e ( 1 x 10 M) a n d i m p r o m i d i n e —8 —4 ( 1 x 10 M) b y t h e o p h y l l i n e ( 3 x 10 M) was significantly _5 d e c r e a s e d b y c i m e t i d i n e ( 1 x 10 M, n o t s h o w n ) . However, t h e -4 p o t e n t i a t i o n o f t h e i n o t r o p i c r e s p o n s e t o P E A (l.'.x 10 M) b y -4 t h e o p h y l l i n e ( 3 x 10 M) w a s n o t s i g n i f i c a n t l y a f f e c t e d b y -5 -6 c i m e t i d i n e ( 1 x 10 M) o r b y p r o m e t h a z i n e (2 x 10 M, n o t shown). H o w e v e r , t h i s p o t e n t i a t i o n was d e c r e a s e d b y p r o p r a n o l o l ( 1 x 10  agonists.  with  not only  theophylline potentiated  histamine  M)  69  4.  The e f f e c t  of histamine  on r a b b i t  atrial  cyclic  AMP  con-  on c y c l i c  AMP  levels  centrations _5 The in  effect  isolated  rabbit  T i s s u e s were (20  of histamine right  frozen  after  ( 1 x 10  and l e f t  atria  exposure  cyclic  AMP  levels  not  statistically  AMP  levels  i n the histamine different  (McNeill treated  a r e shown  t o the drug  seconds) which has been p r e v i o u s l y  increased  M)  reported  i n Table  for a to  time  shown  and Verma, 1978). right  and l e f t  from the c o n t r o l  group.  1.  atria  Cyclic were  70  Figure  23  The e f f e c t  of theophylline  on t h e c h r o n o t r o p i c r e s p o n s e  to  4-methylhistamine. The c o m b i n e d  effect  of theophylline  ( 3 x 10  M)  and'  -4 and  4-methylhistamine  ( 1 x 10. M)  (P > 0.05) g r e a t e r t h a n Each bar graph rate error  indicate  significantly  t h e sum o f t h e i n d i v i d u a l  r e p r e s e n t s t h e mean c h a n g e  (beats per minute) bars  was n o t  +_ S.E.M.  i n right  responses. atrial  Numbers a s s o c i a t e d w i t h  number o f a n i m a l s .  71  4-Methylhistamine 1 0 - M 4  Theophylline  Ztl  3X10- M 4  Theophylline 3 x i - 4 0  /(6)  >  4-Methylhistamine 1 0 ~ M 4  M  +  72  Figure  24 .  The e f f e c t  o f t h e o p h y l l i n e on t h e c h r o n o t r o p i c  response to  impromidine. -4 The c o m b i n e d impromidine greater  than  ( 1 x 10  t h e mean c h a n g e  number o f  ( 3 x 10  M) w a s n o t s i g n i f i c a n t l y  m i n u t e ) +_ S.E.M.  indicate  of theophylline  t h e sum o f t h e i n d i v i d u a l  graph represents per  effect _g  (P >  responses..  i n right  Numbers a s s o c i a t e d  animals.  M)  atrial with  and  0.05) Each bar  rate  error  (beats bars  73  74  Figure  25  The e f f e c t  o f t h e o p h y l l i n e on t h e c h r o n o t r o p i c , r e s p o n s e  to  PEA. -4 The c o m b i n e d PEA than  effect  of theophylline  ( 3 x 10  M) a n d  ( 1 x 1 0 ~ M ) w a s n o t s i g n i f i c a n t l y .(P > 0 . 0 5 ) g r e a t e r 4  t h e sum o f t h e i n d i v i d u a l  represents  t h e mean c h a n g e  m i n u t e ) + S.E.M. indicate  number o f  responses.  i n right  atrial  Numbers a s s o c i a t e d w i t h animals.  Each b a r graph rate.(beats per error  bars  75  PEA 1 0 " M 4  Figure  26  The e f f e c t  o f t h e o p h y l l i n e on t h e i n o t r o p i c r e s p o n s e  to  4-methyIhistamine. -4 The c o m b i n e d 4-methylhistamine greater  than  effect ( 1 x 10  of theophylline -4 M) w a s  ( 3 x 10  significantly  (P <  t h e sum o f t h e i n d i v i d u a l , r e s p o n s e s .  graph represents  t h e mean c h a n g e i n l e f t  atrial  M)  and 0.05)  Each bar  tension  (gm)  + S.E.M. *Significantly individual indicate  greater  responses.  ( P < 0.05) t h a n  t h e sum o f t h e  Numbers a s s o c i a t e d  number o f a n i m a l s .  with  error  bars  77  — — 4-Methylhistamine 10~ M 4  E B B Theophylline 3 x 10 ~ M 4  Theophylline 3 X 1 0 - M + 4-Methylhistamine 10" 4  T-  78  Figure  27  The e f f e c t o f t h e o p h y l l i n e ' on t h e i n o t r o p i c r e s p o n s e  to  impromidine. -4 The c o m b i n e d impromidine greater  ( 1 x 10  than  effect of theophylline _g M)  was  significantly  ( 3 x 10 (P <  t h e mean c h a n g e  i n left  atrial  and  0.05)  t h e sum o f t h e . i n d i v i d u a l . r e s p o n s e s .  graph represents  M)  Each bar tension  (gm) + S.E.M. "Significantly  greater  i n d i v i d u a l - responses. indicate  ( P < 0.05) t h a n  t h e sum o f t h e  Numbers a s s o c i a t e d  number o f a n i m a l s .  with  error  bars  79  80  Figure  28  The e f f e c t  o f t h e o p h y l l i n e on t h e i n o t r o p i c r e s p o n s e  t o PEA.  -4 The c o m b i n e d  effect  PEA  (1 x 10  the  sum o f t h e i n d i v i d u a l  respresents +  - l 4  of theophylline  M ) was s i g n i f i c a n t l y  M) a n d  (P < 0.05) g r e a t e r  responses.  t h e mean c h a n g e  ( 3 x 10  i n left  than  Each b a r graph atrial  t e n s i o n (gm).  S.E.M.  "Significantly individual indicate  greater  responses.  ( p < 0.05) t h a n  t h e sum o f t h e  Numbers a s s o c i a t e d w i t h  number o f a n i m a l s .  error  bars  81  1.0 A  PEA l O ^ M _4  Theophylline 3«10-"*M Theophylline 3x10- AA • PEA 10" M 4  ~  0.5 A  4  82  Table The  I  effect  o f h i s t a m i n e on  Cyclic  AMP  levels  c y c l i c AMP  in right  and  concentrations. left  isolated  atria,  -5 following were n o t (P  >  exposure  t o h i s t a m i n e ( 1 x 10  significantly different  0.05).  from the  M)  f o r 20  control  seconds, group  Tissue Preparations  Right  atria  Sample  Tissue  Number  Treatment  None _5 Histamine  Left  atria  1x10  M  None _5 Histamine  1x10  M  Cyclic  AMP  Xfmol/mg t i s s u e )  4  482 + 14  5  506  6  388 + 3 5  6  437 + 52  + 31  84  DISCUSSION  Histamine atria in  were i d e n t i f i e d  the right  The r e s u l t s in  atria  that  right  agonist)  (figs.  6 and 1 5 ) .  Both  blocked  by e i t h e r  t h e H^  presence  effects  antagonist  histamine effects  agonists.  present are  a n d E^  H^  chronotropic  and  ino-  atria respectively  antagonist cimetidine  7,  PEA h a d a p o s i t i v e  promethazine, (figs.  types  6 and 1 5 ) .  i n the rabbit  to specific  chronotropic  b y t h e E^ r e c e p t o r  were c o m p e t i t i v e l y b l o c k e d  promethiazine.  (a dual  by r e s p o n s e s  (figs.  are  r e s p o n s e s were c o m p e t i t i v e l y  Positive  and i m p r o m i d i n e  atria.  These c o n c l u s i o n s  a n d E^ r e c e p t o r  o f H^  were produced  and l e f t  responses  i n the l e f t  a n d E^ r e c e p t o r s  receptor  i s further illustrated  amine r e c e p t o r  responses  atria.  of these  rabbit  of chronotropic  a positive  i n the right  b y t h e E^ r e c e p t o r  H^  i n isolated  that histamine  produced  response  atria  both  and l e f t  tropic  The  present  by measurement  on t h e o b s e r v a t i o n  receptor  or  types  and i n o t r o p i c  suggest  the isolated  based  receptor  and  agonists  hist-  inotropic  4-methyl-  8, 16 a n d 1 7 ) .  These  by c i m e t i d i n e b u t n o t by inotropic  effect  which  was  —6  blocked of  by p r o m e t h a z i n e  the chronotropic  catecholamine  ( 2 x 10  response  release  that  effects  receptor  through  H^  release, respectively. M c N e i l l and Verma  f i g . 18).  produced  ( f i g . 5).  have a l s o r e p o r t e d  M,  b y PEA was  Broadley  PEA h a d b o t h  However, due t o  and W i l s o n  direct  s t i m u l a t i o n and  (1978) a l s o r e p o r t e d  and  most  (1978)  indirect  catecholamine the presence  of  85  H-^ a n d E^ r e c e p t o r s found  only  i n the r a b b i t i s o l a t e d  receptors  These workers  showed  i n the r a b b i t i s o l a t e d  that  amide  ( 1 x 10  M)  amine  i n right  atria.  right  the  blocked  receptor  later  left  response  but  atria.  antagonist  the chronotropic  However  atria,  metito  hist-  i n v e s t i g a t i o n s showed -5  that  higher  ICI  125,211,  (Yellin duced  of metiamide  a r e c e n t l y developed  inotropic  unpublished  The between  response  results  ( 1 : x 10  specific  et a l . , 1979), d i d i n f a c t  McNeill,  to  concentrations  block  i n the l e f t  H^  M),  and  antagonist  the histamine  atria  pro-  (Longhurst  and  observations).  of the present  the responses  study  of the right  the i n t e r a c t i o n s of s p e c i f i c  and  also revealed left  atria  E^ r e c e p t o r  differences  with  agonists  respect  and  g  antagonists. F o r i n s t a n c e , c i m e t i d i n e 1 x 10 M a n t a g o n i z e d t h e c h r o n o t r o p i c r e s p o n s e s t o t h e E^  significantly receptor  -4-  agonists  4-methyIhistamine  ( 3 x 10  M)  and  impromidine  b u t h a d no  significant  —8 ( 3 x 10  M)  i n the r i g h t  on t h e i n o t r o p i c atria  (figs.  cimetidine the and  7,  responses 8, 16  ( 3 x 10  inotropic  and  M  responses  impromidine  atria,  and  to these 17).  Higher  1 x 10  M)  i n the l e f t  (figs.' 7,8,  16  agonists  i n the  effect  left  concentrations  of  did significantly  atria  and 1 7 ) .  to  block  4-methylhistamine  86  Furthermore,  a Schild-plot  1959)  of the chronotropic  right  and l e f t  presence value  f o rcimetidine  receptors  shana and S c h i l d ,  be  19 a n d 2 0 ) . t o give  between t h e r i g h t  antagonist  attributed.to  the fact  monitored,  but i n the l e f t  This  Therefore,  problem  i n the left As t i s s u e s  and l e f t  on t h e r i g h t  In the right  amine r e c e p t o r  i nthe The  pA  that  atria  2  atria  with  similar  values  (Arunlak-  c a n be f u r t h e r  does  i n  exist.  i n the effects  of the H  and l e f t  may  atria  the chronotropic  the degree  may v a r y w i t h  atria  2  possibly  two d i f f e r e n t r e s p o n s e s  atria  2  ( 7 . 2 7 +_ 0 . 1 2 ) w a s  t h e same p A  differences  measured.  studied.  atria  of the  1959), the p o s s i b l i t y o f d i f f e r e n c e s  These observed receptor  t o histamine  some d i f f e r e n c e s .  i n the right  are expected  receptors  showed  d i f f e r e n t from that  + 0.09, f i g s .  and S c h i l d ,  and i n o t r o p i c responses  respectively,  of cimetidine  significantly (6.68  atria  (Arunlakshana  were  response  was  the i n o t r o p i c response  was  of stimulation  the type  of the hist-  of response  investigated  elicited.  by comparing t h e  87  inotropic  responses  the  inotropic  the  sino-atrial  by  mulation.  should  parison  2  atria  showed  i n guinea p i g  atria,  of  sti-  responses  the responses  to controlf o r of  of the inotropic  responses  would  allow  f o r a more v a l i d  receptor  types  between t h e r i g h t  mediating  A' c o n c e p t by Chand  antagonists  of H  2  on h o r s e  ( 1 9 7 8)  by H  2  com-  that this  similar  to the conventional 2  be d i f f e r e n t and  "atypical"  who  , analogous  2  inotropic  showed  agonists  that  H  2  to block the  ( d i m a p r i t and  S i m i l a r responses (Chand  1977).  receptor H  kinds  subtypes has been  trachea.  (Chand and E y r e ,  suggest  of H  receptor  i n the rabbit trachea  c a t bronchus  may  and b u r i m a m i d e ) f a i l e d  responses produced  observed  there  the chronotropic  and Eyre  (metiamide  4-methylhistamine)  receptor  (1978)  due t o d i f f e r e n c e s i n f r e q u e n c y  and l e f t  with  stimulated  frequency  frequencies  Such an i n v e s t i g a t i o n  receptors  relaxant  atria,  the inotropic  of the l e f t  i s also possible that  postulated  and  that  with  atria.  responses.  also  varies with  atria,  Right  response  when c o m p a r i n g  of the histamine  left  H  atria  with  variability  It of  inotropic  be c o m p a r e d a t s i m i l a r  the right  and  left  atria  stimulation.  atria.  Tenner and M c N e i l l  induced  Therefore,  possible  of  of the left  pacing.  paced  the right  driven right  node r e m o v e d , c a n be a r t i f i c a l l y  the histamine  electrically  of  responses  electrically  that  of electrically  receptor  et_ a l . , 1 9 7 9 ) These  may  were  be  functionally  a n d may  t o the subgrouping  authors  be a n i s o -  o f B-, a n d  3  0  88  adrenoceptors.  The  existence  receptor  has  Clark  a l . (1977) and  et  a l s o been proposed  Fjalland that  the  on  the the  study,  as  r e s p o n s e was inotropic pA  receptors gation  2  potency  be  of  (figs.  as  19  i n the  c i m e t i d i n e on  et  a l . , 1972 ; D u r a n t  McNeill effects,  and on  Verma  et  to  burimamide, a  were  H  pig atrium.  those  the  antagonists  2  of  the  The present  chronotropic that  on  the  differences in  s t i m u l a t e H^  She  beating  atrial  these  histamine  carried  out  pairs. her  as  the  the  the  guinea  specific,  and  H  2  investi-  However  there  Hughes  specific as  H^  the  specific  compounds have been specificity  a l . , 1975 ; M c N e i l l and  perfused  and  data.  receptor  (1974a) were a b l e  isolated  findings  pig ileum  than  the  atria.  Both of  little  (1976),  20).  3-(2-aminoethyl)-1,2,4-triazole with  by  the  2-(2-aminoethyl) pyrazole  agonist.  possess very  Calkins  on  the  the  different  3-(2-aminoethyl)-1,2,4-triazole  to  of  to  in interpreting  a g o n i s t , and  histamine  antagonists  guinea  analogous  also able  rabbit  of  on  guinea  potencies  t o be  and  ( 1 9 7 8 ) was  i n the  receptor  and  receptor  evidenced  i n spontaneously  receptor H  may  some d i f f i c u l t i e s  used  type  Fleisch  i n the  responses  a l s o found  Hughes  are  relative  response,  values  2  the  Fjalland  the  third  (1979).  of  twitches  chronotropic of  by  Fjalland  potencies  induced  same a s  findings  the  (1979) based h i s o b s e r v a t i o n s  relative  electrically not  of  to  block  the  pig heart,  reported  (Black  Verma,1974a). inotropic produced  by  2-(2-aminoethyl)pyrazole,  competitive  H  ?  receptor  blocking  89  agent. to  Also  b o t h o f t h e s e .compounds  an i n c r e a s e  was  i n contractility.  antagonized  with  pounds p o s s e s s did  burimamide,  receptor  not t r y t o block  with  specific Hughes  receptor  suggest that  catecholamine agonists  pretreatment  t o PEA was  pretreatment  (figs.  ( f i g . 5).  i n cyclic  1978 ; R e i n h a r d t 1978). H^ and  Hughes  and  receptor  therefore  12 a n d 1 4 ) .  claim.  responses  n  and H  9  occur  results with  P r o p r a n o l o l or. response  to  chronotropic or  reserpine  i n the  present  to eliminate the  studies  responses  content  possi-  showing that.only ^ are associated  ( M c N e i l l and Verma,  on t h e o t h e r  and M c N e i l l ,  the formation  receptor  adenyl  of cyclic AMP  levels  that  both  cyclase Hughes, support  on t h e p r e m i s e  agonists  with  197 3,  AMP. to  5  1976 , 1977 ,  hand, suggests  She b a s e d h e r c o n c l u s i o n  to H  present  The  the animals  s t i m u l a t i o n can a c t i v a t e  increase  agonists  of catechol-  by p r o p r a n o l o l  however, d i d not measure t h e c y c l i c her  The  the inotropic  e t a l . , 1977-; V e r m a (1978),  com-  release.  mediated AMP  AMP  Hughes  histamine  does indeed  reserpine  a r e many b i o c h e m i c a l  n o t H-^, r e c e p t o r  increases  Therefore  prior  antagonists.  decreased  with  of catecholamine There  but  also  (figs.  both  Furthermore,  of these  AMP  i n cyclic  that  5, 12 a n d 1 4 ) .  depressed  were p r e t r e a t e d  bility  indicating  release  4 - m e t h y l h i s t a m i n e a n d PEA  study  increase  by t h e h i s t a m i n e . a g o n i s t s .  some h i s t a m i n e  response  cyclic  d i d not control, f o r the p o s s i b i l i t y  amine r e l e a s e  reserpine  This  activity.  the effects  histamine  increased  that  were p o t e n t i a t e d  by  90  the  phosphodiesterase  Hughes h y p o t h e s i z e d increases  the  of  and  the  H-^  diesterase increased thesis  inhibitors, papaverine  that, since  l e v e l s of  receptor  inhibitors cyclic  but  cyclic  there  and  theophylline.  phosphodiesterase  inhibition  AMP,  potentiation  the  mediated  observed  responses  must t h e r e f o r e This  by. t h e  h a v e b e e n due  AMP  content.  i s an  are  some p r o b l e m s w i t h  phosphoto  the  i n t e r e s t i n g hypo-  this  type  of  an  experiment. • Although an  increase  papaverine  in cyclic  inhibition,  other  and  AMP  l e v e l s through  m e c h a n i s m s may  effects  produced  Scholz,  1971;  Kukovetz  and  1978).  McNeill  et  Korth, of  papaverine  not  by  these  can  McNeill  p r o d u c e an  increasing that  the  the  crease  AMP  theophylline  guinea pig in cyclic  traction  et  occurred  PSch,  1972;  Donges et  guinea to  produced  increase  atria,  was  However,, a  while  the  cyclic  1972; a l . ,  that  inhibit  agents without reported  of  i n force  did  phospho-  these  i n force  levels  effects  pig heart  a l . (1977)  decline  1977;  the  contraction,  c l o s e l y r e l a t e d to  AMP  produce  cardiac  contractile force  Donges et  AMP.  a l . ,  a l . (1974) showed t h a t i n cardiac  to  i n the  a l . (1972) r e p o r t e d i n the  able  phosphodiesterase  (McNeill et  levels.  left  are  involved  their.abilities  increase  cyclic  be  drugs  theophylline  correlate well with  diesterase.  in  and  theophylline  an  of  in-  con-  remained  elevated. There tractility  i s evidence by  increasing  that the  drugs  enhance m y o c a r d i a l  availability  of  cellular  confree  91  calcium  f o r the  1973).  I t has  interaction been  with  contractile  proteins  (Langer ,  shown t h a t . t h e o p h y l l i n e a c c e l e r a t e s  the  45 uptake and  of  Ca  Reuter,  and  increases, the  slow  1976). D i b u t y r y l - c y c l i c  inward  AMP  has  current  (Scholz  a l s o been  shown  4 5 to  increase  It  has  myocardial  therefore  theophylline to  are  agonists  that  AMP  levels,  not  be  mainly  calcium  very  due  responses  E^  and  receptor (Black  et  effects that  activation  may  i n fact  experiments  a protocol E^  receptor  chosen  as  the  i n the  agonists  present  the  i n o t r o p i c e f f e c t s of  E^  (figs.  study  of not  Kukovetz  Therefore, E^  and  the  receptor  increased  inhibition,  that  she  cyclic  may  in  Hughes chose  M c N e i l l and  a t t r i b u t e d t o H^  fact  present  receptor  study  were  t h a t . o f Hughes, but were employed.  indicate that  inhibitor.  and  E^  However.the. c h r o n o t r o p i c  receptor  agonists  were not  Verma  activation.  performed more  selective  Theophylline The  t h e o p h y l l i n e can  b o t h H^  were  receptor  t o E^  26-28).  23-25).  1971;  and  a l . , 1972;  phosphodiesterase  the  and  agonists  h a v e been, due  similar.to  and  (figs.  effects  correct.  the  H^  the  through phosphodiesterase  H^  1973).  involvement'and  (Scholz,  to  et_ a l . ,  cardiac  (1978) a t t r i b u t e d t o  1974a).and  using  the  a n d . M c N e i l l . , . 1977 ) .  the  selective  Therefore  to  inhibition  Hughes  totally The  not  of  (Meinertz  that  1972 ; M a r t i n e z  potentiation  exchange  been proposed  phosphodiesterase  Poch,  Ca  receptor  results  of  potentiate agonists  responses  potentiated.by  was  to  the  H^  theophylline  92  It of  Is possible that  the chronotropic  agonists  lated  a n d E^  to the  high  concentrations  o f .the t e s t  t o be a maximum c h r o n o t r o p i c  right  studies be  responses  a potentiation receptor  b y t h e o p h y l l i n e may. h a v e b e e n m a s k e d b y  relatively appears  our lack of finding  atria  are not able.to  of the chronotropic  carried  out using  lower  drugs.  response  exceed.  There  which  the iso-  Therefore  effects i n the right concentrations  using  further  atria  should  a n d E^  of the  agonists. The  observed  p o t e n t i a t i o n of the i n o t r o p i c response  to  -4 -8 ( 1 x 10 M) a n d i m p r o m i d i n e C l x 10 M) b y -4 t h e o p h y l l i n e ( 3 x 10 M) w a s s i g n i f i c a n t l y d e c r e a s e d b y t h e _5 r e c e p t o r a n t a g o n i s t c i m e t i d i n e ( 1 x 10 M, n o t s h o w n ) . 4-methylhistamine  However, t h e observed  potentiation of the inotropic effect  of  -4  PEA  -4 M) b y t h e o p h y l l i n e ( 3 x 10 M) w a s n o t s i g n i f i c a n t l y _5 b y c i m e t i d i n e ( 1 x 10 M) o r b y t h e H^ r e c e p t o r —6  C l x 10  affected  antagonist  promethazine  potentiation propranalol  was d e c r e a s e d ( 1 x 10  M).  some o f t h e i n c r e a s e d by  theophylline  in  the cyclic  methazine  i( n1 v ox l v10 ed —6  AMP  M, n o t s h o w n ) .  levels.  I t i s thus  antagonist  possible that t o t h e E^  M) may b e a t t r i b u t e d t o a n But since  M) h a d n o e f f e c t  response  However t h e  by t h e b e t a a d r e n e r g i c  i n o t r o p i c response -4  ( 3 x 10  ( 2 x 10  theophylline  ( 2 x 10  i ti s unlikely  at  least  agonists increase  t h e H^ a n t a g o n i s t p r o on t h e combined that  cyclic  PEA-  AMP i s  i n H^ n dhuec ec do m b r ie ns ep do n se ef sf .e c t A s M) d i dr ed ce ec pr te oa rs e i t o f p Pr Eo Ap raann do l o l  93  theophylline, of  the  i t seems l i k e l y  animals  d i d not  that  completely  catecholamines.  Beta receptor  increased  AMP  the  cyclic  nucleotides  This  may  be  e x p l a i n our  responses  to  There mediated  a l . , 1977). of  by  AMP  levels  tissue  known.to  AMP  i n the  contain  pretreatment  tissues  of  Butcher i n the  et  a l . , 1965 ) ,  with and  i n o t r o p i c response. the  inotropic  theophylline. evidence  receptor  cyclic  the  observed .potentiation of  M c N e i l l and  levels  deplete  1975  i s considerable  cyclic  reserpine  stimulation i s associated  involved  agonists  through  increased et  may  (0ye,  the  that  responses which  s t i m u l a t i o n are (Klein Verma  and  associated  Levy,  1971;  (1978) have  isolated  are  with  Reinhardt  shown  rabbit right  increased  atria  (a  r e c e p t o r s ) , f o l l o w i n g exposure  of  _5 the  atria  unable  to  to histamine  (1 x  show c h a n g e s  i n the  conditions shown t o  (Table  precede  (Verma and  But  of  in  the  left  the  atria at  i n the  atria.  atrial  t i s s u e to histamine The  increase  be  levels  present  and  three  were  under  AMP  study  similar  has.been  several  (1 x  minutes  atria,  and  seconds  there  was  at  10  ^M)  for  t o .reach least  five  20  a minutes  f u r t h e r i n v e s t i g a t i o n s of  c a r r i e d out -5 (1 x  We  i n o t r o p i c response  to histamine  Therefore, should  AMP  in cyclic  In the  right  AMP  2 0 seconds.  i n r e s p o n s e by  least  cyclic  intervals.  levels  for  increase  chronotropic  i t took  maximum r e s p o n s e  M)  cyclic  increase  i n the  exposure  seconds.  the  An  M c N e i l l , 1977a).  some i n c r e a s e after  I).  10  10  M)  in. c y c l i c  AMP  after at  exposure  different  levels  after  of  the  time exposure  94  of the tissue  to histamine  too  small to detect  our  results  after  f o r only  i n the present  (Table I )  shows a . s m a l l  exposure of the t i s s u e s  20  s e c o n d s may  study.  have  Closer analyses  increase i n cyclic  to histamine.  been  AMP  of  95  REFERENCES A r u n l a k s h a n a , 0. a n d S c h i l d , H.O. 195 9. 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