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UBC Theses and Dissertations

Calcitonin and electrolyte homeostasis Walker, Valerie Rosemary 1972

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CALCITONIN AND ELECTROLYTE HOMEOSTASIS  by  V a l e r i e Rosemary  Walker  B.A., 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 ,  1959  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF Ph.D.  i n t h e department o f Physiology  We a c c e p t t h i s t h e s i s a s c o n f o r m i n g t o t h e required standard  THE UNIVERSITY OF BRITISH COLUMBIA A u g u s t , 1972  In  presenting  an  advanced degree at  the  Library  I further for  this  shall  agree  scholarly  by  his  of  this  written  thesis the  f u l f i l m e n t of  University  of  make i t f r e e l y that permission  p u r p o s e s may  representatives. thesis  in p a r t i a l  for  be  available  for  for extensive  granted  by  the  It i s understood  financial  gain  permission.  Depa r t m e n t The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, C a n a d a  British  Columbia  shall  requirements  Columbia,  Head o f my  be  I agree  r e f e r e n c e and copying of  that  not  the  that  study.  this  thesis  Department  copying or  for  or  publication  allowed without  my  i  Abstract  The e f f e c t s o f c a l c i t o n i n o n p l a s m a a n d u r i n a r y e l e c t r o l y t e s were s t u d i e d  I.  i n r a t s and sheep.  Twice-daily  lOOg  r a t , i . p . ) t o young  in u r i n e volume of  a d m i n i s t r a t i o n o f salmon c a l c i t o n i n rats over a period  i.p.)  resulted  i n dose-related  over a six-hour However,  o f 10 d a y s r e s u l t e d  a n d t h e e x c r e t i o n o f Na, C a , P, a n d Mg.  graded doses o f salmon c a l c i t o n i n  period.  in contrast  ( 2 5 0 mU(50 n g ) /  Single  i n increases injections  ( 1 0 0 - 2 0 0 0 mU(20-400 n g ) / l 0 0 g r a t ,  increases  i n u r i n e v o l u m e a n d Na  excretion  P h o s p h a t e e x c r e t i o n was a l s o f o u n d t o i n c r e a s e .  t o the chronic  studies, net decreases i n the  e x c r e t i o n o f C a a n d Mg w e r e f o u n d . S i g n i f i c a n t d e c r e a s e s i n p l a s m a C a , inorganic  P, a n d Mg w e r e f o u n d o n e h o u r a f t e r i n j e c t i o n  salmon c a I c i t o n i n / I O O g and  rat, i.v.  o f 100 mU(20 n g )  No s i g n i f i c a n t d e c r e a s e s i n p l a s m a Na  K were o b s e r v e d . The u r i n a r y e l e c t r o l y t e changes t h a t  following tomized 1. m.),  calcitonin administration  also occurred  r a t s and r a t s p r e t r e a t e d , w i t h and were n o t a s s o c i a t e d  endogenous  2.  thyroparathyroidec-  l a r g e d o s e s o f DOCA ( I mg/IOOg r a t , increases  in the excretion of  creatinine.  A one-hour  sheep was a c c o m p a n i e d returned  with  in  occurred  t o normal  i n f u s i o n o f C a ( 1 0 mg C a / k g ) i n i n t a c t c o n s c i o u s by a r a p i d  rise  i n p l a s m a Ca l e v e l s w h i c h r a p i d l y  when t h e i n f u s i o n was s t o p p e d . P l a s m a P l e v e l s  i m m e d i a t e l y d e c r e a s e d f o l l o w i n g t h e s t a r t o f t h e Ca i n f u s i o n . Following greater sheep  t h y r o i d e c t o m y ( T X ) , Ca i n f u s i o n r e s u l t e d increase  in a  significantly  i n p l a s m a Ca ( A 2 . 3 1 + 0 . 1 0 mg%) a s c o m p a r e d  ( A l . 6 0 + 0 . 0 7 mg%),  and t h e r e t u r n  t o w a r d s normal  to intact  l e v e l s was d e l a y e d .  ii  Plasma P  l e v e l s in the  i n f u s i o n , and  at  1/2  (A+0.42+0.07 mg%) In  P,  and  The  TX  s h e e p showed  3. was  e x c r e t i o n of  less than t h a t  TX  rats  Na,  by  in the  resulted infused  three  i n t o TX  resulted  in contrast  4.  the  did  s.c.)  decreased  e x c r e t i o n of  ( 3 0 0 0 U/mg), t h e K as  in  Na  Mg,  well  as  excretion  P.  i n p l a s m a Ca  was  fell  i n Na  findings  the  of  intact  (5 ml  Ca  despite TX  0.9%  sheep  was  saline  not  rat, the  occur  load.  i n 0.9%  NaCl) i n i n t a c t sheep  levels.  When d e x t r a n  but  returned  volume  TX  e x c r e t i o n of using  was  to  normal  expansion increase  animals.  Na,  Ca,  and  (100  Mg,  and  highly-purified  PTH  a l s o d e c r e a s e d and H o w e v e r , no  the  U/IOOg increased  excretion  significant  decrease  found.  These s t u d i e s  indicated that  in  sheep, which  e x t r a c t t o TPTX r a t s  increase.  larger  i n u r i n e v o l u m e and  intact  Mg  a  NaCI/IOOg  n a t r i u r e s i s in the  and  Na,  infusion.  e x c r e t i o n . H o w e v e r , an  In s i m i l a r s t u d i e s  mg%).  animals.  sheep, the  in the  urinary  higher  e x c r e t i o n of  in the  initially  parathyroid  found t o  the  t h e s e changes d i d  G e n t r a n 75  e x c r e t i o n of P was  but  accompany t h e  to the  Na  increases  In b o t h g r o u p s o f  Administration  of  and  s h e e p , p l a s m a Ca  not  in the  in i n t a c t rats  in a s i m i l a r increase  excretion  rat,  found  fall  the  (A-0.66+0.22  f o l l o w i n g t h e Ca  excretion of  i n f u s i o n (6%  hours.  and  hours f o l l o w i n g the  in a sustained  within three  was  P,  i n t a c t sheep  i n u r i n e v o l u m e , and  significant  K, C a ,  Dextran  Ca  increase  e x c r e t i o n , the  followed  in the  during  Volume e x p a n s i o n  i.p.)  in  no  s t a r t of  i n f u s i o n were s i g n i f i c a n t l y  i n u r i n e volume and  were o b s e r v e d  i n Ca  significantly  hour post  increases  Ca,  increase  sheep r o s e f o l l o w i n g the  t h a n plasma P  i n t a c t sheep, Mg  TX  exogenous a d m i n i s t r a t i o n  of  i ii  salmon c a l c i t o n i n a l t e r s the e x c r e t i o n of Na, Ca, in a d d i t i o n to decreasing I n f u s i o n of Ca plasma and  the  l e v e l s of Ca,  P, and Mg  P, and  s a l t s i n i n t a c t sheep r e s u l t e d  Mg  in the  in the  plasma.  i n c e r t a i n changes i n both  u r i n a r y e l e c t r o l y t e s which were not found f o l l o w i n g  t h y r o i d e c t o m y i n t h e s e a n i m a l s . S i n c e e l e v a t i o n of plasma Ca  levels  would i n c r e a s e c i r c u l a t i n g l e v e l s of c a l c i t o n i n i n i n t a c t but not sheep, endogenous r e l e a s e of c a l c i t o n i n was  implicated  changes t h a t were o b s e r v e d .  a l s o be  plasma and  C a l c i t o n i n may  implicated  in the  t h a t c a l c i t o n i n and  Studies PTH  of Na, Ca, and  may Mg.  with various be a c t i n g  since  c e l l s a l t e r e d the p a t t e r n  c e r t a i n e l e c t r o l y t e changes t h a t o c c u r r e d volume e x p a n s i o n .  TX  in the e l e c t r o l y t e  u r i n a r y changes t h a t o c c u r f o l l o w i n g volume e x p a n s i o n  removal of t h e c a I c i t o n i n - c o n t a i n i n g "C"  handling  urine,  PTH  in the  of  i n t a c t animals f o l l o w i n g  preparations  suggested  i n a n t a g o n i s t i c ways i n t h e  renal  iv  TABLE OF CONTENTS  Page ABSTRACT  i  LIST OF TABLES  vi  LIST OF FIGURES  vi i i  ACKNOWLEDGEMENTS  ix  INTRODUCTION  I  GENERAL METHODS AND MATERIALS  8  SPECIFIC METHODS AND RESULTS  14  I.  EXOGENOUS CALCITONIN ADMINISTRATION  14  A. S t u d i e s on R a t s D u r i n g C h r o n i c Administration of Calcitonin  14  B. S t u d i e s on R a t s F o l l o w i n g Injections of Calcitonin  19  1.  II.  III.  Single  Intact rats  19  2. T h y r o p a r a t h y r o i d e c t o m i z e d r a t s  31  CALCIUM INFUSION STUDIES (ENDOGENOUS CALCITONIN RELEASE)  37  Plasma and U r i n a r y E l e c t r o l y t e Changes i n C o n s c i o u s Sheep F o l l o w i n g C a l c i u m Infusion  38  EXTRACELLULAR VOLUME EXPANSION  58  A. U r i n a r y E l e c t r o l y t e Changes i n Rats FoI lowing a S a I i n e Load  58  I. The e f f e c t s o f s a l i n e l o a d i n g i n i n t a c t , TX, and TPTX r a t s  58  TABLE OF CONTENTS ( c o n t i n u e d )  Page 2. The e f f e c t s o f PTH ( L i l l y PTE) on t h e r e s p o n s e o f TPTX r a t s t o s a I i n e load i ng  63  B. The E f f e c t o f PTH on Plasma Ca and U r i n a r y E l e c t r o l y t e s  67  C. Plasma and U r i n a r y E l e c t r o l y t e Changes i n C o n s c i o u s Sheep F o l l o w i n g Dextran I n f u s i o n  76  EXOGENOUS CALCITONIN ADMINISTRATION  92.  A. C h r o n i c S t u d i e s  92  B. A c u t e S t u d i e s  93  DISCUSSION I.  II.  III.  1. Plasma changes  93  2. U r i n e changes  95  CALCIUM  INFUSION STUDIES (ENDOGENOUS  CALCITONIN RELEASE)  102  EXTRACELLULAR VOLUME EXPANSION  107  A. Volume Expansion i n R a t s  107  B. PTH and Renal E l e c t r o l y t e Changes  109  C. Volume Expansion  116  i n Sheep  1. Plasma changes  116  2. U r i n e changes  I 17  SUMMARY AND CONCLUSIONS I. II.  III. BIBLIOGRAPHY  123  Exogenous C a l c i t o n i n A d m i n i s t r a t i o n  125  C a l c i u m I n f u s i o n S t u d i e s (Endogenous C a l c i t o n i n Release)  125  C a l c i t o n i n and Volume Homeostasis  126 128  L I S T OF T A B L E S  The e f f e c t o f salmon c a l c i t o n i n on urinary electrolytes in dextrose-infused rat E f f e c t s o f salmon c a l c i t o n i n on electrolyte excretion in intact  urinary rats  Plasma e l e c t r o l y t e changes f o l l o w i n g salmon c a l c i t o n i n i n i n t a c t r a t s The e f f e c t s o f s i m u l t a n e o u s administration o f DOCA a n d c a l c i t o n i n o n u r i n a r y electrolyte excretion in intact rats E f f e c t o f c a l c i t o n i n on u r i n a r y electrolyte excretion in rats of ages  different  Urinary electrolyte excretion i n TPTX a n d TX r a t s f o l l o w i n g s a l m o n c a l c i t o n i n The e f f e c t o f c a l c i t o n i n o n u r i n a r y electrolyte excretion i n TPTX a n d i n t a c t rats Control urinary e l e c t r o l y t e excretion in TPTX, TX, and i n t a c t r a t s d u r i n g a 24hour c o l I e c t i o n P l a s m a c h a n g e s f o l l o w i n g Ca i n f u s i o n i n t a c t , T X , a n d TX + CT s h e e p  in  C h a n g e s i n u r i n e v o l u m e f o l l o w i n g Ca i n f u s i o n i n i n t a c t , T X , a n d TX + CT s h e e p C h a n g e s i n o s m o l a l o u t p u t f o l l o w i n g Ca i n f u s i o n i n i n t a c t , T X , a n d TX + CT s h e e p U r i n a r y P e x c r e t i o n f o l l o w i n g Ca i n i n t a c t , TX, a n d TX + CT s h e e p  infusion  Changes i n u r i n a r y e l e c t r o l y t e excretion f o l l o w i n g Ca i n f u s i o n i n i n t a c t , T X , a n d TX + CT s h e e p  VI  L I S T OF T A B L E S  (continued)  Table XIV  XV  XVI  XVII  XVIII  XIX  XX  XXI  XXII  XXIII  XXIV  Page E f f e c t s o f s a l i n e l o a d i n g on u r i n a r y electrolyte excretion i n i n t a c t , TX, a n d TPTX r a t s  60-61  T h e e f f e c t o f PTE o n u r i n a r y excretion following a saline TPTX r a t s  65  electrolyte load i n  E f f e c t o f T C A - p r e c i p i t a t e d PTH and PTE o n t h e r e s p o n s e o f i n t a c t r a t s s a l i n e loading PTE  Lilly to 69-70  Log-dose response rats  to L i l l y  i n TPTX  Log-dose response i n TPTX r a t s  to highly-purified  71  Plasma changes f o l l o w i n g d e x t r a n i n i n t a c t , TX, a n d TX + CT s h e e p  PTH 72  infusion 79  Changes i n u r i n e volume f o l l o w i n g d e x t r a n i n f u s i o n i n i n t a c t , T X , a n d TX + CT s h e e p  82  Changes i n o s m o l a l o u t p u t f o l l o w i n g i n f u s i o n i n i n t a c t , TX, a n d TX + CT  83  C l e a r a n c e o f Ca f o l l o w i n g d e x t r a n i n i n t a c t , T X , a n d TX + CT s h e e p  dextran sheep infusion  86  Urinary P excretion following dextran i n f u s i o n i n i n t a c t , TX, and TX + CT s h e e p  87  Changes i n u r i n a r y e l e c t r o l y t e excretion f o l l o w i n g d e x t r a n i n f u s i o n i n i n t a c t , TX, a n d TX + CT s h e e p  89  I  vi i i  L I S T OF FIGURES  Figure 1  2  3  4  5  6  7  8  9  Page Time-course of action o f a s i n g l e i n j e c t i o n o f salmon c a l c i t o n i n ( 2 5 0 mU/100 g body w e i g h t , i . p . ) on p l a s m a Ca l e v e l s i n s i x - w e e k - o l d rats.  15  U r i n e volume changes i n r a t s treated c h r o n i c a l l y w i t h salmon c a l c i t o n i n ( 2 5 0 mU/100 g body w e i g h t , i . p . t w i c e daily).  16  The e f f e c t o f c h r o n i c t r e a t m e n t w i t h s a l m o n c a l c i t o n i n ( 2 5 0 mU/100 g b o d y weight, i . p . , t w i c e d a i l y ) on urinary electrolyte excretion i n young r a t s .  18  E l e c t r o l y t e c h a n g e s i n 460-g r a t (age s e v e n m o n t h s ) g i v e n 5 0 0 mU c a l c i t o n i n , i . v . during dextrose(2.5$)s a l i n e (75 meq/l) i n f u s i o n g i v e n a t a rate of 3ml/hr.  21  U r i n a r y changes i n young r a t s i n r e s p o n s e t o graded doses o f salmon c a l c i t o n i n .  24  Comparison o f a b s o l u t e changes i n urinary e l e c t r o l y t e excretion i n response to a single injection of c a l c i t o n i n ( 1 0 0 mU/100 g b o d y w e i g h t , i . p . ) i n t o non-DOCA t r e a t e d a n d DOCA t r e a t e d r a t s .  29  Changes i n plasma Ca l e v e l s f o l l o w i n g Ca i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p i n f u s e d w i t h salmon c a l c i t o n i n (2 U / k g / h r ) .  40  C h a n g e s i n p l a s m a P l e v e l s f o l l o w i n g Ca i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p i n f u s e d w i t h salmon c a l c i t o n i n (2 U / k g / h r ) .  43  C h a n g e s i n p l a s m a Mg l e v e l s following Ca i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p i n f u s e d w i t h salmon c a l c i t o n i n (2 U/kg/hr).  44  IX  L I S T OF  FIGURES  (continued)  Figure 10  11  12  13  14  15  16  17  18  19  20  Page Changes i n u r i n e volume and o s m o l a l o u t p u t f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, a n d TX s h e e p i n f u s e d w i t h s a l m o n c a l c i t o n i n (2 U / k g / h r ) .  45  C h a n g e s i n U.. V f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, a n d TX s h e e p i n f u s e d w i t h s a l m o n c a l c i t o n i n (2 U / k g / h r ) .  49  C h a n g e s i n Up V f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, a n d TX s h e e p infused w i t h salmon c a l c i t o n i n (2 U / k g / h r ) .  50  C h a n g e s i n U V d u r i n g t h e p e r i o d o f Ca i n f u s i o n i n i n d i v i d u a l i n t a c t , TX, a n d TX s h e e p i n f u s e d w i t h s a l m o n c a l c i t o n i n (2 U / k g / h r ) .  51  C h a n g e s i n U^ V f o l l o w i n g Ca i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p i n f u s e d w i t h salmon c a l c i t o n i n (2 U / k g / h r ) .  52  C h a n g e s i n U^V a n d U„ ^ V f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, and TX s h e e p i n f u s e d w i t h s a l m o n c a l c i t o n i n (2 U / k g / h r ) .  54  p  Changes i n u r i n a r y e l e c t r o l y t e e x c r e t i o n i n i n t a c t , TX, a n d TPTX r a t s d u r i n g t h e f i r s t t h r e e hours f o l l o w i n g a s a l i n e load (.0.9% N a C l , 5 m l / 1 0 0 g b o d y w e i g h t , i . p . ) .  62  T h e e f f e c t o f L i l l y PTE ( 1 0 0 U/IOOg body w e i g h t , s . c . ) o n t h e r e s p o n s e o f TPTX r a t s t o a s a l i n e load as compared t o t h e r e s p o n s e i n TX r a t s w i t h f u n c t i o n i n g parathyroid transplants.  66  T i m e - c o u r s e o f a c t i o n o f L i l l y PTE ( 1 0 0 U / I 0 0 g body w e i g h t , s . c . ) o n p l a s m a Ca l e v e l s i n TPTX r a t s .  74  Log-dose response t o L i l l y TPTX r a t s .  75  PTE i n  C h a n g e s i n p l a s m a Ca l e v e l s f o l l o w i n g a 15-minute d e x t r a n i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p t r e a t e d w i t h s a l m o n c a l c i t o n i n ( 2 X 50 U).  77  X  L I S T OF  FIGURES  (continued)  Figure 21  22  23  24  25  Page C h a n g e s i n p l a s m a P a n d p l a s m a Mg f o l l o w i n g a 15-minute d e x t r a n i n f u s i o n i n i n t a c t , I X , a n d TX s h e e p t r e a t e d w i t h s a l m o n c a l c i t o n i n ( 2 X 50 U ) . Changes  80  i n u r i n a r y volume and U  V osm f o l l o w i n g a 15-minute d e x t r a n i n f u s i o n i n i n t a c t , TX, and TX s h e e p t r e a t e d w i t h s a l m o n c a l c i t o n i n ( 2 X 50 U ) .  81  C h a n g e s i n U V and U ^ V f o l l o w i n g a 15m i n u t e d e x t r a n i n f u s i o n i n i n t a c t , TX, and TX s h e e p t r e a t e d w i t h s a l m o n c a l c i t o n i n (2 X 50 U ) .  85  C h a n g e s i n U^ V f o l l o w i n g a 1 5 - m i n u t e d e x t r a n i n f u s ? o n i n i n t a c t , TX, a n d TX sheep t r e a t e d w i t h salmon c a l c i t o n i n ( 2 X 50 U ) .  88  C h a n g e s i n U^V a n d ^r f ^ following a 15-minute d e x t r a n i n f u s i o n i n i n t a c t , TX, a n d TX s h e e p t r e a t e d w i t h s a l m o n c a l c i t o n i n ( 2 X 50 U).  91  N g  rea  xi  AcknowIedgements  The a u t h o r  wishes t o extend  Committee f o r t h e i r continued and  f o r t h e i r help  special  interest  and d i r e c t i o n  t o her  in the experimental  in p r e p a r a t i o n of t h e  The g u i d a n c e  thanks  studies  thesis.  o f D r . R.  Keeler, the  Committee Chairman, i n t h e approach t o renal p h y s i o l o g y i s greatly  appreciated.  Many t h a n k s Mr. with  a r e a l s o extended t o Dr. J .  K. H e n z e , a n d M r . G. surgical  constant  for instruction  and a s s i s t a n c e  techniques.  To h e r R e s e a r c h continual  Schulz  Ledsome,  S u p e r v i s o r , D r . D.H.  Copp,  for his  i n s p i r a t i o n and d i r e c t i o n , and t o t h e "Lab" f o r t h e i r support  and  fellowship,  the author  i s deeply  indebted.  INTRODUCTION  The e l e c t r o l y t e s i n t h e e x t r a c e l l u l a r f l u i d at constant This  levels despite  wide a l t e r a t i o n s i n mineral  c o n s t a n c y depends on t h e e x i s t e n c e  of e f f i c i e n t  m e c h a n i s m s , many o f w h i c h a r e h u m o r a l . concerned  with  (ECF) a r e m a i n t a i n e d  This  thesis  intake o r excretion. homeostatic is primarily  t h e r o l e o f c a l c i t o n i n a s one o f t h e hormones  which can  m o d i f y t h e l e v e l s o f c e r t a i n body e l e c t r o l y t e s i n t h e ECF. consideration in t h i s  of t h e a c t i o n of parathyroid  investigation since  hormone (PTH)  i t i s becoming  i s a target  house o r r e s e r v e source of mineral t o t h e body. of  the total  firmly  the  of mineral  obtained  which,  in contrast  from d i e t a r y s o u r c e s ,  M o s t o f t h e b o d y ' s Ca body Na and Mg,  (99%)  and  store-  to the fluctuating  i s constantly  inorganic  available  P (85%),  and a b o u t 8% o f t h e K i n t h e body  50% i s i n bone.  i s r e a d i l y e x c h a n g e a b l e , and r e l e a s e o f t h e m o r e with  f a c t o r s which  may  b o n e b r e a k d o w n o r r e s o r p t i o n . Hormones w h i c h c a n i n f l u e n c e  r e s o r p t i o n o r a c c r e t i o n o f bone  found  that  ways.  bound f r a c t i o n c a n a l s o o c c u r c o i n c i d e n t  initiate  included  s i t e f o r both o f t h e s e hormones and s e r v e s a s a  supply  Some o f t h i s m i n e r a l  i s also  increasingly apparent  c a l c i t o n i n and PTH c a n a c t i n a n t a g o n i s t i c  Bone  However,  i n f l u e n c e t h e movement o f t h o s e  either minerals  i n bone.  The p a r a t h y r o i d p l a s m a Ca is secreted  level.  g l a n d s have a c r i t i c a l  Parathyroid  role in maintaining  a  hormone f r o m t h e c h i e f c e l l s o f t h e s e  i n r e s p o n s e t o a h y p o c a l c e m i c s t r e s s and a c t s  by  normal glands  enhancing  2  osteolysis  ( I ) , resulting in the release  Hypomagnesemia hormone  was a l s o  shown  i n iri v i t r o  ( 2 ) , a n d PTH a d m i n i s t r a t i o n  f r o m b o n e t o ECF  (3, 4 ) .  Parathyroid  major  bone  hormone h a s a l s o  release  i s also  released  lowered plasma  been i m p l i c a t e d (7).  of  this  f r o m b o n e by  P level  a s Ca  PTH.  following  PTH  hormone  (5,6).  i n t h e movement o f Na f r o m  Thus, i t would  appear  that  PTH  bone  i s one o f  h o r m o n e s w h i c h c a n i n i t i a t e t h e movement o f e l e c t r o l y t e s f r o m t h e  pool.  The s e c o n d calcitonin. older  major  This  hormone  involved  was d i s c o v e r e d  activity  a n d t h u s may a l s o  bone ( 9 ) .  i n t h e dynamics  C a l c i t o n i n i s described  (8).  I t has been r e p o r t e d  be i n v o l v e d  It i s released  o f bone m i n e r a l  is  m o r e r e c e n t l y t h a n PTH a l t h o u g h i t i s a n  hormone p h y l o g e n e t i c a l l y .  d e p r e s s e s bone r e s o r p t i o n  new  t o cause  i s secondary t o t h e phosphaturlc a c t i o n of t h i s  i n r e s p o n s e t o Na d e p l e t i o n the  studies  r e s u l t s i n movement o f Mg a s w e l l  Phosphate  However, t h e o b s e r v e d e f f e c t o f a administration  o f Ca f r o m b o n e t o t h e ECF.  i n mineral  a s a hormone  that  t o enhance o s t e o b l a s t i c  accretion  i n response t o an e l e v a t e d  and f o r m a t i o n  plasma  Ca  of  level,  d e p r e s s e s b o n e r e s o r p t i o n , a n d t h u s r e d u c e s t h e i n p u t o f b o n e Ca t o t h e ECF so t h a t the  plasma Ca  l e v e l s are returned  involvement of c a l c i t o n i n i n phosphate  recognized. treatment  The hypophosphatemia i s apparently  t o PTH s t i m u l a t i o n still  of t h i s  no p l a s m a  f a c t t h a t a Mg  lowering load  i s observed  Ca, that  i tacts  been  i s not secondary homeostasis i s  i n a s i m i l a r way  i s by l o w e r i n g  bone r e s o r p t i o n  years,  following calcitonin  T h e r o l e o f c a l c i t o n i n i n Mg  i o n a s i t does w i t h  Mg  h o m e o s t a s i s has a l s o  i s some e v i d e n c e t h a t  l e v e l s as a r e s u l t of decreasing found  which  (10). During recent  a d i r e c t a c t i o n o f t h e hormone a n d  (II-14).  not c l e a r . There  control  the  t o normal  (4, 15).  e f f e c t o f c a l c i t o n i n ( 1 6 - 18).  plasma  in the  Mg  O t h e r s have Nevertheless,  r e s u l t s i n a h y p o c a l c e m i c r e s p o n s e , prov ided t h e  3 caIcitonin-containing be i n v o l v e d  a r e two m a j o r hormonal  a p p e a r t o be w o r k i n g  in opposite  may  s y s t e m s , PTH a n d c a l c i t o n i n ,  d i r e c t i o n s with  b o n e a c c r e t i o n . The d u a I - h o r m o n a I c o n c e p t  C a by PTH a n d c a l c i t o n i n  i s now w e l l  ship  o f t h e s e two hormones  found  i n bone i s f a r f r o m c l e a r .  input of mineral  respect  t o bone  which  resorption  (20) o f t h e c o n t r o l o f plasma  accepted.  in the control  Besides the input of mineral an  suggests that c a l c i t o n i n  i n Mg m e t a b o l i s m a s w e l l ( 1 9 ) .  Thus t h e r e  and  "C" c e l l s a r e i n t a c t ,  However, t h e  of the other  interrelation-  major e l e c t r o l y t e s  f r o m t h e b o n e p o o l , t h e ECF a l s o  from t h e gut v i a i n t e s t i n a l  absorption.  receives  Once t h e  e l e c t r o l y t e s a r e i n t h e ECF, t h e y c a n e i t h e r be t a k e n up by c e l l s o r b o n e , o r c a n be l o s t f r o m t h e b o d y v i a v a r i o u s control  mechanism must t h e r e f o r e  excretory  have n o t o n l y  m e c h a n i s m s . An  efficient  some i n f l u e n c e o n t h e  i n p u t t o t h e E C F , b u t a l s o some i n f l u e n c e o n t h e o u t p u t f r o m i t .  Parathyroid increasing (21, of  hormone r a i s e s p l a s m a Ca a n d Mg t o n o r m a l  t h e r a t e o f b o n e r e s o r p t i o n a n d by d e c r e a s i n g  5, 6, 2 2 - 2 6 ) a n d Mg  these  protect  (24-26) i n t h e u r i n e .  ions from t h e kidney t u b u l e , t h e bone f r o m undue  l e v e l s o f Ca a n d Mg  in  t h e l o s s o f Ca  increased  reabsorption  u n d e r t h e i n f l u e n c e o f PTH,  loss of mineral  t h e ECF.  An  l e v e l s by  and would  The p h o s p h a t u r i c  help  restore  A l b r i g h t and E l l s w o r t h  phosphaturia occurred  i m m e d i a t e l y f o l l o w i n g PTH t r e a t m e n t . T h i s  stimulated  (27) f i r s t observed t h a t  i n a hypophosphatemia which they e r r o n e o u s l y  i n d i r e c t c a u s e o f t h e Ca r e l e a s e  from bone.  by t h e i n v e s t i g a t i o n s o f B a r n i c o t  h a v e shown t h a t t h e a c t i o n o f PTH o n b o n e major e f f e c t on phosphate exerted  by PTH  normal  e f f e c t o f PTH h a s b e e n  known f o r many y e a r s .  resulted  would  Numerous  considered studies  a  in turn as t h e  since  then,  (28) and G a i l l a r d ( 2 9 ) ,  i s a d i r e c t one.  However, t h e  i s n o t v i a b o n e b u t by  kidney.  4  The  r o l e of the kidney as a p o s s i b l e t a r g e t organ of  is only just i n t h e ECF  becoming  by  recognized. Calcitonin  inhibiting  C a l c i t o n i n may which would observed  d e c r e a s e s t h e amount o f  bone r e s o r p t i o n a n d ^ s  by d e c r e a s i n g t h e r e a b s o r p t i o n o f t h i s  has  Mg  i o n f r o m t h e k i d n e y t u b u l e ([4, by t h e k i d n e y  lowering e f f e c t which  following c a l c i t o n i n treatment.  Calcitonin  to cause a phosphaturic response. Since t h i s  effect  calcitonin administration 32,  16) h a s  The  changes  e i t h e r PTH major  implicated  glands (11-14).  i s followed  this  in the renal  or calcitonin administration  t a r g e t o r g a n o f t h e s e h o r m o n e s . The  of  either  mental  (31,  14,  well.  electrolytes  following  t h a t the kidney i s a  changes  intervention  t h a t occur as  bone. However, t h e  evidence i s f a r from complete f o r c l a r i f y i n g  second  in reabsorptive  ions f o l l o w i n g  hormone c a n e n h a n c e o r m o d i f y t h e plasma  a r e s u l t o f t h e a c t i o n o f PTH o r c a l c i t o n i n o n  that  response  apparent changes  to certain  in  hypocaIcemic  homeostasis as  indicate  (30)  b e e n shown  The o b s e r v a t i o n  excretion of certain  c a p a c i t y of the kidney t u b u l e c e l l s  has a l s o  by a n a t r i u r e t i c  h o r m o n e i n Na  30).  i s sometimes  i s a l s o found  parathyroidectomized a n i m a l s , i t i s not secondary t o stimulation of the parathyroid  Ca  been s u g g e s t e d ,  a l s o d e c r e a s e t h e r e a b s o r p t i o n o f Mg  enhance t h e plasma  calcitonin  experi-  t h e a c t i o n o f PTH  or  c a l c i t o n i n on t h e k i d n e y .  The  p a r t i c i p a t i o n o f PTH  intensively considered normal  explored.  and c a l c i t o n i n  A l d o s t e r o n e and  i n Na  h o m e o s t a s i s has  the renin-angiotensin  n o t been  system  are  t o be t h e p r i m a r y h o r m o n e s c o n c e r n e d w i t h t h e m a i n t e n a n c e  a m o u n t o f Na  aldosterone,  i n t h e ECF.  Alterations  i n a d d i t i o n t o changes  hemodynamics, o r " S t a r l i n g  in the c i r c u l a t i n g  in glomerular f i l t r a t i o n  of a  l e v e l s of  rate  (GFR),  f o r c e s " w i t h i n t h e k i d n e y a r e t h o u g h t t o be  the  5 major c o n t r o l l i n g mechanisms explanation  for thecontrol  i n Na r e g u l a t i o n  (33-35).  i n r e s p o n s e t o ECF v o l u m e e x p a n s i o n  cross-circulation involved the  when i n j e c t e d systems  into assay r a t s  The o b s e r v a t i o n  its  (40).  inthe regulation of this  calcitonin  f a c t o r has been found i n  man a n d s h e e p w h i c h c a u s e d a n a t r i u r e s i s Therefore, a search f o r f u r t h e r  important  ion i s indicated.  suggests t h e v a l u e o f an i n t e n s i v e study o f t h i s  r e l a t i o n t o Na c o n t r o l .  i n some p a r t o f t h e n e p h r o n C a  pathway  (45).  known  i f hormonally-induced changes i n t h e renal  leled  by s i m i l a r c h a n g e s i n N a .  understand  deal  hormone and  A p a r a l l e l i s m seems t o e x i s t i n t h e r e n a l  Na may s h a r e a common r e a b s o r p t i v e  A great  control  t h a t a n a t r i u r e s i s accompanies t h e a d m i n i s t r a t i o n o f  hand I i n g o f Ca a n d Na ( 4 1 - 4 4 ) , a n d a t l e a s t and  suggests that t h e f a c t o r ( s )  i n nature. Also, a Na-losing  plasma and u r i n e o f s a l t - l o a d e d  l o s s o f Na c a n s t i l l  ( 3 6 , 3 7 ) , and e v i d e n c e f r o m  (38, 39) and o t h e r s t u d i e s  i s humoral  this  o f body Na i s n o t e n t i r e l y s a t i s f a c t o r y .  When a l l t h e s e v a r i a b l e s a r e c o n t r o l l e d , a n i n c r e a s e d occur  However,  of experimental  However,  handling  i ti s not  o f Ca a r e p a r a l -  work has been p e r f o r m e d i n a n a t t e m p t t o  t h e a c t i o n o f PTH o n t h e k i d n e y . Many o f t h e f i n d i n g s r e s u l t i n g  f r o m t h i s work have been r e v i e w e d  by R a s m u s s e n  (46).  These s t u d i e s  have  c o n c e n t r a t e d o n t h e C a , P, a n d Mg c h a n g e s t h a t o c c u r f o l l o w i n g PTH administration, or theclinical of  the parathyroid  gland.  abnormalities  However, p o s s i b l e  o t h e r e l e c t r o l y t e s h a s n o t been w i d e l y  The s t u d i e s that occur or during  reported  that  maneuvers d e s i g n e d  malfunction  i n v o l v e m e n t o f PTH i n r e g a r d  to  investigated.  i n t h i s thesis explore  i n plasma and u r i n e  r e s u l t from  t h e e l e c t r o l y t e changes  f o l l o w i n g exogenous c a l c i t o n i n a d m i n i s t r a t i o n ,  t o promote endogenous c a l c i t o n i n r e l e a s e .  6  It  was  hoped t h a t a c o n c u r r e n t s t u d y o f  calcitonin  involvement would  mechanism of  These  a c t i o n of  this  p l a s m a and  lead t o a g r e a t e r  urine  understanding of  of  i n v e s t i g a t i o n s were prompted  treatment  observations  and  n a t r i u r e s i s and by  by  the  revealed  a  author's observation  showed t h a t  been  the  a l s o changes  confirmed  d i u r e t i c r e s p o n s e was  in other urinary  and  these  a  initial  a c c o m p a n i e d by  with  the  renal  e f f e c t s of  a  10-day  electrolytes. Earlier  Rasmussen e t a j _ . (31)  i n v e s t i g a t i o n of  that  a studies  porcine c a l c i t o n i n but  at  salmon c a l c i t o n i n  had  reported.  These gations  initial  findings with  salmon c a l c i t o n i n led t o f u r t h e r  investi-  in order to e s t a b l i s h :  Was  the  for  example, r e l a t e d to  (b)  Was  the  (c)  Were t h e o b s e r v e d  (d)  V/ere c h a n g e s In mi n e r a l o c o r t i c o i d a c t i v i t y  (e)  Would e l e c t r o l y t e c h a n g e s s i m i l a r t o t h o s e f o u n d  e f f e c t of  p l a s m a Ca  the  hormone o n  release of  I eve I per renal  the  se  the  responses a  k i d n e y a d i r e c t one  PTH  in response to  initiating  factor?  r e s u l t of  changes  implicated  o r was  i n GFR? i n any  way?  following  endogenous Iy-reI eased  hormone i n r e s p o n s e t o  l e v e l s which are  If t h e  release  elevated  p l a s m a Ca  of c a l c i t o n i n (47,  caIcitonin-containing  "C"  c h a n g e s t h a t o c c u r f o l l o w i n g Ca  i t ,  hypocalcemia?  exogenous c a l c i t o n i n t r e a t m e n t o c c u r w i t h  increase (f)  during  n a t r i u r e t i c r e s p o n s e f o l l o w i n g hormone a d m i n i s t r a t i o n ,  t h a t t i m e no  (a)  in r a t s . Repeat s t u d i e s  A r d a i l l o u _£+£_[_• ( 1 4 )  the  hormone.  profound d i u r e t i c response t o salmon c a l c i t o n i n o c c u r r e d period  following  known  to  48)?  cells stress  are  removed, a r e  altered?  the e l e c t r o l y t e  7 (g)  Is t h e n a t r i u r e s i s which accompanies t h e i n c r e a s e d Ca f o l l o w i n g Ca s t r e s s  (h)  (49-54) r e l a t e d t o c a l c i t o n i n  i s c a l c i t o n i n involved  secretion?  i n t h e n a t r i u r e s i s and c a l c i u r e s i s t h a t  f o l l o w i n g volume e x p a n s i o n ( 4 1 , 43, 55, 44, The e x p e r i m e n t s r e p o r t e d answer t h e s e q u e r i e s .  excretion  occur  56)?  i n t h i s t h e s i s were d e s i g n e d  i n an a t t e m p t t o  8  GENERAL METHODS AND  ExperimentaI  MATERIALS  an imaIs and d i e t s  R a t s : Male r a t s of t h e Long-Evans s t r a i n were used i n a l l r a t s t u d i e s and were s u p p l i e d by B l u e Spruce Farms, C h a r l e s R i v e r , Ont. maintained  They were  on P u r i n a Rat Chow and water and were w i t h o u t food d u r i n g  c o l l e c t i o n periods unless otherwise s t a t e d . Sheep: Female lambs, f i v e - s i x months of age, were o b t a i n e d s t u d i e d d u r i n g t h e e n s u i n g six-month  t i m e s e x c e p t f o r 24 hours p r i o r t o and removed. An  Both r a t and  iodized s a l t  Procedures  hay, and  during experimental  l i c k was  water a t a I I  p e r i o d s when  a l s o provided.  sheep d i e t s c o n t a i n e d V i t a m i n s A and D i n amounts  c o n s i d e r e d adequate f o r normal n u t r i t i o n and metabolism t h e Food and  were  p e r i o d . These a n i m a l s were g i v e n  f r e e a c c e s s t o crushed o a t s , Omolene ( P u r i n a ) , a l f a l f a  food was  l o c a l l y and  as recommended by  N u t r i t i o n Board, N.R.C., Canada.  f o r pIasma and u r i n e c o l l e c t i o n s  R a t s : Blood samples were o b t a i n e d e i t h e r from t h e t a i l  v e i n o r by c a r d i a c  p u n c t u r e , depending on t h e number o f a n a l y s e s t o be performed. U r i n e c o l l e c t e d w h i l e a n i m a l s were housed i n metabolism  cages (Acme Metal  P r o d u c t s , C i n c i n n a t i , Ohio) o r i n some s t u d i e s by f r a c t i o n a l v i a a bladder  was  collection  cannula.  Sheep: Blood samples were o b t a i n e d from a c a t h e t e r (Abbocath c a t h e t e r , Abbott  L a b o r a t o r i e s , M o n t r e a l , Que.)  inserted  18-guage i v .  into the  lateral  9  saphenous v e i n . The c a t h e t e r a l l o w e d f r e q u e n t blood sampling and was removed a t t h e end o f each e x p e r i m e n t . C a t h e t e r , 14 FR, C R .  Bard  p r i o r t o each experiment  A b l a d d e r c a t h e t e r (Bardex  International  Foley  L t d . , England) was a l s o i n s e r t e d  and u r i n e was c o l l e c t e d d u r i n g 15-minute  intervals  w i t h u n i n t e r r u p t e d f l o w f o l l o w i n g an e q u i l i b r a t i o n p e r i o d o f one hour. These c a t h e t e r s were h e l d i n p o s i t i o n by i n f l a t i o n o f an i n t e r n a l 5-cc ba I I con.  Surgical Rats:  Procedures  A l l s u r g e r y was performed w i t h t h e a i d o f a d i s s e c t i n g  w h i l e t h e a n i m a l s were a n a e s t h e t i z e d w i t h e t h e r . i n v o l v e d t h e removal o f both t h y r o i d s and t h e c o n n e c t i n g  microscope  Thyroparathyroidectomy  lobes o f t h e t h y r o i d w i t h t h e a t t a c h e d isthmus.  para-  Thyroidectomy included t h e s e p a r a t i o n  o f t h e s u p e r i o r p a r a t h y r o i d s from u n d e r l y i n g t h y r o i d t i s s u e on each lobe and their  immediate t r a n s p l a n t a t i o n deep i n t o t h e muscle mass o f t h e p o s t e r i o r  a s p e c t o f t h e t h i g h . The t h y r o i d t i s s u e was then c o m p l e t e l y removed. C o n t r o l a n i m a l s were s u b j e c t e d t o sham s u r g e r y which s i m p l y c o n s i s t e d o f exposure o f t h e t h y r o i d complex. The e f f e c t i v e n e s s o f t h e s u r g e r y was determined  two  weeks a f t e r s u r g e r y by plasma Ca measurements f o l l o w i n g o v e r n i g h t s t a r v a t i o n . Those a n i m a l s w i t h plasma Ca l e v e l s below thyroparathyroideetornized Ca  7.5 mg% were c o n s i d e r e d  successfully  (TPTX), and t h e t r a n s p l a n t a n i m a l s w i t h plasma  l e v e l s g r e a t e r than 9.0 mg% were c o n s i d e r e d e f f e c t i v e l y  thyroidectomized  (TX). Plasma Ca l e v e l s i n i n t a c t c o n t r o l a n i m a l s were a l s o determined  at  t h i s time. Those r a t s w i t h t h y r o i d s removed were immediately  s t a r t e d on t h y r o x i n e  ( S y n t h r o i d - S o d i u r n L e v o t h y r o x i n e , U.S.P., F l i n t L a b o r a t o r i e s , A l l i s t o n , Ont.)  10  which they obtained T h i s d o s e was  Sheep:  from t h e i r  based on  Thyroidectomy  anaesthesia  following  a study  initial  Since the parathyroids  thyroid  gland, thyroidectomy  thyroid  t r a n s p l a n t s and  the connecting were g i v e n Flint  Kennedy and  w  i  +  Talmage  Sodium  e  i n s e r t i o n o f an  removal isthmus.  thyroid  an  which the  a c t i v i t y of s t u d i e s . The  hypocalcemic  Standard  (MRC)  I % NaAc  i n 0.\%  was  (PTE)  para-  Following surgery, the  in a daily oral  dose of  5 0 0 0 MRC  (Armour P h a r m a c e u t i c a l U/mg  was  I mg  and animals  U.S.P., (58).  a c t i v i t y of the  response  was  pH  Hormone: B o v i n e  obtained  Kankakee,  hormone was  determined  The  v e h i c l e used  by  bioassay  Kumar e t a I . ( 5 9 )  compared t o t h a t o f M e d i c a l  B of porcine c a l c i t o n i n . glycine,  Co.,  used f o r a l l c a l c i t o n i n  i n young r a t s a c c o r d i n g t o a m o d i f i c a t i o n o f t h e method o f  and  the  lobes  t h y r o x i n e (Synthroid-Sodiurn Levothyroxine,  Pure salmon c a l c i t o n i n  administration  Parathyroid  from  Infusates  CaIcitonin:  in  endotracheal  necessity of  o f t h e two  oxide  (Abbott  separate*  performed without the  c o n s i s t e d of  ug/l .  (57).  p ntothaI  n  i n sheep a r e c o m p l e t e l y was  100  under h a l o t h a n e - n i t r o u s  which enabled  L a b o r a t o r i e s , A l l i s t o n , Ont.)  having  performed  induction  more caudaI I y - p I a c e d  replacement  H o r m o n e s and  III.)  by  i n s h e e p was  L a b o r a t o r i e s , M o n t r e a l , Que.) tube.  d r i n k i n g water a t a c o n c e n t r a t i o n of  Research  for calcitonin  was  4.6.  PTH  was  used  i n v a r i o u s degrees of  f o r a l l PTH  purity.  ( P a r a - t h o r - m o n e , U.S.P., E l i L i l l y  Co.  Lilly  administration studies Parathyroid Extract  Canada, L t d . , Toronto,  Ont.),  O c c a s i o n a l l y , t h e s m a l l i n f e r i o r p a r a t h y r o i d s may be i n c o r p o r a t e d i n t h e t h y r o i d mass. However, t h e p r e d o m i n a n t s u p e r i o r p a r a t h y r o i d s a r e q u i t e d i s t i n c t and a r e f o u n d h i g h up i n t h e t h y m u s t i s s u e .  11  TCA-precipifated  PTH ( 2 4 0 U/mg)  ( 3 0 0 0 U/mg), k i n d l y p r o v i d e d  and a f u r t h e r h i g h l y p u r i f i e d  by D r . N a d i n e W i l s o n  used f o r t h e d i f f e r e n t i n v e s t i g a t i o n s .  of this  Bioassays  preparation  laboratory,  were  f o r PTH w e r e b a s e d o n t h e  method o f C a u s t o n e t a I . ( 6 0 ) .  Desoxycorticosterone  acetate  (DOCA):  Percorten  (Ciba Co., L t d . ,  Q u e . ) , a s y n t h e t i c m i n e r a l o c o r t i c o i d , was u s e d t o s i m u l a t e of  Dorval,  the activity  aldosterone.  D e x t r a n : 6% G e n t r a n 75 i n 0.9% Morton Grove,  I I I . ) was u s e d  s o l u t i o n (Travenol  Laboratories, Inc.,  f o r t h e volume e x p a n s i o n s t u d i e s  D e x t r o s e - S a I ? n e : 5% d e x t r o s e Malton,  NaCl  a n d 0.9$ N a C l , U.S.P.  O n t . ) was u s e d a s t h e i n f u s i o n v e h i c l e  (Baxter  i n sheep.  Laboratories,  in the C a C ^ studies in  sheep.  CaCI ^ s o l u t i o n : a  d o s e o f 10 mg  Plasma and u r i n e Blood  C a C ^ was d i s s o l v e d  determined  analyses  samples were c o l l e c t e d i n h e p a r i n i z e d  (Mg), sodium  measured.  separated.  (Na),  timed  and p o t a s s i u m  (Ca),  The a n a l y s e s  samples, urine analyses (U  r  immediately  inorganic  (K) c o n c e n t r a t i o n s  phosphorus ( P ) , were  i n some s t u d i e s .  u r i n e samples were c o l l e c t e d and t h e volume were c a r r i e d o u t immediately f o l l o w i n g  In a d d i t i o n t o t h e a n a l y t i c a l  excretion  Calcium  tubes,  t h e same d a y a n d o s m o l a l i t y was a l s o m e a s u r e d  Individual  solution t o give  Ca/kg/hour.  c e n t r i f u g e d , and t h e plasma magnesium  in dextrose-saline  also  , V). This  collection.  p r o c e d u r e s which were c a r r i e d o u t on plasma i n c l u d e d a measurement o f endogenous c r e a t i n i n e  measurement gave an i n d i c a t i o n o f changes i n  12  GFR  and a l s o o f c o m p l e t e n e s s o f b l a d d e r  were a l s o d e t e r m i n e d  Ana I y t i c a I CaIciurn: N-31  emptying. Urine osmolal  concentrations  i n some s t u d i e s .  Methods P l a s m a Ca was  P, m o d i f i e d  measured  on t h e T e c h n i c o n A u t o A n a l y z e r ,  by Newsome ( 6 1 ) . U r i n e Ca c o n c e n t r a t i o n s w e r e  by A t o m i c A b s o r p t i o n  Method measured  S p e c t r o p h o t o m e t r y u s i n g t h e J a r r e l l - A s h Model  280  Atom-  sorb.  Phosphorus:  Both plasma and  A u t o A n a l y z e r , M e t h o d N-4  u r i n e samples were measured  b which  on t h e T e c h n i c o n  i s based on t h e method o f F i s k e and  Sub-  barow ( 6 2 ) .  Magnesium:  P l a s m a and  u r i n e samples were measured  S p e c t r o p h o t o m e t r y u s i n g t h e J a r r e l l - A s h Model  Sodium and on  Potassium:  Instrumentation  C r e a t i n i ne:  and  C r e a t i n i n e was  143 f l a m e  estimated  E r b a A u t o m a t i c A n a l y z e r , Model  point depression Precision  StatisticaI  and  using t h e Osmette  Systems,  Atomsorb.  CLA  by  emission  photometer.  as the a l k a l i n e  f o r use on automated  OsmolaI i t y : O s m o l a l i t y o f plasma  Absorption  u r i n e samples were measured  L a b o r a t o r i e s Model  method b e i n g m o d i f i e d (Carlo  Plasma  280  by A t o m i c  picrate,  colorimetric  the  analyzers  1510).  u r i n e s a m p l e s was  measured  P r e c i s i o n Osmometer, Model  by f r e e z i n g 2007  Inc.  Methods  Student's t  test  f o r s m a l l , unpaired  e v a l u a t i o n o f t h e d a t a . Where £ v a l u e s were c o n s i d e r e d  significantly  of  different.  g r o u p s was  used  for  statistical  <_ 0.050 w e r e f o u n d , t h e  results  13  Abbrev i a t i o n s Clearance  of x;  t h e number of ml of plasma c o m p l e t e l y  cleared  of  s u b s t a n c e x_ per m i n u t e : C  = U V = Urine concentration Plasma  X Volume of u r i n e e x c r e t e d  (ml) X minute  concentration x_  CT  Calcitonin  ECF  Extracellular fluid  GFR  Glomerular f i l t r a t i o n  mg^  mg  per  Na/Creat.  rate  100 ml s o l u t i o n The  r a t i o of sodium t o endogenous c r e a t i n i n e i n t h e u r i n e . T h i s  r a t i o g i v e s an a p p r o x i m a t i o n assuming plasma sodium and d u r i n g the e x p e r i m e n t a l  of t h e f r a c t i o n a l  e x c r e t i o n o f sodium,  c r e a t i n i n e c o n c e n t r a t i o n s a r e unchanged  period.  Na/K  The  r a t i o of sodium t o p o t a s s i u m i n t h e u r i n e .  P  The  chemical  and  u r i n a r y phosphate s i n c e t h e chemical  a b b r e v i a t i o n f o r phosphorus i s used when r e f e r r i n g t o plasma a n a l y s i s measures i n o r g a n i c  phosphorus. PTE  Lilly  parathyroid extract.  PTH  P a r a t h y r o i d hormone. T h i s term i s used when r e f e r r i n g g e n e r a l l y t o parathyroid  TCA-precipitated The  hormone. PTH  T r i c h l o r o a c e t i c - a c i d p r e c i p i t a t e d parathyroid  a b b r e v i a t i o n s PTE  and  TCA-precipitated  i n a d d i t i o n t o t h e term h i g h l y - p u r i f i e d PTH  PTH  (240  (3000 U/mg)  U/mg)  x  ,  a r e used t h e n  comparing t h e r e s p o n s e s t o hormone p r e p a r a t i o n s of v a r y i n g U V  hormone.  degrees  of p u r i t y . The r a t e of e x c r e t i o n o f a g i v e n s u b s t a n c e x i n t h e u r i n e : U V = u r i n e x concentration X Volume of u r i n e e x c r e t e d X t i m e '. x  14  S P E C I F I C METHODS AND RESULTS  I.  EXOGENOUS C A L C I T O N I N ADMINISTRATION A.  S t u d i e s o n R a t s P u r i ng C h r o n i c  Adrnirii s t r a t i o n o f C a I c i t o n i n  Methods Thirty-day-old for  12  housed  i n metabolism  cages  10 d a y s a n d u r i n e was c o l l e c t e d o v e r 2 4 - h o u r p e r i o d s . T h e y h a d f r e e  access 250  r a t s were i n d i v i d u a l l y  t o food  and w a t e r d u r i n g  mU s a l m o n c a l c i t o n i n  t h i s t i m e p e r i o d . Ten r a t s were each  i . p . i n v e h i c l e (\% NaAc  h o u r s a n d a c o n t r o l g r o u p o f 10 a n i m a l s  same t i m e . order  A p r e l i m i n a r y study  given  i n 0.\% g l y c i n e , pH 4 . 6 ) e v e r y  was g i v e n  vehicle only a t t h e  o n r a t s o f a s i m i l a r a g e was p e r f o r m e d i n  t o determine t h e hypocalcemic  response t o t h i s  d o s e o f hormone a n d  to determine t h e constancy o f t h e hypocalcemia during  a 10-day  period.  Results In F i g . I i t c a n be s e e n t h a t s a l m o n c a l c i t o n i n  exerts a long-lasting  h y p o c a l c e m i c r e s p o n s e f o l l o w i n g a s i n g l e i n j e c t i o n o f t h e hormone. Twice-daily a d m i n i s t r a t i o n of c a l c i t o n i n maintained throughout t h e experimental  The  period as revealed  p o l y u r i a which accompanied c h r o n i c  h o r m o n e was t h e i n i t i a l of c a l c i t o n i n  i n renal  observation  that  a hypocalcemic  by r a n d o m s p o t  checks.  a d m i n i s t r a t i o n °^ t h e  indicated a possible  involvement  f u n c t i o n . In some i n s t a n c e s , 7 5 - g r a t s  a s much a s 4 5 - 5 0 ml o f u r i n e p e r d a y .  state  excreted  F i g u r e 2 shows t h e p e r s i s t e n t a n d  progressive  polyuria during  t h e 10-day p e r i o d o f t r e a t m e n t  with  salmon  calcitonin,  t h e d i f f e r e n c e i n u r i n e volume between t h e c a I c i t o n i n - t r e a t e d  I5  II.OT  10.0 £  9.0-1  E  O o E  CO  8.0-  7.0-1  o  0_  Mean ± S E M 6.0 H 5.0  J  2  Fig  I.  Time  —i 4  in  1—:—r Hours  6  Time-course of a c t i o n of a s i n g l e injection o f s a l m o n c a l c i t o n i n ( 2 5 0 ml)/100 g b o d y w e i g h t , i . p . ) o n p l a s m a Ca l e v e l s i n s i x - w e e k o l d r a t s . E a c h p o i n t r e p r e s e n t s t h e Mean +_ SEM of f ive animaIs.  -i 8  16  26 -, «- 22O  I  2  3  4 Time  Fig  2.  5  6 in  7  8  9  Days  U r i n e volume changes i n r a t s t r e a t e d c h r o n i c a l l y w i t h salmon c a l c i t o n i n (250 mU/100 g body w e i g h t , i . p . t w i c e d a i l y ) , (n = 10 r a t s per group.)  10  17 and  control animals  Urinary P  (UpV)  seen  g  of  e x c r e t i o n of  i n F i g . 3.  An  Na  mean o u t p u t f r o m Day  i n U^V  was  different  ( U ' ^ V ) , Ca  increase  initial  were found t o o c c u r  increase UpV  significantly  were a l s o found t o  elevated U^ V  being  < U V ) , Mg C g  4 - Day  10.  M  f r o m Day  in the c a I c i t o n i n - t r e a t e d rats occurred  in U  N g  V),  V was  Significant  4 of treatment,  found t o occur  <U  2.  and  i n t h e c a I c i t o n i n - t r e a t e d r a t s as  t r a n s i e n t increase  f r o m Day  f r o m Day  increases  whereas the  2 - Day only  followed  7.  An  during  the  is by  an  in  greatest increased  first  five  days  treatment.  This  study  indicated that  i n young r a t s c o u l d e l e c t r o l y t e s as  increase the  w e l l as  urine  chronic treatment  with  normal e x c r e t i o n o f  volume.  salmon  calcitonin  certain urinary  18  f  ~  60  i  40 X  > 3>cr  eg  3  Si  20  o  n  a O  0  Calcitonin Vehicle  C  a-  lOOOn  S —  400-  0  J  l U i I l w i i I  2  3  4 Time  F i g 3.  5 in  6  7  8  9  10  Days  The e f f e c t o f c h r o n i c t r e a t m e n t w i t h salmon c a l c i t o n i n (250 mU/100 g body w e i g h t , i . p . , t w i c e d a i l y ) on u r i n a r y e l e c t r o l y t e e x c r e t i o n i n young r a t s . Mean o u t p u t s a r e shown from groups o f t e n r a t s . S i g n i f i c a n t increases in e l e c t r o l y t e e x c r e t i o n a r e i n d i c a t e d by an a s t e r i s k (*).  19  B.  I.  Stud i e s on R a t s F o l l o w i n g  S i ngIe I n j e c t i o n s of C a I c i t o n i n  Intact Rats Methods In o r d e r t o d e t e r m i n e t h e t i m e - c o u r s e of t h e u r i n a r y e l e c t r o l y t e  changes t h a t o c c u r f o l l o w i n g a s i n g l e i n j e c t i o n of c a l c i t o n i n , u r i n e c o l l e c t e d during was  timed  c a n n u l a t e d and  i n t e r v a l s from i n d i v i d u a l r a t s i n which t h e  a c o n s t a n t i n f u s i o n o f 2.5$  These r a t s were r e s t r a i n e d  c o l l e c t i o n p e r i o d and t h e s t a r t of the  were a l l o w e d  given  in a holding  v i a the  s t u d i e s , t h e a n i m a l s were p r e - l o a d e d w i t h  external  device during  to e q u i l i b r a t e for several  i n f u s i o n b e f o r e c a l c i t o n i n was  bladder  dextrose or dextrose  (2.5$)-saI i n e ( 7 5 meq/l) a t a r a t e of 3 ml/hour was jugular vein.  was  given.  the  hours f o l l o w i n g  In some of  these  l a r g e doses of DOCA (1-1.5 m g / r a t ) .  S i n c e t h e major e l e c t r o l y t e changes appeared t o o c c u r w i t h i n a period  f o l l o w i n g hormone a d m i n i s t r a t i o n , t h i s p e r i o d was  collection  chosen f o r  six-hour urine  i n subsequent s t u d i e s .  Graded doses of c a l c i t o n i n were t h e n g i v e n t o s e p a r a t e groups of r a t s and  one  group was  given v e h i c l e only.  E l e c t r o l y t e changes were  measured a t t h e s e v a r i o u s dose l e v e l s i n a d d i t i o n t o changes i n endogenous creatinine  excretion.  Plasma e l e c t r o l y t e l e v e l s were a l s o d e t e r m i n e d experiments with animals starved Blood samples were o b t a i n e d 10-11  r a t s a t one  hour and  i n a f u r t h e r s e r i e s of  12 hours p r i o r t o hormone a d m i n i s t r a t i o n .  by c a r d i a c p u n c t u r e on s e p a r a t e g r o u p s o f three  groups were g i v e n v e h i c l e and  hours a f t e r hormone i n j e c t i o n . C o n t r o l  were b l e d a t s i m i l a r t i m e s .  20  In o r d e r  to determine  i f changes  in m i n e r a l o c o r t i c o i d  block or  p o t e n t i a t e the  natriuretic  injected  i n t o groups of  intact rats with  administration.  The  Appropriate  e f f e c t o f age  on  since  i t i s known t h a t t h e  greater  i n young r a p i d l y - g r o w i n g  and  u r i n e was  Control  5 - w e e k - o l d and  the  calcitonin simultaneously.  response to c a l c i t o n i n  animals than 28-week-old  same a g e  without  was  was  also  hypocalcemic e f f e c t of c a l c i t o n i n  collected over a period  groups of  and  g r o u p s were f o l l o w e d  urinary  studied  s t u d y , groups of  r e s p o n s e t o c a l c i t o n i n , DOCA  control  the  levels could  of  24  in adults  (63).  r a t s were g i v e n hours  In  this  calcitonin,  in six-hour  d i f f e r e n c e were g i v e n  is far  vehicle  intervals. only.  ResuIts As  can  graphically  be  seen  in Table  i n F i g . 4,  a  I , and  natriuretic  i n a n o t h e r e x p e r i m e n t shown response occurred  h o u r f o l l o w i n g hormone a d m i n i s t r a t i o n . A t and  the  general  r a t i o s of decrease  marked a t a b o u t comparing the  Na/K in  and  UQ V  | 1/2-2  changes  3  t h e s e two  Table  i o n s was  N a / C r e a t . were a l s o  and  U^gV  i n L)Q  in the  v a  and  U^V  immediate  in the  increase  seven-month-old  half  u r i n e volume,  increased.  UpV,  However, a  found. These r e s p o n s e s were most  in Table  i t i s seen t h a t the  I, whereas a t r a n s i e n t  observed  was  first  hours f o l l o w i n g c a l c i t o n i n a d m i n i s t r a t i o n .  calcitonin administration, of  t h i s time,  in the  I and  Fig. 4  decrease  three-month-old in the  rat studied  in F i g .  4.  following  in the  excretion  rat studied  e x c r e t i o n o f Ca  In  and  Mg  in was  F i g 4.  E l e c t r o l y t e changes i n 460-g r a t (age seven months) g i v e n 500/mll c a l c i t o n i n , i . v . d u r i n g d e x t r o s e ( 2 . 5 % ) s a I i n e (75 meq/l) i n f u s i o n g i v e n a t a r a t e of 3ml/hour.  TABLE I  The e f f e c t of salmon c a l c i t o n i n on urinary  electrolytes  i n dextrose-infused r a t * Time  Vol/lOOg/hr  Na  K  Ca  P  Mg  Creat.  Na/K  Na/Creat.  (hr)  (ml)  yequiv/lOOg/hr  •2h ~ 2  0.594  38.0  69.5  14.4  250  121.3  309  0.547  0.123  -2 - 1»5 IH - 1  1.862  7.4  46.6  9.2  279  100.5  205  0.160  0.036  2.683  13.4  37.6  14.5  215  102.0  188  0.357  0.071  -1 -  *t  2.972  17.8  47.6  16.7  208  136.7  208  0.375  0.085  -  0  1.538  23.1  89.2  11.8  461  152.3  200  0.258  0.115  1.241  54.6  120.4  8.8  918  114.2  211  0.453  0.258  1.958  68.5  101.8  7.5  1410  76.4.  215  0.673  0.318  2.220  62.2  66.6  6.2  1043  42.2  178  0.933  0.350  1.556  82.5  70.0  4.9  902  56.0  187  1.177  0.441  1.792  52.0  52.0  6.9  860  35.8  179  1.000  0.290  1.136  36.4  37.5  5.1  608  40.9  148  0.969  0.246  3 - 3>5  2.194  35.1  39.5  3.9  899  43.9  198  0.888  0.177  3*s " 4 4 - 4*5 4% - 5  1.503  37.6  33.1  8.1  736  76.7  188  1.136  0.200  1.294  38.8  33.6  8.4  725  88.0  181  1.153  0.214  2.281  25.1  25.1  10.3  707  93.5  205  1.000  0.122  1.040  46.8  36.4  10.5  385  171.6  198  1.285  0.236  0.760  52.4  41.0  10.1  502  126.9  190  1.277  0.275  1.084  41.2  41.2  10.0  650  124.7  173  1.000  0.238  ug/lOOg/hr  Control  -H  Calcitonin 0 H  -  1  1 - Us 1*5 - 2 2 - 2H 21j - 3  5 -  SH  5H - 6  6 -  6H  Ia tt 3tm ?l //h o u r'. rT-! . -!?^' , C a l c i t o n i n ( 2 5 0 mU, 9  ra+  h  3  S;  We  229 9>  P r e + r e a + e d  wi+h  1-5 mg DOCA, i.m. a n d i n f u s e d i . v . ) g i v e n a t time 0 hour.  w i t h 2.5% d e x t r o s e  23 Changes  in urinary  excretion over a six-hour  period  a r e shown  i n F i g . 5 w h e r e r e s p o n s e s t o 0, 10, 1 0 0 , 5 0 0 a n d 2 0 0 0 ml) c a l c i t o n i n p e r 100 g body w e i g h t a r e i n d i c a t e d .  Itwill  be n o t e d t h a t  increases  i n urine  v o l u m e a n d t h e e x c r e t i o n o f Na w e r e r e l a t e d t o t h e d o e s o f hormone Increases  i n P e x c r e t i o n and d e c r e a s e s  a l s o f o u n d . However, a t t h e h i g h e s t  given.  i n t h e e x c r e t i o n o f Ca a n d Mg w e r e  dose  level  ( 2 0 0 0 mU) t h e r e d u c t i o n ,  i n t h e e x c r e t i o n o f Ca a n d i n p a r t t h a t o f Mg was o v e r c o m e .  A n a l y s i s o f a n o t h e r s t u d y a t t h e 100 mU d o s e shows a n i n c r e a s e calcitonin by  i n t h e Na/K r a t i o w h i c h  treatment since t h e increase  l i t t l e o r no i n c r e a s e  gives  following  were found  not changed. hours a f t e r  e x c r e t i o n o f Na, a l s o  i n t h e plasma  i n Table  The decrease  concentrations  Table  III.  i n plasma  Plasma  increased  in  and w i t h o u t  r e s p o n s e s when  calcitonin  I t c a n be s e e n t h a t DOCA c a u s e d  V, a c c o m p a n i e d  by a s l i g h t d e c r e a s e  i n U^V.  by t h e DOCA. When  a t t h e same t i m e a s DOCA, t h e a b s o l u t e  i n U., V v/as v i r t u a l l y t h e same a s t h a t Na '  time  controls.  i n rats with  H o w e v e r , t h e e x c r e t i o n o f C a , P, a n d Mg was u n a f f e c t e d was a d m i n i s t e r e d  were  Mg l e v e l s a t t h i s  d i f f e r e n t from t h e v e h i c I e - i n j e c t e d  i n a d d i t i o n t o DOCA t r e a t m e n t .  rats  o f C a , P, a n d Mg  Ca a n d P was a l s o s i g n i f i c a n t a t t h r e e  I t a l s o compares t h e r e l a t i v e  s i g n i f i c a n t decrease  treated  which  Na a n d K c o n c e n t r a t i o n s  IV c o m p a r e s t h e e l e c t r o l y t e o u t p u t s  DOCA a d m i n i s t r a t i o n .  calcitonin  accompanied  ( 1 0 0 mll/100 g body w e i g h t , i . v . )  i n j e c t i o n o f t h e hormone a l t h o u g h p l a s m a  were n o t s i g n i f i c a n t l y  a  following  The r a t i o o f Na/Creat.,  following calcitonin administration  a t o n e hour a s i s seen  given  i n v a r i a b l y occurred  hormone a d m i n i s t r a t i o n .  S i g n i f i c a n t decreases  was  i n T a b l e II  i n Na e x c r e t i o n was  in K excretion.  an i n d i c a t i o n o f t h e f r a c t i o n a l  level  found  increase  i n t h e non-DOCA, c a l c i t o n i n -  (non-DOCA, c a I c i t o n i n - t r e a t e d : 11.4  uequiv/1OOg/hr;  DOCA,  24  F i g 5.  U r i n a r y changes i n young r a t s i n r e s p o n s e t o graded doses o f salmon c a l c i t o n i n a d m i n i s t e r e d i . p . U r i n e was c o l l e c t e d o v e r a s i x - h o u r p e r i o d . Each bar i n d i c a t e s t h e Mean + SEM i n s i x r a t s .  TABLE I I Effects  Treatment  o f salmon c a l c i t o n i n on u r i n a r y e l e c t r o l y t e  excretion  P Mg ug/IOOg/hr  in intact  Volume ml/IOOg/hr  Na K uequiv/IOOg/hr  Ca  Vehicle (9)  0.264 +0.054  27.3 +3.1  41.3 +2.2  12.1 +1.1  414 +29  86.4 +8.3  120 +4  0.658  0.225  Calcitonin (12)  0.542 +0.059  57.9 +5.7  36.9 +1.5  6.6 +1.0  455 +29  19.2 +3.7  130 +4  1.569  0.440  p  <0.005  <0.00l  NS  <0.005  NS  <0.00l  Creat.  rats*  Na/K  Na/Creat.  NS  *Age o f r a t s , 3 m o n t h s . U r i n e c o l l e c t e d over s i x hours f o l l o w i n g injection 100 mU/100 g body w e i g h t , I . p . Mean + SEM; n = number i n p a r e n t h e s i s .  of salmon  calcitonin,  TABLE I I I  Plasma e l e c t r o l y t e  changes f o l l o w i n g salmon in i n t a c t r a t s *  Ca  Na  Treatment  calcitonin  meg/ I  mg%  O n e - h o u r samp I e Vehicle  (10)  141 + 1  4.1+0.2  8.98+0.14  7.41+0.26  2.339+0.077  138+1  3.8+0.I  7.19+0.15  5.31+0.19  2.027+0.083  NS  NS  Vehicle (II)  128+1  4.1+0.I  8.55+0.14  8.55+0.14  2.096+0.077  CaIc iton in ( I I )  129+1  4.0+0.I  6.14+0.06  6.22+0.08  I.983+0.054  NS  NS  Calcitonin  (10)  <0.00l  <0.00l  <0.025  T h r e e - h o u r samp Ie  <0.00l  <0.00l  *Age o f r a t s , 26 d a y s . D o s e o f c a l c i t o n i n , 100 mU/100 g body w e i g h t , i . v . A n i m a l s b l e d by c a r d i a c p u n c t u r e and s t a r v e d 12 h o u r s p r i o r t o s t u d y . Mean +_ SEM; n_ = number i n p a r e n t h e s i s .  NS  TABLE IV The e f f e c t s o f s i m u l t a n e o u s a d m i n i s t r a t i o n o f DOCA a n d c a l c i t o n i n o n u r i n a r y electrolyte excretion i n intact rats*  Vo1ume Treatment  Na  K  Ca  P  Mg  ml/IOOg/hr  usqu i v/1 OOg/hr  Vehicle (6)  0.239 +0.025  22.6 +3.2  49. 1 +5. 5  18.0 + 1 .8  226 +58  94. 7 +3. 5  Calcitonin (6)  0.318 +0.041  34.0 +4.6  51 . 6 +3. 3  6.9 + 1 .5  468 +56  63. 5 + 12.9  DOCA + Vehicle(6)  0.205 +0.035  8.6 + 1 .4  42. 3 +2. 4  20.8 +6.9  308 + 19  91 .4 +9. 6  DOCA + C a 1 c i t o n1n (6)  0.201 +0.035  18.7 +3.7  50. 0 +3. 4  7.8 +2.9  435 +39  47. 4 +8. 8  Creat.  Na/K  Na/Creat  yg/lOOg/hr  146 +8  0.484  0.155  162  0.689  0.216  134 +8  0.201  0.067  147 +4  0.367  0.126  +1 1  *Age o f r a t s , t w o m o n t h s . DOCA, I mg/100 g body w e i g h t , i.m.; C a l c i t o n i n , 100 mU/IOOg body w e i g h t , Urine c o l l e c t i o n over s i x hours. Mean + SEM; n = number i n p a r e n t h e s i s .  I. p.  28  10.1  ca I c i t o n i n - t r e a t e d ; UpV  in DOCA-treated  from t h o s e found changes rats  in urinary e l e c t r o l y t e  i n j e c t i o n of following  on  are  calcitonin  V was  greater  persisted  m o r e a c u t e and  rats  balanced  by  (a)  calcitonin  i n j e c t i o n of studies,  (b) of  (c)  '  The  The  t h e r e were net  u r i n a r y changes  for a  intact  the  the  than  in the  older  given a  it  was  in  in these  studies  calcitonin older  hormone i n t h e  in the  rats  single  period  rats  in response to time  a  % drop  However,  response  rats  so  younger  animals.  single  injection  that:  but  U^V  in c o n t r a s t to  decreases  in U  n  Ca  occurred  the  V and  U^ V g  following  findings  U.,  Mg  in the  a  single  chronic  V.  were r e l a t e d  to  the  dose  given.  plasma changes which o c c u r r e d  However, a  hours a f t e r  six-hour  5-week-old  longer period of  in  DOCA-treated  response to  younger r a t s .  i n u r i n a r y v o l u m e and  urinary collections Mg.  in the  different absolute  non-DOCA and  during the  i n u r i n e v o l u m e , l l ^ V , and  changes  appreciably  and  6.  hormone i n t h e  experiments  calcitonin,  calcitonin  in the  immediate response t o  indicated  Increases  the  larger  ^^V,  a n i m a l s . The  natriuretic  a more p r o l o n g e d  In summary, t h e of  much  ages the  t h a t the was  was  i n U^gV,  rats. Also during t h i s time period  different  administration  in F i g .  i t i s seen t h a t the  28-week-old  rats of  were not  excretion  shown  a d m i n i s t r a t i o n of  and  a  given c a l c i t o n i n  Changes  i n non-DOCA, c a I c i t o n i n - t r e a t e d  In T a b l e V,  U^ V  rats  given c a l c i t o n i n  in the  u e q u i v/1 0 0 g / h r ) .  indicated  significant  i n j e c t i o n of  within  the  time  s i g n i f i c a n t decreases decrease  h o r m o n e , and  i n p l a s m a Mg no  was  interval  of  i n plasma Ca, not  P,  found a t  s i g n i f i c a n t changes  in  the and three  plasma  Na  Ca  -Z  12SZ o> 10O O 8V > 6-  cr  Mg  12£ \  10-  >§'. = i : <u 2 •  la-  DOCA treated  —  s' 6  4-  =3.+ 2 -  -2  [ ] Non-DOCA treated  60-,  \  a. o 3  250  200 150  O  <J \ 100' CP  _5  50-  50-  f  " JZ \ O  3  Q  30-  >  I  40-  <3 o> 2 0 —  + 10- 10-  4  20-  6  30-  8  40-  10  50-  I  12-  14  Comparison o f a b s o l u t e changes i n u r i n a r y e l e c t r o l y t e e x c r e t i o n i n response t o a s i n g l e i n j e c t i o n o f c a l c i t o n i n (100 mU/100 g body w e i g h t , i . p . ) i n t o non-DOCA t r e a t e d a n d DOCA t r e a t e d r a t s . ( C o m p i l e d f r o m T a b l e I V )  E f f e c t of c a l c i t o n i n on urinary Age (wks) 28  Weight (g) 474 +18  460 +23  135 +6  130 +6  ^Calcitonin,  Treatment Vehicle  Time (hr)  K  Ca  P  Mg ug/lOOg/hr  Creat  13.8 +1.7  24.5 + 2.0  11.1 + 1.9  223 + 18  16.1 + 4.3  115 +2  0.567  6-12  0.119 +0.410  4.5 +0.68  11.1 + 1.6  5.3 + 1.1  127 + 20  17 .4 + 4.8  101 +11  0.437  12-24  0.151 +0.350  4.2 + 0.54  6.3 + 1.4  3.4 +0.6  181 + 25  8.1 +1.4  92 +7  0.800  0-6  0.299 +0.019  24.3 +3.5  26.5 + 1.5  5.4 +0.8  322 +18  2.6 + 0.3  128 + 11  0.915  6-12  0.162 +0.029  12.1 +1.5  8.0 + 1.1  3.4 + 0.7  189 + 22  1.7 +0.3  90 +8  1.633  12-24  0.371 +0.124  18.4 + 5.2  4.9 + 1.4  3.7 + 0.5  190 +4 2  16.6 + 2.5  0-6  0.314 +0.055  20.0 +1.4  41.0 + 3.2  68.6 +18.4  362 + 66  6-12  0.256 +0.061  9.5 +0.4  24.3 + 4.0  18.8 +4.4  12-24  0.244 +0.041  11.2 + 1.7  15.6 + 1.7  0-6  0.704 +0.086  63.8 + 5.3  6-12  0.314 +0.105  12-24  0.377 +0.071  (5)  Calcitonin  Na  yequiv/10 Og/hr  0.195 +0.024  (5)  Vehicle  Volume ml/lOOg/hr  0-6  (5)  Calcitonin  Table V e l e c t r o l y t e excretion i n r a t s of d i f f e r e n t ages*  (5)  121 +11  5.208  79.6 +14.3  122 +5  0.502  352 + 58  58.9 +8.3  95 +7  0.447  4.6 +1.9  508 + 32  22.2 +9 . 4  87 +6  0.790  50.9 +3.7  21.7 + 4.3  525 +25  9.1 +2.5  123 +11  1.272  15.3 + 1.2  19.5 + 2.5  5.4 + 1.1  509 +66  16.3 + 5.9  102 +11  0.826  7.7 +2.1  14.8 + 2.7  10.8 + 3.7  769 + 119  59.0 +18.5  100 mU/IOOg, i . p . g i v e n a t t i m e 0 h o u r .  Mean +_ SEM;  98 +8  n = number i n p a r e n t h e s i s .  0.498  31  Na  and K were found a t e i t h e r one o r t h r e e hours a f t e r  injection of c a l -  citonin.  (d)  The a b s o l u t e  unaffected  (e)  in  V i n r e s p o n s e t o c a l c i t o n i n was  by l a r g e d o s e s o f t h e s y n t h e t i c  C a l c i t o n i n c a u s e d a g r e a t e r a n d more  changes  i n the excretion  in o l d e r  2.  increase  DOCA.  immediate response  in the  o f N a , C a , P a n d Mg  i n young r a t s t h a n  i t did  rats.  Thyroparathyroidectomized Since hypocalcemia  calcitonin  rats  i s known t o s t i m u l a t e  i nthe intact rats  experiments  PTH r e l e a s e ,  induced a l o n g - a c t i n g  and s i n c e  hypocalcemic  i n the urine  following  c a l c i t o n i n t r e a t m e n t were a  r e s p o n s e t o t h e hormone o r were p e r h a p s s e c o n d a r y t o  stimulation.  response,  i n TPTX r a t s w e r e c a r r i e d o u t i n o r d e r t o d e t e r m i n e w h e t h e r t h e  e l e c t r o l y t e changes primary  mineralocorticoid,  Were t h e y  related  to thealtered  parathyroid  plasma Ca l e v e l p e r s e ?  Methods Groups o f r a t s were t h y r o p a r a t h y r o i d e c t o m i z e d according  t o Surgical  Procedures  i n t h e GENERAL METHODS s e c t i o n .  g r o u p s o f r a t s were w i t h o u t t h y r o i d only difference parathyroid  t i s s u e , and t h u s  b e t w e e n them was t h e p r e s e n c e  transplants,  m a i n t a i n a normal  and t h y r o i d e c t o m i z e d  as indicated  lacked  functioning  of these rats t o  p l a s m a Ca l e v e l . T h u s , t h e TX a n i m a l s w e r e a n  appropriate control  g r o u p f o r t h e TPTX r a t s .  g i v e n c a l c i t o n i n and t h e i r u r i n a r y  Both groups were t h e n  e l e c t r o l y t e outputs  were  both  "C" c e l l s , t h e  i n t h e TX g r o u p o f  by t h e a b i l i t y  Since  32  measured o v e r a p e r i o d o f s i x hours. A f u r t h e r to  comparison of t h e response  c a l c i t o n i n was made b e t w e e n TPTX a n d i n t a c t  Control were a l s o altered  rats.  u r i n e o u t p u t s d u r i n g v a r i o u s t i m e p e r i o d s f r o m 3-24  examined  i n t h e TPTX a n d TX r a t s  pattern of e l e c t r o l y t e  with widely d i f f e r e n t  resting  excretion p l a s m a Ca  i n order t o determine  was e v i d e n t  hours i f an  i n t h e s e two g r o u p s  levels.  Results T a b l e VI shows t h e e f f e c t s excretion  i n TPTX and TX r a t s .  reduction  in the natriuretic  the  compared t o t h o s e r a t s  a consistent finding  The in  response occurred  having  p a t t e r n of changes  groups o f r a t s  r a t s as i s seen  tissue  response  TPTX  rats, was  studies.  in other urinary  parameters  i n t h e TPTX  was s i m i l a r t o t h a t f o u n d  i n T a b l e s VI a n d V I I .  Thus i n a l l  rats  in the  three  despite the altered  levels  i n t h e TPTX r a t s  ( p l a s m a C a : 5.78+0.32 mg%)  normal  p l a s m a Ca  i n t h e TX a n d i n t a c t r a t s  levels  by t h e p r e s e n c e o r  glands.  shown i n T a b l e V I I I ,  intact:  despite  (TX a n d i n t a c t ) ,  e x o g e n o u s c a l c i t o n i n was u n a l t e r e d  absence of t h e parathyroid  mg%;  in  no  (TPTX, TX, and i n t a c t ) , t h e d i r e c t i o n o f t h e e l e c t r o l y t e  changes f o l l o w i n g  As  In f a c t , a n e v e n g r e a t e r  parathyroid  response t o c a l c i t o n i n administration  TX a n d i n t a c t  i n t h e TPTX r a t s  of t h e n a t r i u r e t i c response  in these  electrolyte  I t i s e v i d e n t from t h i s study t h a t  absence of t h e p a r a t h y r o i d glands.  was f o u n d . T h e p o t e n t i a t i o n as  o f c a l c i t o n i n on u r i n a r y  10.20+0.13 mg%),  p e r i o d was r e m a r k a b l y s i m i l a r  the excretion  resting  p l a s m a Ca  a s compared t o t h e ( p l a s m a C a , TX:  10.13+0.12  o f Na a n d K o v e r a 2 4 - h o u r  in t h e t h r e e groups of  rats.  TABLE VI  Urinary e l e c t r o l y t e excretion i n TPTX and TX rats following salmon c a l c i t o n i n * Group  TPTX 1st 3 hr  Plasma Ca  Volume  mg%  ml/10Og/hr  Na  K  Ca  yequiv/lOOg/hr  P  Mg  Creat. Na/K  Na/Creat.  ug/lOOg/hr  6.16 ±0.14  Vehicle (8)  0. 507 ±0. 073  43 .3 ±8 .3  57.,6 ±8,.2  71..5 ±16,.4  136 ±23  101..2 ±16,.8  139 ±14  0. 773  0..312  Calcitonin (10)  0. 536 ±0. 067  81 .6 ±10 .5  77.,9 ±8..0  36..3 ±8,.6  356 ±38  53,.2 ±9,.5  133 ±11  1. 064  0,.611  Vehicle  0. 236 ±0. 036  24 .9 ±5 .5  27.,1 ±5.,5  39.,7 ±6.,8  51 ±10  50..6 ±10.,8  87 ±17  0. 963  0.,286  Calcitonin  0. 633 ±0. 079  93 .1 ±15 .8  46..5 ±5.,3  13..6 ±1..7  317 ±38  41.,5 ±7,,9  106  1.970  0.,835  Vehicle (7)  0. 413 ±0. 070  33 .9 ±10 .4  57.,9 ±13..7  88..1 ±30..7  196 ±70  133.,2 ±16.,5  148 ±20  0. 479  0. 229  Calcitonin (7)  0.252 ±0. 031  48 .3 ±7 .9  49.,6 ±6,.6  37..0 ±10..6  257 ±41  43,.0 ±4,.9  116 ±11  0. 964  0.,399  Vehicle  0.219 ±0. 061  12 .5 ±5 .5  23..8 ±6..3  29..3 ±9,.2  83 ±23  63,.6 ±14,.4  125 ±23  0. 539  0.,100  Calcitonin  0.333 ±0. 044  59 .3 ±11 .4  31..7 ±4.,3  7..6 ±0..8  213 ±31  43,.5 ±7..4  116 ±7  1. 800  0..492  2nd 3 hr  TX 1st 3 hr  _10.12 ±0.33  2nd 3 hr  *Age o f r a t s ,  2 1/2 m o n t h s .  Calcitonin,  100 mU/100 g body w e i g h t ,  i . p . Mean + SEM; n_ = number i n parenthes i s .  TABLE V I I The e f f e c t o f c a l c i t o n i n on u r i n a r y e l e c t r o l y t e  Group  Vo1ume m l/IOOg/hr  K  Na  excretion  Ca  i n TPTX a n d i n t a c t  P  uequiv/lOOg/hr  Mg  Creat.  rats*  Na/K  Na/Creat  y g / l OOg/hr  TPTX 44.3 +6.7  61 .2 +2.6  51.4 + 10.5  124 +27  68.0 + 12.4  161 +7  0.716  0.271  0.570  62.5 +6.7  55.0 +4.3  1 1 .9 +3.3  205 +55  39.6 +6.4  128 + 12  1 . 169  0.495  0.469  40.9 + 10.3  67.4 +5. 1  26.2 +7.7  433 +63  85.9 + 16.9  165 +3  0.575  0.247  52.9 +7.2  69. 1 +4.8  4.3 +0.45  599 +35  62.3 + 15.6  163 + 15  0.761  0.329  0.408  Veh i c 1 e (5)  to.066  Ca1c i t o n I n (6)  to. 074  1 ntact Vehicle (5)  to.049  Ca Ic i t o n i n (5)  to.064  0.428  *Age o f r a t s , I 1/2 m o n t h s . C a l c i t o n i n , 100 mU/IOOg body w e i g h t , Mean + SEM; n = number i n p a r e n t h e s i s .  i . p . U r i n e c o l l e c t e d over s i x hours.  TABLE V I I I Control  Group  TPTX (12)  urinary electrolyte excretion  P l a s m a Ca  5.78 t O . 32  Volume ml/IOOg/hr  i n TPTX, TX, and i n t a c t r a t s d u r i n g a 2 4 - h o u r c o l l e c t i o n *  Na  Ca  uequ iv/1OOg/hr  16.7 + 1 .7  26.0 + 1 .9  TX (6)  10. 13 +0. 12  0.459 +0.109  15.4 +3.2  22.7 +3.1  Intact (12)  10.20 t O . 13  0.153 tO.017  17.4 + 1.5  33.4 + 1.5  food  Creat.  Na/K  Na/Creat.  yg/IOOg/hr  0.257 +0.031  *Age o f r a t s , two m o n t h s . A n i m a l s w e r e w i t h o u t _n = number i n p a r e n t h e s i s .  Mg  47.7 +4.4  120 + 10  61 . I +5.4  I 18  36.7 + 10.9  206 +27  51 .6 +8.2  306 +27  102.3 + 18.7  14.5 + 1 .9  during c o l l e c t i o n  period.  0.647  0.140  129 + 10  0.650  0.114  I 10 +3  0.523  0.153  +3  Mean +_ SEM;  36  The e x c r e t i o n o f Ca o v e r a 24-hour p e r i o d s i m i l a r t o t h a t found  i n t h e TX r a t s as i s seen  i n t h e TPTX r a t s was in Table VIII i n  s p i t e o f t h e lower plasma Ca l e v e l i n t h e TPTX group. excretion  o f P was l e s s i n t h e TPTX group  TX o r t h e i n t a c t groups where p a r a t h y r o i d  However, t h e  as compared t o e i t h e r t h e t i s s u e was p r e s e n t .  In summary: (a)  The presence o f f u n c t i o n i n g  for the increase excretion  parathyroid  i n the excretion  o f Ca and Mg o b s e r v e d  t i s s u e was not e s s e n t i a l  of Na and P and t h e d e c r e a s e i n t h e i n young r a t s f o l l o w i n g a s i n g l e i n j e c t i o n  of c a l c i t o n i n . (b)  An a l t e r e d r e s t i n g plasma Ca l e v e l d i d n o t a f f e c t t h e n e t e x c r e t i o n  of Na and K o v e r a 24-hour  period.  37  II.  CALCIUM INFUSION STUDIES (ENDOGENOUS CALCITONIN RELEASE) In t h e r a t e x p e r i m e n t s , plasma  s t u d i e s were n e c e s s a r i l y  performed  s e p a r a t e l y from t h e u r i n e s t u d i e s because o f t h e trauma i n v o l v e d i n b l o o d s a m p l i n g and t h e e f f e c t t h i s might have on k i d n e y f u n c t i o n .  Also,  t h e s i z e o f t h e r a t imposed a l i m i t on t h e number o f blood samples t h a t c o u l d be t a k e n from any one animal  in a s i n g l e study.  I t seemed o f g r e a t advantage  t o be a b l e t o f o l l o w  changes i n plasma and u r i n e s i n c e t h i s would  simultaneous  enable a c l e a r e r  concept  o f t h e r e l a t i o n s h i p between t h e two and show how changes i n one parameter might be r e f l e c t e d by a l t e r a t i o n s  i n t h e o t h e r . Thus, a l a r g e r animal  was t h o u g h t t o o f f e r d i s t i n c t a d v a n t a g e s . The sheep was chosen  not o n l y  f o r i t s s u i t a b l e s i z e b u t a l s o because i t s t h y r o i d g l a n d i s s e p a r a t e from t h e l a r g e s u p e r i o r p a r a t h y r o i d s . T h e r e f o r e , s u r g e r y i n t h e s e a n i m a l s would  not r e q u i r e t r a n s p l a n t a t i o n o f t h e p a r a t h y r o i d s i n those  where t h y r o i d e c t o m y was r e q u i r e d .  In a d d i t i o n ,  experiments  in the larger animal,  any m a n i p u l a t i o n s r e g a r d i n g c a t h e t e r i z a t i o n f o r s a m p l i n g o r i n f u s i o n c o u l d be performed  w i t h o u t t h e use o f a n a e s t h e s i a so t h a t t h e a n i m a l s c o u l d be  s t u d i e d f o r long p e r i o d s o f t i m e i n a c o n s c i o u s s t a t e .  The r a t s t u d i e s a l l changes f o l l o w i n g  i n v o l v e d an i n v e s t i g a t i o n o f t h e e l e c t r o l y t e  i n t e r v e n t i o n o f exogenous c a l c i t o n i n from a n o t h e r c l a s s  o f a n i m a l . The sheep s t u d i e s were d e s i g n e d o f endogenous c a l c i t o n i n  secretion.  i n order t o assess the e f f e c t s  38  S i n c e t h e i n f u s i o n o f Ca s a l t s increase i n c i r c u l a t i n g c a l c i t o n i n  i s known t o c a u s e a p r o p o r t i o n a l  l e v e l s (47, 4 8 ) , a c o m p a r i s o n o f t h e  plasma and u r i n a r y e l e c t r o l y t e changes i n i n t a c t and a n i m a l s f o l l o w i n g a Ca s t r e s s s h o u l d o f endogenous c a l c i t o n i n  thyroidectomized  i n d i c a t e t h e degree o f involvement  i n t h e responses found.  PIasma and Ur? nary E l e c t r o l y t e Changes i n C o n s c i o u s Sheep F o l l o w i n g CaIciurn I n f u s i o n Methods All  sheep s t u d i e s were performed w h i l e t h e a n i m a l s were l o o s e l y  r e s t r a i n e d on a stand  by a s h o u l d e r and h i p h a r n e s s . T h i s  allowed  c o n s i d e r a b l e freedom o f movement and t h e a n i m a l s were q u i e t and r e l a x e d d u r i n g t h e 6-8 hour p e r i o d o f t h e e x p e r i m e n t .  Following preparations according  t o p r o c e d u r e s i n t h e GENERAL  METHODS s e c t i o n , a maintenance i n f u s i o n o f d e x t r o s e - s a l i n e was g i v e n a t a r a t e o f 23 ml/hour which balanced t h e mean h o u r l y u r i n e o u t p u t s determined  in preliminary control c o l l e c t i o n s . This  maintained  throughout t h e experiment.  i n f u s i o n r a t e was  Blood and u r i n e c o l l e c t i o n s began a t t h e c o m p l e t i o n  o f a one-hour  e q u i l i b r a t i o n p e r i o d , blood samples being t a k e n a t t h e m i d p o i n t o f each 15-minute u r i n e c o l l e c t i o n . A f t e r a c o n t r o l c o l l e c t i o n p e r i o d o f I 1/4 h o u r s , Ca was added t o t h e infusate ( C a C ^ in dextrose-saline) body w e i g h t f o r one hour. Blood  in a concentration t o give  10 mg Ca/kg  and u r i n e c o l l e c t i o n s t h e n c o n t i n u e d  f u r t h e r t h r e e hours f o l l o w i n g c o m p l e t i o n  for a  o f t h e one-hour Ca i n f u s i o n so t h a t  39  the t o t a l and  c o l l e c t i o n t i m e was 5 1/4 h o u r s .  individual  used  s h e e p w e r e g i v e n a 10-day  Catheters  were t h e n  t o 2-week r e c o v e r y  removed  before  being  again.  Upon c o m p l e t i o n  of studies in intact  s h e e p , t h e same  were t h y r o i d e c t o m i z e d and s u b j e c t e d t o a f u r t h e r  The  final  series  beginning  o f Ca  infusions.  of experiments included t h e addition  c a l c i t o n i n , g i v e n a t a r a t e o f 2 U/kg body period  series  animals  a t t h e s t a r t o f t h e Ca  weight/hour f o ra  infusion  i n t h e TX  o f salmon two-hour  sheep.  ResuIts PI asma  changes F o l l o w i n g t h e s t a r t o f t h e Ca  Ca  levels  immediately  of t h e i n f u s i o n . r e t u r n e d t o normal  infusion  in the intact  sheep,  r o s e w i t h a n i n c r e a s e o f 1.60+0.07 mg% a f t e r o n e h o u r  As i s seen  i n F i g . 7, t h e p l a s m a C a  v a l u e s when t h e i n f u s i o n  levels  was s t o p p e d .  rapidly  Calcium  infusion  i n t h e TX s h e e p was f o l l o w e d by a s i g n i f i c a n t l y g r e a t e r a b s o l u t e i n p l a s m a C a l e v e l s o f 2.31+0.10 mg%. line  l e v e l s was d e l a y e d  experimental beginning rise  during the  p e r i o d . When s a l m o n c a l c i t o n i n was i n f u s e d f o r t w o h o u r s  i n plasma Ca  P l a s m a Ca  rise  The r e t u r n o f plasma Ca t o b a s e -  i n t h i s g r o u p a n d was n o t a c h i e v e d  a t t h e s t a r t o f t h e Ca  calcitonin,  plasma  l e v e l s was  infusion  i n t h e TX s h e e p , t h e a b s o l u t e  l e s s , a s compared  and t h e r e t u r n t o b a s e - l i n e c o n t r o l  l e v e l s a t 1,2, a n d 4 h o u r s a f t e r  t o t h e TX s h e e p  l e v e l s was a c c e l e r a t e d .  t h e s t a r t o f t h e Ca  i n t h e t h r e e g r o u p s o f s h e e p a r e shown i n T a b l e  without  IX.  infusion  40  F i g 7.  Changes TX, and Changes control  i n plasma Ca l e v e l s f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX sheep i n f u s e d w i t h salmon c a l c i t o n i n (2 U / k g / h r ) . i n plasma Ca e x p r e s s e d as mg$ changes from b a s e - l i n e v a l u e s . (Mean v a l u e s a r e i n d i c a t e d ; f o r n see T a b l e IX.)  TABLE IX Plasma changes  following  Ca i n f u s i o n  T i m e a f t e r s t a r t o f Ca infusion (hr): A  Plasma  1/2  I.60 + 0.07 2.31 + 0.10 I.82 + 0.26 <0.001  0.03 + 0.18 I.42 + 0.18 0.83 + 0.30 <0.001  -0.08 + 0.03 0.52 + 0.30 -0.32 + 0.31  -0.71 + 0.27 0.36 + 0.07 -0.86 + 0.30 <0.005 <0.005  -I.29 + 0.21 -0.80 + 0. 19 - I . 4 2 + 0.45  -0.224 + 0.040 -0.251 + 0.073 -0.498 + 0.092  -0.201 + 0.050 -0.261 + 0.097 -0.563 + 0.063  P  Intact (4) TX ( 5 ) TX + CT ( 4 ) £ I n t a c t v s TX TX v s TX+CT  A  sheep  P l a s m a Ca Intact (5) TX ( 6 ) TX + CT ( 4 ) £ I n t a c t v s TX  A  i n i n t a c t , T X , a n d TX + CT  -0.24 + 0.15 0.18 + 0.07 •0.38 + 0.12 O.050 <0.005  -0.66 + 0.22 0.42 + 0.07 -0.73 + 0.19 <0.005 <0.00I  P l a s m a Mg Intact (3) TX ( 6 ) TX + CT ( 4 )  -0.108 + 0.027 -0.096 + 0.055 -0.218 + 0.072  £  <0.050 <0.010  TX v s TX+CT I n t a c t v s TX+CT mg% c h a n g e s  from b a s e l i n e  control  v a l u e s a r e shown. Mean +_ SEM;  n_ = number In  parenthesis.  >+2  A s t h e p l a s m a Ca P  levels  l e v e l s were r i s i n g  were found t o f a l l  as  i s shown  a n i m a l s , t h i s d e c r e a s e i n plasma  P  infusion.  Plasma P  +0.42+0.07 mg?  levels  i n t h e TX  showed a d e c r e a s e o f -0.66+0.22 mg%. following  was o b s e r v e d w h i c h was  I , I 1/2,  the in  s t a r t o f t h e Ca t h e TX  i n plasma  P  an  levels  t h e end o f t h e  increase of levels  infused  in the  i n plasma  in the three groups of  TX P  i n p l a s m a Mg  which occurred  i n t h e i n t a c t s h e e p was infused  Ca  following  similar to that  in this levels  sheep  infusion.  l e v e l s a r e shown f o l l o w i n g  s h e e p . O n l y when c a l c i t o n i n was  latter found  found  group  (Table IX).  changes In r e s p o n s e t o t h e Ca  r e s p o n s e w h i c h was put  preceded  i n t h e i n t a c t s h e e p . T a b l e IX  w e r e s i g n i f i c a n t l y g r e a t e r d e c r e a s e s i n p l a s m a Mg  Urine  i n t h e TX  immediate f a l l  t h e s t a r t o f t h e Ca  i n p l a s m a Mg  infusion  showed a n  plasma  t o t h e i n t a c t group where  infusion,  I t i s seen t h a t t h e f a l l  hour a f t e r  When c a l c i t o n i n was  2,and 4 h o u r s f o l l o w i n g  In F i g . 9, c h a n g e s infusion.  sheep  s i m i l a r t o t h a t seen  shows t h e a b s o l u t e c h a n g e s at  t h e Ca  However,  d e l a y e d a n d was  1/2 t o 3/4  a t t h i s t i m e as compared  g r o u p d u r i n g and  i n F i g . 8.  l e v e l s was  by a s l o w r i s e r e a c h i n g a p e a k a b o u t Ca  i n t h e i n t a c t sheep,  out less  infusion,  not observed  i n t h e TX a n i m a l s .  sheep  i n u r i n e volume  l e v e l s . The  of c a l c i t o n i n  in urine  volume.  period.  T a b l e X where t h e d a t a were  a c c o r d i n g t o changes infusion  showed a  s h e e p was  sheep  These  treated  f r o m t h e mean o f b a s e - l i n e  i n t h e TX  diuretic  In f a c t , t h e TX  urine than they did during the pre-infusion  c h a n g e s a r e shown i n F i g . 10 a n d  increase  the intact  control  accompanied  by  an  43  Fig  8.  C h a n g e s i n p l a s m a P l e v e l s f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, a n d TX s h e e p i n f u s e d w i t h s a l m o n c a l c i t o n i n (2 U / k g / h r ) . C h a n g e s i n p l a s m a P e x p r e s s e d a s mg% c h a n g e s f r o m b a s e - l i n e c o n t r o l v a l u e s . (Mean v a l u e s a r e i n d i c a t e d ; f o r n_ s e e T a b l e IX.)  44  TX  intact  o  +(  Time  Fig  9.  TX + Calcitonin  in Hours  C h a n g e s i n p l a s m a Mg l e v e l s f o l l o w i n g C a i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p i n f u s e d w i t h s a l m o n c a l c i t o n i n (2 U / k g / h r ) . C h a n g e s i n p l a s m a Mg e x p r e s s e d a s mg% c h a n g e s f r o m b a s e - l i n e c o n t r o l v a l u e s . (Mean v a l u e s a r e i n d i c a t e d ; f o r n_ s e e Table IX.)  45  •fi  jcoci,|-  t  '  1  L Calcitonin J |CoGl | (K3 mg Ca/fco/w) t  Time in Hours  Fig  10. Changes i n u r i n e volume (upper t r a c e ) and osmolal o u t p u t ( l o w e r t r a c e ) f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, and TX sheep i n f u s e d w i t h salmon c a l c i t o n i n (2 U / k g / h r ) . Changes from b a s e - l i n e c o n t r o l o u t p u t s a r e i n d i c a t e d . (Mean + SEM; f o r n see T a b l e s X and X I . )  TABLE X Changes  i n urine  volume f o l l o w i n g  Ca i n f u s i o n  i n i n t a c t , TX, and  TX t CT s h e e p *  Time a f t e r s t a r t o f Ca i n f u s i o n ( h r ) :  - 2  0 - I  2 - 3  Changes i n volume o u t p u t from b a s e - l i n e c o n t r o l values (ml/hr)  I n t a c t (3)  I 1.0 + 3.2  TX ( 6 )  -8.3 + 3.I  -15.4 + 5.9  -19.5 +  6.6  4.3 t I.9  3.8 t 3.3  - 2.5 +  2.3  TX t CT ( 4 )  £  I n t a c t v s TX TX v s TX+CT I n t a c t v s TX+CT  *Mean +_ SEM; n_ = number i n  <0.0I0 <0.025  parenthesis.  24.I  <0.005 <0.050 <0.050  + 6.8  27.0 + 21.1 - 1 9 . 3 + 4.7 - 2.7 t |.5  <0.050 <0.050  47  The  d i u r e s i s o b s e r v e d i n t h e i n t a c t s h e e p was a c c o m p a n i e d  increase increase  in osmolal  output as  i n osmolal  Figs  enhanced  The c h a n g e s  I I , 12, 14, and  i n U V a r e shown P  i n F i g 10 a n d T a b l e X I .  o u t p u t i n t h e TX s h e e p was c o n s i d e r a b l y  c o m p a r i s o n , b u t was calcitonin.  i s seen  ( d u r i n g t h e p e r i o d o f t h e Ca  i n U^V  found  t h e Ca  by t h e TX  i n U^ V g  s h e e p was i s seen  i n t h i s group.  In f a c t , U ^ V  i n t h e i n t a c t sheep and  i n U^V  Resting  UpV  i t was  to obtain  f o l l o w i n g Ca Fig  excreted  Not o n l y  was  the  was  t h e enhanced  i n t h e TX a n i m a l s was  significantly  by no c h a n g e  in the individual  so d u r i n g t h e TX  in  the period  not o n l y  between  the Absolute  from any one s e r i e s o f  s t u d i e s a r e shown, t h e r e f o r e , i n  i n f u s i o n r a t h e r t h a n an a b s o l u t e p  large  variation.  some c o n c e p t o f t h e d i r e c t i o n o f c h a n g e s t h a t  in U V  of  U^V.  sheep from day t o day.  impossible t o group t h e data  13 s h o w s t h e c h a n g e s  less than  sheep, a  i n f u s i o n a l s o showed a w i d e  experiments. Outputs from i n d i v i d u a l order  The  but a l s o t h e h y p e r c a I c i u r i a  levels varied considerably,  i n r e s p o n s e t o t h e Ca  Therefore,  than that  in Table XIII.  In t w o s t u d i e s w i t h  was a c c o m p a n i e d  d i f f e r e n t sheep but a l s o changes  greater  levels.  i n t h e TX s h e e p d i d n o t p a r a l l e l  i n f u s i o n (p_<0.005).  increase  Changes  duration.  Increases  ihat found  i n f u s i o n ) by  a p p e a r e d t o r e f l e c t t h e p l a s m a Ca  h o u r l y o u t p u t i n t h e TX g r o u p g r e a t e r ,  g  l e s s by  15-minute changes a r e r e c o r d e d .  by t h e i n t a c t o r TX+CT g r o u p s a s  U^ V  The  i n u r i n a r y e l e c t r o l y t e e x c r e t i o n a r e shown i n  15 w h e r e  a m o u n t o f Ca e x c r e t e d  longer  large  i n F i g 13 a n d T a b l e X I I .  Changes  of  by a  that occurred  occurred  quantitative evaluation. during  t h e p e r i o d o f t h e Ca  TABLE XI C h a n g e s In o s m o l a l  o u t p u t f o l l o w i n g Ca I n f u s i o n  Time a f t e r s t a r t o f Ca I n f u s i o n ( h r ) :  0 - I  i n i n t a c t , TX, and T X + C T  - 2  2 - 3  sheep*  3 - 4  Changes  in U V from osm base-1ine controI v a l u e s (mOsm/hr) 3  Intact (3)  6.88 + I.69  8.76 + 2.57  7.05 + 2.93  TX ( 6 )  0.43 + 0.72  I .73 + 0.27  0.92 + 0.70  0.98 + I.62  TX + CT ( 4 )  4.20 + 2.08  I .23 + I.40  - I .71 + 2.65  -2.09 + 2.14  p_ I n t a c t v s TX I n t a c t v s TX+CT  *Mean + SEM; n_ = number i n  <0.005  parenthesis.  <0.005 <0.050  <0.050  49  Fig  II.  Changes i n V f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, and TX sheep i n f u s e d w i t h salmon c a l c i t o n i n (2 U / k g / h r ) . Changes from b a s e - l i n e c o n t r o l o u t p u t s a r e i n d i c a t e d . (Mean vaIues a r e shown; f o r n see T a b l e X I I I . )  50  Fig  12.  Changes i n UQ V f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, and TX sheep i n f u s e d w i t h salmon c a l c i t o n i n ( 2 U / k g / h r ) . Changes from b a s e - l i n e c o n t r o l o u t p u t s a r e i n d i c a t e d . (Mean v a l u e s a r e shown; f o r n see T a b l e X I I I . )  51  intact  Fig  13.  TX  TX +  52  Intact  CaCl2 + l  CaCI  14.  + Calcitonin  CoCI  2  O + l Time  Fig  TX  TX  2 in  -l  2  (IOmgCa/kg/hr)  +1  Hours  Changes i n V f o l l o w i n g Ca i n f u s i o n i n i n t a c t , TX, and TX s h e e p ? n f u s e d w i t h s a l m o n c a l c i t o n i n ( 2 U / k g / h r ) . Changes from b a s e - l i n e c o n t r o l o u t p u t s a r e i n d i c a t e d . (Mean v a l u e s a r e s h o w n ; f o r n see Table X I I I . )  TABLE. XI I Urinary  Time (hr)  UV p  P excretion  following  Control  Calcium infusion  - 1 - 0  0  -  calcium  infusion  Post i n f u s i o n 1  1  i n I n t a c t , T X , a n d TX + CT s h e e p  -  2  2  -  3  3  -  4  (mg/hr)  Intact  TX  TX + CT  0 . 1 8 2  0 . 4 2 9  0 . 9 5 1  t  0 . 2 6 9  f  0 . 2 0 2  3 . 0 4 1  6 . 2 1 6  f  6 . 3 3 0  +  0 . 0 5 5  0 . 0 7 3  0 . 0 5 7  t  0 . 0 6 0  0 . 0 7 5  0 . 0 9 7  0 . 0 8 4  t  0 . 0 7 7  +  0 . 0 6 6  2 . 6 0 1  4 . 8 6 7  1 2 . 4 9 1  +  8 . 2 9 9  t  1 . 8 3 6  0 . 1 8 2  0 . 1 7 6  0 . 2 0 3  0 . 3 8 3  0 . 3 4 7  +  1 . 4 1 1  +  0 . 5 9 6  1 . 3 7 1  1 . 2 9 6  +  1 . 5 1 7  t  0 . 9 2 9  0 . 1 1 4  0 . 1 1 2  0 . 0 9 7  0 . 1 1 3  *  0 . 1 0 2  0 . 0 8 4  0 . 1 0 4  i  0 . 0 7 4  0 . 0 6 5  3 4 . 1 1 9  3 5 . 6 4 3  i  2 9 . 8 2 6  2 1 . 1 2 3  0 . 1 1 6  0 . 1 3 2  t  0 . 1 0 9  0 . 1 1 0  0 . 1 0 2  0 . 0 6 5  0 . 0 9 4  t  0 . 0 4 7  0 . 0 5 1  0 . 0 7 9  f  0 . 0 8 9  0 . 0 9 0  t  0 . 0 8 5  0 . 0 7 1  0 . 0 9 1  +  Arrows indicate either increase  +  0 . 0 7 2  0 . 1 7 7  f  0 . 1 0 8  (+) or decrease (+) from control period  +  +  0 . 1 1 1  t  0 . 2 9 5  +  0 . 1 0 1  0 . 1 0 3  t  1 . 2 1 4  0 . 0 9 9  t  0 . 1 1 3  +  +  values.  t  0 . 0 6 4  +  1 8 . 2 1 0  +  54  E >  x  => & <J  ©  TX +• Calcitonin  TX  Intact  20  + 10 0 - 10 20 30 -  + 500  I  I  I  I  0 O  - 500  r  I CaCI  CaCI;  CaCU  2  O  +1  Calcitonin -| (lOmgCa/kg/hr)  —i  2  Time in Hours  Fig  15.  Changes i n U V (upper t r a c e ) and U „ V (lower trace) f o l l o w i n g C a i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p i n f u s e d w i t h salmon c a l c i t o n i n (2 U / k g / h r ) . Changes from basel i n e c o n t r o l o u t p u t s a r e i n d i c a t e d . (Mean v a l u e s a r e s h o w n ; f o r n see T a b l e X I I I . ) K  r e a +  55 TABLE XIII Changes in urinary electrolyte excretion following Ca infusion in intact, TX, and TX + CT sheep* Time after start of Ca infusion (hr); AU  0 - I  2-3  V (meq/hr)  Intact (3)  I.64+0.40  2.34+0.87  2.42+1.27  TX (6)  0.45+0.09  I.08+0.25  I.04+0.31  I.45+0.65  TX t CT (4)  0.98+0.28  I.39+0.50  I.13+0.35  I.88+0.81  p_ I ntact vs TX  <0.005  AU V (mg/hr) Cg  Intact (3)  0.64+0.44  2.12+0.49  0.91+0.38  TX (6)  2.87+2.54  2.74+0.47  3.19+0.97  I.37+0.56  TX+CT (4)  0.74+0.27  3.47+1.17  I.34+0.76  0.08+0.33  Intact (5)  5.48+0.80  9.31+1.98  4.89+0.94  I.24+0.52  TX (6)  2.66+0.50  8.96+1.I 9  6.83+1.82  3.65+1.72  TX+CT (4)  3.82+0.76  8.97+2.31  4.35+1.98  -0.25+0.67  -0.13+0.13  -0.41+0.28  -0.37+0.35  -0.68+0.43  -0.69+0.21  -I.45+0.36  -I .52+0.38  -I.31+0.35  -0.04+0.43  -I.22+0.29  -I.86+0.55  -I.89+0.63  AU V (mg/hr) Mg  p_ I ntact vs TX AlO  <0.025  (meq/hr)  IN  Intact (5) TX (6) TX+CT (4)  ^Changes in output from base-line control values are shown. Mean +_ SEM; n = number in parenthesis.  56  infusion.  T a b l e X I I shows t h e h o u r l y o u t p u t s b e f o r e ,  following  t h e p e r i o d o f t h e Ca  W h e r e a s UQQV  d u r i n g and  infusion.  i n t h e t h r e e g r o u p s o f sheep appeared t o r e f l e c t t h e  p l a s m a C a c h a n g e s , t h i s was n o t o b s e r v e d when r e l a t i n g changes.  In t h e f i r s t ,  infusion,  the intact  Table XIII. found  second, and t h i r d  sheep  hours f o l l o w i n g  showed a n i n c r e a s e  This occurred  Increases  i n P e x c r e t i o n as i s seen i n  p  during  t h i s t i m e were j u s t  i n F i g 13. beginning  Plasma P to rise,  t h e s t a r t o f t h e Ca i n f u s i o n ,  reflected  by a t r a n s i e n t i n c r e a s e  increase  to  t h a t found  less to  than t h a t found  t h e TX s h e e p , U ^ V  seen  i n Tab Ie X I I I .  i n t h e TX  and i n t h e second  in P excretion  hour was  i n the intact animals  ( F i g . 1 4 ) . However, d u r i n g  U^V  sheep  (Table X I I ) .  t h e s t a r t o f t h e Ca i n f u s i o n  i n t h e TX s h e e p  p e r i o d o f t h e Ca i n f u s i o n ,  levels  t h e hyperphosphatemia  i n U„ V w h i c h o c c u r r e d Mg  in t h e f o u r hours f o l l o w i n g  during  and i n f o u r o f t h e s i x s t u d i e s , a s l i g h t  following  The  only  infusion.  p e r i o d o f t h e Ca i n f u s i o n ,  d r o p was f o u n d a s i s s e e n  in the  However, t h i s o c c u r r e d  In t h e TX s h e e p , no c o n s i s t e n t c h a n g e i n U^V was f o u n d the  t h a t were  i n U V were a l s o found  TX+CT s h e e p when p l a s m a P l e v e l s w e r e f a l l i n g . t h e p e r i o d o f t h e Ca  P  t h e s t a r t o f t h e Ca  d e s p i t e t h e decreased plasma P l e v e l s  i n t h i s group a t t h i s time.  during  UpV t o p l a s m a  was  similar  the actual  i n t h e TX g r o u p s was s i g n i f i c a n t l y  in the intact was i n c r e a s e d  s h e e p . When c a l c i t o n i n during  this  was g i v e n  same t i m e p e r i o d a s i s  57  During a n d TX The  preliminary control  sheep, I O  was  urine collections in intact  found t o decrease o v e r a p e r i o d  decrease in the e x c r e t i o n of t h i s  control  s t u d i e s was  a p p e a r e d t o have  similar.  The  i o n i n t h e two g r o u p s  i n f u s i o n o f Ca  no e f f e c t o n t h e n o r m a l  shows t h e mean c h a n g e s  i n U^V  during  i n t h e i n t a c t sheep  calcitonin  i n t h e TX g r o u p .  in the three  changes were n o t s i g n i f i c a n t . T h i s  hours.  pattern of K excretion  g r o u p , and t h e a d m i n i s t r a t i o n o f e x o g e n o u s t h e m a g n i t u d e o f t h e d e c r e a s e i n U^V  o f 4-5  in this  d i d not a f f e c t Figure  groups of sheep.  f i g u r e a l s o shows c h a n g e s  15  These in  t h r e a t V a n d , a s c a n be s e e n , no c o n s i s t e n t c h a n g e s w e r e o b s e r v e d i n r e s p o n s e t o Ca  infusion in the three  groups of  sheep.  58  III.  EXTRACELLULAR VOLUME EXPANSION A n a t r i u r e t i c and  f o l lov/ing increase  a saline i n GFR  load and  (64).  administration also  been s u g g e s t e d  implicated  results  loading  a TPTX  suggested a t f i r s t  major  series  o f e x p e r i m e n t s was  following  saline  a Iteration A further TX  i n Na series  loading  had  carried  The  was  in a typical not  involved.  l o a d i n g an a n i m a l  out  39,  Calcitonin  response.  There-  between  this  natriuresis  i n i n t a c t , TX,  and  TPTX r a t s  (32)  However, t h e  i n the absence  of  Therefore, a  i n o r d e r t o compare t h e t o see  responses i f any  excretion occurred in those animals without c a l c i t o n i n . o f e x p e r i m e n t s was  carried  o u t on c o n s c i o u s i n t a c t  changes  i n both plasma  r e s p o n s e t o v o l u m e e x p a n s i o n by d e x t r a n  I.  response.  diuretic  n o t been p e r f o r m e d .  sheep t o compare t h e e l e c t r o l y t e  A.  in t h i s  be a n a s s o c i a t i o n  r a t resulted  that calcitonin  source of c a l c i t o n i n  concomitant  loading.  more d e f i n i t i v e e x p e r i m e n t o f s a l i n e the  observed  by some ( 6 5 , 3 8 , 6 6 , 3 6 ,  i n a n a t r i u r e t i c and  the response t o s a l i n e  Saline  i s commonly  i n some way  i t seemed p o s s i b l e t h a t t h e r e m i g h t  hormone and  which  be  response  c a n o c c u r a p p a r e n t l y w i t h o u t any  I t has  6 7 ) t h a t a h o r m o n e may  fore,  diuretic  Ur i nary El e c t r o l y t e Changes  effects  of s a l i n e  loading  and  and  urine in  loading.  i n R a t s FoI l o w i ng a_ Sa I i ne  i n i n t a c t , TX,  a n d TPTX  Load  rats.  Methods Groups of load of s a l i n e  i n t a c t , TX,  ( 5 ml  0.9$  a n d TPTX r a t s  were g i v e n an i . p .  N a C I / 1 0 0 g body w e i g h t ) a n d  immediately placed  59  in metabolism cages f o r u r i n e c o l l e c t i o n hour  during  two c o n s e c u t i v e  three-  periods.  Results T a b l e X I V shows t h e u r i n a r y e l e c t r o l y t e c h a n g e s f o l l o w i n g a s a l i n e load  i n i n t a c t , TX, a n d TPTX r a t s . A g r a p h i c a l  i s shown  in part  i n F i g 16 w h e r e t h e a b s o l u t e  e x c r e t i o n a r e shown. with  electrolyte excretion  Both increasing loading. very  (The a b s o l u t e  i n t a c t a n d TPTX  u r i n e volume and U  changes were d e t e r m i n e d  N g  V  in the f i r s t  However, t h e s e changes i n o u t p u t  During t h i s  animals.)  three  by  hours f o l l o w i n g  i n i n t a c t a n d TPTX  r a t s were  i n t h e TX a n i m a l s w h e r e u r i n e v o l u m e a n d  were not s i g n i f i c a n t l y a l t e r e d d u r i n g  r a t s showed a c o n t i n u e d  data  by c o m p a r i s o n  r a t s responded t o t h e s a l i n e load  t h i s time  During t h e second t h r e e - h o u r c o l l e c t i o n TPTX  of t h i s  changes i n e l e c t r o l y t e  i n non-loaded c o n t r o l  d i f f e r e n t from t h o s e found  U^gV  representation  increase  period.  period,  both  i n t a c t and  i n u r i n e v o l u m e a n d U.. V. Na  same t i m e p e r i o d , TX a n i m a l s a l s o showed a  large  increase i n  u r i n e v o l u m e a n d U.. V. Na The t r a n s i t o r y r e d u c t i o n a s a l i n e load) i n t a c t a n d TPTX these animals. April  (during the f i r s t  i n u r i n e v o l u m e and  three  hours f o l l o w i n g  V i n t h e TX r a t s a s c o m p a r e d t o  r a t s was a c o n s i s t e n t f i n d i n g i n a l l l o a d i n g Groups of r a t s t h y r o i d e c t o m i z e d  i n J u n e , November, and  a l l showed t h i s t y p e o f r e s p o n s e , t h e r e f o r e  attributed  t o e i t h e r one p a r t i c u l a r  attributed  t o seasonal  variation.  "batch"  studies in  i tcould  of r a t s ,  n o t be  nor could  i t be.  TABLE X I V E f f e c t s o f s a l i n e l o a d i n g on u r i n a r y e l e c t r o l y t e e x c r e t i o n i n i n t a c t , TX, a n d TPTX r a t s *  Volume ml/IOOg/hr  Na K uequ iv/1OOg/hr  Ca  P yg/IOOg/hr  Mg  Great.  Na/K  Na/Creat.  1st 5 hr Intact Non-loaded (10)  0.255 tO.026  31 .9 +4.3  62.6 +4.8  38.7 +5.6  191 +30  102.3 + 10.5  162 +8  0.502  0.193  Sa1ine (10)  0.567 tO.084  84.4 +9.6  85.4 +6.7  98.4 + 13.4  359 +57  152.9 + 13.8  175 +5  1 .01 1  0.485  <0.005  <0.00l  <0.025  <0.00l  Non-loaded (10)  0.307 +0.047  37.6 +5.1  60.2 +5.2  48.7 +8.4  158 +31  86. 1 + 16.9  150 +7  0.615  0.243  S a 1 i ne (10)  0.271 +0.037  41.1 +3.7  47.8 +3.7  59.9 +9.6  99 + 13  61 .9 + 1 1 .6  125 +5  0.917  0.333  NS  NS  NS  NS  NS  load  £  <0.025  <0.0I0  NS  TX  load  £  NS  <0.0I0  TPTX Non-loaded (5)  0.199 +0.025  34.5 +6.3  32.0 +4.0  38.4 +5.8  46 + 14  39.8 + 10.3  107 +7  1 . 1 17  0.324  Sa1Ine (6)  0.481 +0.103  82.2 + 17.9  47.3 +4.7  63.8 +9. 1  76 + 16  60. 1 + 10.7  132 + 13  1 .702  0.621  <0.050  < 0.050  < 0.050  NS  NS  NS  NS  £  load  TABLE XIV ( c o n t i n u e d )  Group  Vo1ume ml/IOOg/hr  Na  K  Ca  uequ i v/1OOg/hr  P  Mg  C r e a t . Na/K  Na/Creat,  ug/lOOg/hr  2nd 3 hr 1ntact Non-loaded  0. 167 +0.031  14.1 +2.7  29.3 +3.4  12.9 +2.8  172 + 14  59.4 +9.6  Sa1ine load  0.686 +0.114  89.5 + 1 1 .0  48.4 +6.0  53.9 +9.2  338 +57  <0.00l  <0.00l  <0.025  <0.00l  Non-loaded  0.229 +0.031  26.6 +4.5  36.3 +3.8  23.1 +4.5  Sa1i ne load  0.527 +0.062  56.4 +8.3  42.8 +5.1  64.7 +9.3  <0.00l  <0.0I0  Non-loaded  0. 189 +0.036  20.0 +2.3  Sa1i ne load  0.752 +0.186 <0.025  £  1 18 0.464 +9  0. 1 16  103.4 + 13.4  158 +7  1 .892  0.557  <0.025  <0.005  169 +28  61 .6 +9.0  138 +8  0.765  0. 196  193 +25  . 64.3 + 12.4  143 +7  1 .303  0.385  <0.025  TX  NS  <0.00l  NS  NS  NS  TPTX  £  24.8 +6. 1  52.8 +9.1  19 +9  63.5 +2.1  132 + 14  0.940  0.160  82.7 + 14.1  35.6 +5.0  91 .6 + 10.6  33 + 12  87.1 +5.6  150 + 12  2.281  0.553  <0.005  NS  <0.025  NS  <0.010  *Age o f r a t s , two months. F i v e ml 0.9% saline/IOOq body w e i g h t , i . p . was, a d m j n i s t e r e d p r i o r t o s t a r t o f 1st 3-hr c o l l e c t i o n . Mean + SEM; n_ = number i n p a r e n t h e s i s .  NS  Changes i n u r i n a r y e l e c t r o l y t e e x c r e t i o n i n i n t a c t , TX, and TPTX r a t s d u r i n g t h e f i r s t t h r e e hours f o l l o w i n g a s a l i n e load (0.9% N a C l , 5ml/l00g body w e i g h t , i . p . ) . (Compiled from T a b l e XIV.)  63 S i g n i f i c a n t increases  i n U^V, U ^ V ,  LLV, and ^gV accompanied u  t h e n a t r i u r e t i c and d i u r e t i c r e s p o n s e s i n t h e i n t a c t r a t s i n t h e f i r s t t h r e e hours f o l l o w i n g t h e s a l i n e l o a d . However, i n t h e TPTX r a t s no significant a  increases  i n I L V, U V, and U.. V were found when u r i n e volume, Ca ' p ' Mg  U^ V, and U^V were s i g n i f i c a n t l y g  increased.  In TX r a t s , no s i g n i f i c a n t  changes i n any o f t h e u r i n a r y e l e c t r o l y t e s measured were o b s e r v e d f i r s t t h r e e hours f o l l o w i n g t h e s a l i n e l o a d . period  In t h e second t h r e e - h o u r  i n t h e TX r a t s , however, a s i g n i f i c a n t i n c r e a s e  accompanied t h e i n c r e a s e s  in the  i n u r i n e volume and  u N  i n LL.gV  g V t h a t were found a t t h i s  time. 2.  The e f f e c t s o f PTH ( L i l l y PTE) on t h e r e s p o n s e o f TPTX r a t s t o  saIine  loading Methods Thyroparathyroidectomized  (TPTX) r a t s were d i v i d e d  into three  groups where t h e r e s p o n s e s t o s a l i n e l o a d i n g were compared w i t h and w i t h o u t t h e a d d i t i o n o f PTE g i v e n a t t h e same t i m e as t h e s a l i n e l o a d . The  t h i r d group of TPTX r a t s was g i v e n PTE o n l y . A second s e r i e s o f e x p e r i m e n t s compared t h e r e l a t i v e r e s p o n s e s  f o l l o w i n g a s a l i n e load tissue  i n those animals having f u n c t i o n a l  (TX r a t s ) w i t h TPTX r a t s g i v e n PTE.  PTH a d m i n i s t r a t i o n s t u d i e s  parathyroid  L i l l y PTE was used i n a l l  i n t h i s s e c t i o n , g i v e n as a s i n g l e i n j e c t i o n o f  100 U/100 g body w e i g h t , s . c .  64  Results In T a b l e XV loaded  i t i s s e e n t h a t t h e a d m i n i s t r a t i o n o f PTE t o s a l i n e -  TPTX r a t s r e s u l t e d  in a reduction  i n u r i n e volume and t h e  e x c r e t i o n o f N a , s i m i l a r t o t h a t e x h i b i t e d by t h e TX a n i m a l s parathyroid load.  Lilly  Na o u t p u t in  transplants) during PTE i n n o n - l o a d e d  in the f i r s t  experiments  occurred  i n part  in the f i r s t  three  the f i r s t  r a t s r e d u c e d U^ V g  hours f o l l o w i n g  I of this three  three  (functioning  hours f o l l o w i n g a s a l i n e t o about  injection.  A s was o b s e r v e d  Section, the reduction  hours o f u r i n e c o l l e c t i o n  l / 6 t h t h e normal  i n U^gV  which  was f o l l o w e d  by a n  i n c r e a s e d U.. V. Na Figure in one  17 c o m p a r e s t h e r e s p o n s e t o a s a l i n e l o a d  TPTX r a t s g i v e n  having  therapy  PTE.  Both o f t h e s e g r o u p s were w i t h o u t  functional parathyroid  with  t r a n s p l a n t s and t h e o t h e r  extract of the parathyroid  glands  t h e s e two g r o u p s a r e compared t o t h o s e found parathyroid tissue).  t i s s u e ) a n d TPTX r a t s  As i s seen  ECF  volume s t r e s s .  (PTE).  in intact  that  calcitonin,  replacement  The r e s p o n s e s o f (both  t h y r o i d and  (no s o u r c e o f c a l c i t o n i n o r  i n F i g 17, t h o s e r a t s w i t h  e x o g e n o u s ) a n d no c a l c i t o n i n  i n TX r a t s w i t h  parathyroid  PTH ( e i t h e r e n d o g e n o u s o r  showed a t r a n s i e n t r e d u c t i o n o f U ^ V  following  TABLE XV The e f f e c t o f PTE o n u r i n a r y e l e c t r o l y t e e x c r e t i o n i n TPTX  Volume  Treatment  'ml/IOOg/hr  SaIine  load  following a saline  load  rats*  Na  K  ,Na/K  yequiv/IOOg/hr  (5)  1st 3 hr  0.402+0.109  49.0+14.7  38.3+4.4  I .284  2nd  0.42|t0.044  60.3+  8.0  40.3+5.5  I .628  3 hr  Saline  l o a d + PTE ( 6 )  1st 3 hr  0.227+0.044  17.0+ 4.4  28.1+5.7  0.614  2nd  0.602+0.094  87.1+18.6  49.2+7.7  I .924  I.4  22.6+3.6  0.261  60.3+10.8  61.9+9.2  0.600  3 hr  N o n - l o a d e d + PTE ( 6 ) 1st 3 h r  0.123+0.020  2nd  0.372+0.031  3 hr  5.8+  *Age o f r a t s , 2 1/2 m o n t h s . L i l l y PTE, 100 U/100 g body w e i g h t , s . c . g i v e n a t same t i m e a s l o a d , 5 ml 0.9% N a C I / 1 0 0 g body w e i g h t , i . p . Mean + SEM; n_ = number i n p a r e n t h e s i s .  saline  60 Intact 20  c  \ d>  O O  100  60-  TPTX Z3  20  cr  3  100 60  TX  20-  lOO-i  60-  TPTX + P T E with Saline load  20Non-Loaded  SalineLoaded 0-3hrs.  SalineLoaded 3 - 6 hrs.  The e f f e c t o f L i l l y PTE (100 U/100 g body w e i g h t , s.c.) on t h e r e s p o n s e o f TPTX r a t s t o a s a l i n e load a s compared t o t h e r e s p o n s e i n TX r a t s w i t h f u n c t i o n i n g p a r a t h y r o i d t r a n s p I a n t s . ( V a I u e s shown a r e Mean + SEM; n = e i g h t r a t s per group.)  67  B. T h e E f f e c t o f PTH o h P l a s m a Ca a n d U r i n a r y E l e c t r o l y t e s The f i n d i n g s f r o m t h e e x p e r i m e n t s suggested t h a t t h e transplanted extract  (Lilly  P T E ) was  effects of purified clarify  whether  transplanted for  parathyroid  involved  antinatriuretic activity.  I t seemed a p p r o p r i a t e  i t was PTH  itself  with  i n Na e x c r e t i o n , o r t o study  that of L i l l y  o r some o t h e r  t i s s u e o r present  section  tissue or the parathyroid  in the reduction  PTH p r e p a r a t i o n s  parathyroid  in part A of t h i s  the relative  PTE  in order  substance produced  i n t h e PTE w h i c h was  to  by t h e  responsible  the antinatriuresis.  Methods In o r d e r precipitated  t o study  the relative effects of purified  PTH) w i t h t h a t o f L i l l y  were pre-loaded  Urine  (TCA-  groups of i n t a c t  rats  w t t h s a l i n e and a t one hour a f t e r l o a d i n g were i n j e c t e d  with either TCA-precipitated vehicle.  PTE, t h r e e  PTH  PTH  (activity,  240 U/mg), L i l l y  o u t p u t s were determined a t h o u r l y  PTE, o r  intervals f o r four  hours f o l l o w i n g t h e s a l i n e l o a d .  Serial 3 0 0 0 U/mg)  dilutions of L i l l y  PTE a n d h i g h l y - p u r i f i e d PTH  w e r e t h e n made a n d g i v e n  (activity,  t o TPTX r a t s s o t h a t t h e u r i n a r y  r e s p o n s e s t o g r a d e d d o s e s o f t h e hormone c o u l d  be d e t e r m i n e d .  In a f u r t h e r s e r i e s o f e x p e r i m e n t s , t h e t i m e - c o u r s e o f a c t i o n o f Lilly  PTE o n p l a s m a Ca  three-hour time period TPTX r a t s w e r e g i v e n  l e v e l s was s t u d i e d during  which an  in order  t o compare t h i s w i t h t h e  i n h i b i t i o n o f U^ V g  a s i n g l e s.c. i n j e c t i o n of L i l l y  w e i g h t ) and were b l e d a t v a r i o u s  time  PTE  occurred.  Groups of  ( 1 0 0 U/100  g body  intervals f o r determination  o f p l a s m a Ca  68  levels. order of  Graded doses of  Lilly  PTE  t o compare the magnitude of  the  were a l s o g i v e n  the  hypercaIcemic  U , V f o l l o w i n g d i f f e r e n t doses of Na k  the  3  t o TPTX r a t s  in  response with  that  hormone.  Results Both p u r i f i e d and seen  Lilly  PTE  PTH  (TCA-precipitated  caused a r e d u c t i o n  i n T a b l e XVI.  in U  b o t h hormone p r e p a r a t i o n s .  injection,  however, t h e  group, although T a b l e XVII  doses of and  the  Lilly  PTE.  purified  to the  increases and  In t h e t h i r d  evident  increasing  effect that  in the  'Lilly'  group.  i n U^V  with 3  I t i s seen t h a t  i n Ca  and  in  Lilly  U^V  and  administration. highly-  significant  Mg  PTE.  the  increasing  decrease  h i g h l y - p u r i f i e d PTH,  s i m i l a r doses of  decreases  no  to  hormone  apparent  r e s p o n s e o f TPTX r a t s t o g r a d e d d o s e s o f  findings with  and  not  o c c u r s f o l l o w i n g PTH  f o l l o w i n g a d m i n i s t r a t i o n of  i n P,  hour f o l l o w i n g  decreased U Q V  shows t h e  is  U.. V w e r e f o u n d Mg  V was  reduction  normally  3 0 0 0 U/mg).  U/mg)  in  Significant  highly-purified  e x c r e t i o n were a l s o  PTH found  study.  The  changes  in urinary  f o l l o w i n g a d m i n i s t r a t i o n of apparent changes ranges.  i n U„ V and La  g  still  240  f o l l o w i n g a s a l i n e load as  In K e x c r e t i o n w e r e f o u n d , h o w e v e r , w i t h  increases  in t h i s  activity,  i n LL. V and  This Table also  (activity,  i n U., V o c c u r r e d Na contrast  i t was  shows t h e  PTH  decrease  shows t h e  phosphaturic  Table XVIII  V  In a d d i t i o n , d e c r e a s e s  occur with  'TCA'  N g  PTH;  i n GFR  body w e i g h t )  in the  highly-purified  since  A c o n t r o l group of  e l e c t r o l y t e e x c r e t i o n t h a t were  u C  r  e  three  a  t  V was  r a t s was  same e x p e r i m e n t shown  not  PTH  occurred  altered  given  Lilly  without  in the PTE  in Table XVIII  found  three  (100  dose  U/100  in order  to  g compare  TABLE XVI Effect  Group  of TCA-precipitated  Time ( h r )  ^  K  Veh i c I e TCA**  TCA  :— yequiv/IOOg/hr  ^—  / l A n  ^.f^'/u yg/IOOg/hr  rats to  Na/K  Na/Creat.  •1-0  50.0t_7.2  63.5+12.3  157+ 6  0.823  0.314  it  49.8+ 3.3  55.5+ 4.3  166+10  0.908  0.304  53.5t  4.5  6 3 . 0 t 4.1  159+12  0.865  0.349  79.5+13.5  57.0+10.8  191+ 8  I .418  0.416  26.3+ 3.9  37.0+ 3.5  142+ 3  0.710  0. 186  11.5+ I.2  16.5+ 0.5  70+ 2  0.713  0. 170  t Li I l y  Veh i c I e  PTH a n d L i l l y PTE o n t h e r e s p o n s e o f i n t a c t saline loading*  0 - I  it  Li I l y  Veh i c I e  - 2  43.3+ 3.9  37.5+ 5.5  I 62+10  I .208  0.269  TCA  II  21.0+ 4.9  23.0+ 4.7  130+21  0.908  0. 168  ti  5.9+  1.0  32.3+ 2.5  164+13  0. 178  0.036  Vehicle  48.3+  6.8  39.3+ 9.I  I 55+18  I .388  0.325  TCA  37.5+ 3.8  34.3+ 3.8  146+18  I . 100  0.270  35.8+  152+12  0.260  0.054  Li I l y  LI I l y  8.0+  0.9  6.5  TABLE XV!  (continued)  Group  Ca  Time ( h r )  Vehicle  Mg yg/IOOg/hr  I - 0  8.4+2.6  67.8+16.3  TCA  II  16.4+2.6  95.6+14.0  Li I ly  II  7.0+1.6  52.2+ 9.2  0 - I  10.2+3.0  66.0+ 6.9  5.0+0.3  47.0+ 7.5  2.6+0.5  29.4+ 5.I  4.8+1.4  46.8+ 6.0  2.7+0.9  40.2+ 6.7  I.0+0.02  30.6+ 2.8  6.2+2.4  51.0+1 I.0  TCA  8.6+2.6  68.4+13.4  Li I ly  I.0+0.02  41.0+ 9.I  Vehicle  it  TCA Lilly  Veh i c I e  I - 2 II  TCA Li I ly  Vehicle  2 - 3  *Mean w e i g h t PTE,  o f r a t s , 345 g . T i m e - I h r : 10 ml 0.9%  PTE, o r v e h i c l e  **TCA-precipitated +  LiIly  (0.2%  bovine  phenol  i n 20 meq/l  NaCI/rat,  i . p . Time 0 h r : T C A - p r e c i p i t a t e d  saline).  PTH, 200 U / r a t , s . c . i n v e h i c l e .  P T E , 200 U / r a t , s . c .  Mean + SEM; n = f o u r r a t s p e r g r o u p .  TABLE XV I I Log-dose response t o L i l l y  D o s e PTE Volume U/100 g m l / I OOg/hr  I  (5)  P '.  Mg yg/IOOg/hr  Creat.  28.6  48.6  101.2  221  113.9  114  tO.122  +6.0  +6.4  +13.7  +23  +11.2  +9  0.379  19.0  49.8  43.4  498  79.3  113  +0.134  +6.2  +11.5  +14.8  +77  +37.3  +19  0.223  10.3  34.7  23.4  332  43.7  98  +3.1  +6.5  +4.8  +37  +7.3  +8  (5)  +0.044  *Age o f r a t s , serially  Ca  rats*  0.573  10 ( 5 )  100  Na K ueqii i v / 1 OOg/hr  PTE i n TPTX  two m o n t h s . U r i n e c o l l e c t e d  diluted  with water.  over a three-hour  period  following  Mean + SEM; n = number i n p a r e n t h e s i s .  Na/K  Na/Creat.  0.587  0.251  0.295  0.168  0.263  0.105  s.c. i n j e c t i o n of L i l l y  PTE,  TABLE XV I I I Log-dose response t o h i g h l y p u r i f i e d  D o s e PTH U/IOOg I (5)  Volume ml/IOOg/hr  PTH i n TPTX  P Mg yg/IOOg/hr  rats*  Na K uequiv/IOOg/hr  Ca  Creat.  0.325 +0.088  31 .7 +7.8  28.4 + 1 .8  13.2 +0.9  174 + 17  69.7 +8.2  163 + 13  .. , N  a  /  K  .085  Na/Creat. 0. 198  10  (6)  0.252 +0.025  29.5 +2.5  40.9 +2.6  13.4 +4.5  574 +63  65.7 +9.0  160 +5  0.721  0. 185  100  (6)  0.260 +0.059  26.8 +5.9  42.4 +4.7  5.3 + 1 .2  759 +42  37.6 +7.0  169 +1 I  0.600  0. 156  8.1 +3.2  23.4 +4.3  4.1 +0.5  435 +64  11.7 +3.1  125 +16  0.350  0.065  Lilly 100  PTE  (3)  0.105 +0.024  *Age o f r a t s , f o u r m o n t h s . Urine collected over a three-hour period following s.c. i n j e c t i o n of highly p u r i f i e d PTH ( a c t i v i t y , 3000 U/mg) i n 0.5 ml v e h i c l e ( 2 0 meq/l s a l i n e ) , o r L i l l y PTE ( 1 0 0 U/IOOg, s . c . ) Mean + SEM; n = number i n p a r e n t h e s i s .  73  responses under was  identical conditions.  r e d u c e d a s compared  purified the  PTH.  to the Q u  The e x c r e t i o n  v r e a +  '  n  V  i t i s s e e n t h a t ^Q f  Here  rea  +  n e  rats  given  highly-  o f N a , K, C a , P, a n d Mg was a l s o  less  with  Lilly  PTE by c o m p a r i s o n w i t h t h e 100 U d o s e r a n g e o f  highly-purified  The  h y p e r c a I c e m i c r e s p o n s e t o a g i v e n dose o f L i l l y  PTE ( 1 0 0 U/100  PTH.  g body  weight) i s a long-lasting  levels did not decrease until A  linear relationship  irinary rising in  excretion and U  F i g 19.  N g  o n e a s i s shown  10-12 h o u r s a f t e r  was f o u n d b e t w e e n  i n F i g 18 w h e r e p l a s m a Ca i n j e c t i o n o f t h e hormone.  t h e plasma Ca l e v e l s and t h e  o f Na, and t h e l o g - d o s e o f L i l l y  V falling  with  increasing  P T E , p l a s m a Ca  levels  d o s e s o f t h e hormone a s i s s e e n  74  Fig  18.  T i m e - c o u r s e o f a c t i o n o f L i I l y PTE (100 U/100 g body w e i g h t , s . c . ) o n p l a s m a Ca l e v e l s i n TPTX r a t s . ( E a c h p o i n t r e p r e s e n t s Mean +_ SEM f r o m s e p a r a t e g r o u p s of f i v e r a t s . )  75  Fig  19.  L o g - d o s e r e s p o n s e +o L i l l y PTE i n TPTX r a + s . ( E a c h p o i n t r e p r e s e n t Mean +_ SEM from f i v e r a t s . )  76  C. P I a s m a a n d U r i n a r y FoI Iow i ng D e x + r a n I n f u s i o n  E l e c + r o l y + e Changes  i n Consc ious  Sheep  Methods The dextran (see  sheep were p r e p a r e d  using  Section  a similar  f o r t h e volume-expansion s t u d i e s  protocol  t o t h a t used  I I , Methods), with t h e exception  a dextrose-saline  infusion.  Following  a control  I 1/4 h o u r s , d e x t r a n  with  in the Ca-infusion  studies  t h a t t h e y were n o t g i v e n  plasma and u r i n e c o l l e c t i o n o v e r a p e r i o d o f  i n a volume e q u i v a l e n t  t o \% body w e i g h t was  infused  o v e r a p e r i o d o f 15 m i n u t e s . P l a s m a a n d u r i n e s a m p l e s w e r e c o l l e c t e d f o r a  f u r t h e r 2 3/4 h o u r s s o t h a t t h e e n t i r e c o l l e c t i o n  4  1/4 h o u r s . C a t h e t e r s  given  repeated out  covered  w e r e t h e n removed a n d t h e i n d i v i d u a l  a 10-day t o 2-week r e c o v e r y  This  period  before  being  e x p e r i m e n t was p e r f o r m e d w i t h  i n t h e TX a n i m a l s .  The f i n a l  used  sheep were  again.  t h e i n t a c t sheep and t h e n  was  s e r i e s o f e x p e r i m e n t s was c a r r i e d  i n t h e same TX s h e e p w i t h t h e a d d i t i o n o f s a l m o n c a l c i t o n i n w h i c h  administered completion  i n two d o s e s o f 50 U e a c h . T h e f i r s t  o f t h e 15-minute d e x t r a n  d o s e was g i v e n  was  at the  i n f u s i o n , and t h e second o n e hour  later.  ResuIts PI asma c h a n g e s Following Ca  the completion  l e v e l s were d e c r e a s e d  d e c r e a s e was m a i n t a i n e d hours post  o f t h e 15-minute d e x t r a n  a s i s seen  i n F i g 20.  In t h e i n t a c t s h e e p ,  throughout the experimental  i n f u s i o n , t h e change  i n p l a s m a Ca  i n f u s i o n , plasma  level  period.  this  At three  was - 0 . 7 2 t 0 . 2 2 mg%.  In  77  Fig  20.  Changes i n plasma Ca l e v e l s f o l l o w i n g a 1 5 - m i n u t e d e x t r a n i n f u s i o n i n i n t a c t , TX, and TX s h e e p t r e a t e d w i t h s a l m o n c a l c i t o n i n (2 X 50 U ) . C h a n g e s i n p l a s m a Ca l e v e l s e x p r e s s e d a s mg% c h a n g e s f r o m b a s e - l i n e c o n t r o l v a l u e s . (Mean v a l u e s a r e i n d i c a t e d ; f o r n_ see T a b l e X I X . )  78  t h e TX s h e e p , and  by  however, t h e plasma  t h r e e hours  following  -0.18+0.I I mg% f r o m plasma  Ca l e v e l s  normal  Ca l e v e l s g r a d u a l l y  the dextran  Ca  showed a p r o g r e s s i v e f a l l  infusion,  When c a l c i t o n i n was g i v e n t o t h e TX s h e e p ,  both plasma  load.  hour  Plasma  following  plasma  P  P a n d Mg l e v e l s  Urine  Fig  level  i n F i g 21.  Following the dextran  i n t h e i n t a c t sheep and  during the three-hour period  infusion.  A similar  following  Plasma  Mg c h a n g e s  b u t showed a s l i g h t l y  in the  fall  when t h e s e a n i m a l s w e r e g i v e n c a l c i t o n i n  f o r a longer period.  in  b u t was  i n t h e TX a n d T X + C T  greater fall  in levels  i n t h e i n t a c t a n i m a l s . T h i s c h a n g e was n o t s i g n i f i c a n t  than  (Table X I X ) .  changes  Similar in  lower  plasma  i n t h e TX a n i m a l s showed a p r o g r e s s i v e f a l l  sheep were v e r y s i m i l a r was f o u n d  The  i n F i g 20.  decreased  completion of the dextran  P was o b s e r v e d  continued  a s i s seen  P a n d Mg c h a n g e s a r e shown  were m a i n t a i n e d a t t h i s the  i n Table XIX.  i n t h e i n t a c t a n d TX s h e e p a t t h i s t i m e w e r e s i g n i f i c a n t l y  (p_<0.050).  Plasma  showed a c h a n g e o f o n l y  b a s e - l i n e l e v e l s as i s seen  different levels  load  r e t u r n e d t o normal  i n c r e a s e s i n u r i n e volume and osmolal o u t p u t were  t h e i n t a c t a n d TX s h e e p f o l l o w i n g 2 2 a n d T a b l e s XX a n d X X I .  TX animals, a larger  dextran  infusion,  observed  a s i s seen i n  H o w e v e r , when c a l c i t o n i n was g i v e n t o t h e  i n c r e a s e i n u r i n e v o l u m e a n d o s m o l a l o u t p u t was  observed.  The  changes  in U  M  V i n t h e t h r e e groups  c h a n g e s t h a t w e r e o b s e r v e d , a s i s shown  o f sheep r e f l e c t e d  t h e osmolal  i n F i g 2 3 . The a d m i n i s t r a t i o n o f  c a l c i t o n i n was f o l l o w e d by a g r e a t e r i n c r e a s e i n Na e x c r e t i o n e s c o m p a r e d to t h a t observed  i n t h e i n t a c t a n d TX s h e e p  (Table XXIV).  TABLE X I X Plasma changes f o l l o w i n g  Time a f t e r s t a r t o f d e x t r a n load ( h r ) :  dextran  infusion  i n I n t a c t , TX, a n d TX + CT s h e e p *  . ,.  APIasma Ca (mg$) I n t a c t (3)  -0.72+0.06  -0.58+0.07  -0.60+0.15  -0.72+0.22  TX ( 6 )  -0.95+0.04  -0.66+0. 15  -0.56+0.13  -0.18+0.I I  TX + CT ( 3 )  -0.88+0.21  -].25+0.22  -I.72+0.36  - I .97+0.34  £  I n t a c t v s TX  <0.025  <0.050  TX v s TX+CT I n t a c t v s TX+CT  <0.050  <0.0I0  < 0*001  <0.050  <0.050  APIasma P (mg$) Intact (3)  -0.20+0.15  -0.40+0.06  -0.35+0.10  -0.70+0.15  TX ( 6 )  -0.38+0.12  -0.97+0.16  -I.23+0.22  - I . 2 6 + 0 . 19  TX + CT ( 3 )  -0.20+0.15  -0.37+0.16  -0.68+0.23  -I.03+0.27  £  I n t a c t v s TX  <0.050  <0.050  APIasma Mg (mg%) Intact (3)  -0.16+0.02  -0.17+0.03  -0.21+0.05  -0.22+0.08  TX ( 6 )  -0.20+0.03  -0.29+0.09  -0.34+0.09  -0.32+0.09  T X + C T (3)  -0.22+0.03  -0.24+0.03  -0.35+0.04  -0.29+0.01  * D e x t r a n (6% G e n t r a n 7 5 i n 0.9$ N a C l ) , \% body w e i g h t , i n f u s e d o v e r b a s e - l i n e c o n t r o l l e v e l s . Mean + SEM; n = number In p a r e n t h e s i s .  15 m i n . C h a n g e s i n p l a s m a  levels  from  Intoct  TX  TX  Time  in  +  Calcitonin  Hours  C h a n g e s i n p l a s m a P a n d p l a s m a Mg f o l l o w i n g a 1 5 - m i n u t e d e x t r a n i n f u s i o n i n i n t a c t , TX, and TX s h e e p t r e a t e d with s a l m o n c a l c i t o n i n (2 X 50 U ) . C h a n g e s i n p l a s m a l e v e l s e x p r e s s e d a s mg% c h a n g e s f r o m b a s e - l i n e c o n t r o l values. (Mean v a l u e s a r e i n d i c a t e d ; f o r n see T a b l e XIX.)  Intact  tt  tt I  TX  TX  + Calcitonin  tt  I  I I  I I  I I  I I  I I  I l  + 4.  0 A Dextran  2  t  A Dextran  n  +1 O + l Time  in  ^Calcitonin  Dextran  1 1  2  3  Hours  Changes i n u r i n a r y volume (upper t r a c e ) and U V (lower t r a c e ) f o l l o w i n g a 15-minute d e x t r a n i n f u s i o n i n i n t a c t , T X , a n d TX s h e e p t r e a t e d w i t h s a l m o n c a l c i t o n i n ( 2 X 50 U ) . C h a n g e s f r o m b a s e - l i n e c o n t r o l values a r e i n d i c a t e d . (Values expressed as Mean + SEM; f o r n s e e T a b l e s XX a n d X X I . )  TABLE XX Changes  i n u r i n e volume f o l l o w i n g d e x t r a n TX t CT  Time a f t e r s t a r t o f dextran load ( h r ) :  0 -  i n f u s i o n i n I n t a c t , TX, a n d  sheep*  I - 2  2 - 3  Changes i n u r i n e volume from b a s e l i n e c o n t r o l values (ml/hr)  I n t a c t (5)  30.6+18.9  38.7+10.5  18.3+5.3  TX ( 6 )  37.1+15.9  44.3+14.3  15.3+4.8  TX t CT ( 3 )  49.0+38.3  69.9+29.I  35.8+2.3  £ TX v s TX+CT  *Mean + SEM;  n = number i n p a r e n t h e s i s .  <0.025  TABLE XXI Changes  i n osmolal  output following  dextran  infusion  i n i n t a c t , TX, a n d  TX + CT s h e e p *  Time a f t e r s t a r t o f dextran load ( h r ) :  I - 2  2 - 3  I I.3+2.3  8.4+4.1  5.5+2.6  TX ( 6 )  10.5+2.7  13.4+6.7  6.5+1.7  TX + CT ( 3 )  17.3+8.0  25.6+7.5  I I.9+4.4  Changes i n osmolal o u t p u t from b a s e - l i n e c o n t r o l v a l u e s (mOsm/hr)  Intact  (5)  *Mean + SEM;  n = number i n p a r e n t h e s i s .  oo UJ  84  A c a l c i u r i a was f o u n d dextran was to  infusion  not observed t h a t found  t o accompany t h e n a t r i u r e t i c  inthe intact  s h e e p a s i s shown  When c a l c i t o n i n  t h e TX s h e e p , a c a l c i u r i a was o b s e r v e d magnitude than excretion fall  t h a t found  in theT X + C T  although  sheep o c c u r r e d  not  i n Table  variation.  magnitude  was a d m i n i s t e r e d t o  The I n c r e a s e  i n Ca greater  i n t h i s g r o u p . T h e c l e a r a n c e o f Ca i n t h e  XXII.  i n response t o t h e dextran  In t h e TX s h e e p , c l e a r a n c e  UpV a n d a b s o l u t e c h a n g e s  Outputs from  individual  compared t o c o n t r o l o u t p u t s  ratesd i d  was o b s e r v e d  given  before t h e dextran  following t h e dextran  calcitonin,  very  considerable  infusion  in the intact  t o t h e TX s h e e p , a p h o s p h a t u r i c  sheep w i t h o u t  i n UpV showed  s h e e p a r e shown,, t h e r e f o r e , a n d a r e  In f o u r o f t h e f i v e s t u d i e s  of  this  change.  Control  UpV  of similar  despite the significantly  i n t a c t a n d TX + CT g r o u p s was f o u n d t o i n c r e a s e as i s seen  However,  i t was o f s m a l l e r  i n the intact animals.  i n p l a s m a C a w h i c h was f o u n d  infusion,  i n F i g 23.  i n t h e TX s h e e p d e s p i t e a n a t r i u r e s i s  i n the intact animals.  response t ot h e  infusion.  i n Table  sheep, an i n c r e a s e i n When c a l c i t o n i n  r e s p o n s e was a l s o s e e n .  l i t t l e c h a n g e was o b s e r v e d  t h e s t u d i e s , and an i n c r e a s e  i n U V was f o u n d  XXIII.  was  In t h e TX  i n U^V  i n t h e remaining  i n four two  P  although  t h i s was o n l y t r a n s i e n t i n o n e o f t h e s e  Changes as  i s seen  i n O^gV  i n F i g 24.  following t h e dextran s h e e p b u t was r e s t o r e d Table sheep,  XXIV  '  n  +  n e  t h r e e groups o f sheep were f a r b e t t e r d e f i n e d  A m a g n e s u r i a was o b s e r v e d infusion.  in the intact  T h i s r e s p o n s e was d i m i n i s h e d  i n p a r t when t h e s e  shows t h e h o u r l y c h a n g e s  i n a d d i t i o n t o changes  animals.  animals  were g i v e n  animals i n t h e TX  calcitonin.  i n Mg e x c r e t i o n i n t h e t h r e e g r o u p s o f  i n U.. V, Up V, a n d U V . K  85  | >  Intact  TX  TX + Calcitonin  250-1  Time in Hours  Fig  23.  Changes i n following a and TX s h e e p Changes from (Mean v a l u e s  V (upper t r a c e ) and IL^V (lower t r a c e ) iB-minute d e x t r a n i n f u s i o n i n i n t a c t , TX, t r e a t e d w i t h s a l m o n c a l c i t o n i n ( 2 X 50 U ) . base-line control values are indicated. a r e shown; f o r n see Table XXIV.)  TABLE XXI I C l e a r a n c e o f Ca f o l l o w i n g  Time ( h r )  dextran  Control - 1 - 0  infusion  i n i n t a c t , TX, a n d TX + CT  Post 0 - I  Infusion** - 2  sheep*  2 - 3  Clearance of Ca ( m l / m i n )  I n t a c t (3)  0.124+0.066  0.272t0.09l  0.379+0.125  0.237+0.052  TX ( 6 )  0.086t0.034  0.091+0.023  0.081+0.023  0.079+0.025  TX t CT ( 3 )  0.081+0.039  0.158+0.063  0.138+0.039  0.062+0.022  * Clearance,  [Urine ] X Vol.(ml)/min LPIasmaJ  D e x t r a n i n f u s i o n g i v e n a t t i m e 0 h o u r o v e r a p e r i o d o f 15 m i n . Mean + SEM; n = number i n p a r e n t h e s i s .  TABLE XXI I I Urinary P excretion following dextran infusion in intact, TX, and TX + CT sheep  Time (hr):  Control 0  Post infusion* 1-2  0-1  2-3  U V (mg/hr) Intact  TX  TX t CT  0.107 0.1 12 0.134 0.142 20.772  0. 165 0.222 0.272 0.993 20.027  0.092 0.097 0.237 0.278 1 .289 17.865  0.089 0.1 13 t 0.232 0.265 2.337 t 25.223 +  0.023 0.046 0.516 0.615  0.097 t 0.080 t 1 .791 t 0.758 t  + + t t  0.131 t 0.1 14 t 0.248 t 2.926 t 19.517 0.098 0.091 0.21 1 0.200 3.120 14.853  0.073 0.096 0. 147 t 3.657 t 8.561  t  + +  0.100 + 0.050 + 6.645 t 0.579  0.082 0.081 0. 153 0.210 6.012 t 17.025 0.064 t 0.056 + 6.813 t 0. 146  *Dextran load given at time 0 hr over a period of 15 minutes. Arrows indicate either increase ( t) or decrease ( +) from control period value.  +  +  +  88  TX  Intact  TX + Calcitonin  e \  CTJ  tt  tt  t  I I  •/ D e x t r a n  I I  I I  I I  I I  I l  I  y  Dextran  1  ~i  +1 O + l Time  F i g 24.  /.  2 in  1 3  L  L  Calcitonin  Dextran  2 —r  +i  Hours  Changes i n V f o l l o w i n g a 15-minute d e x t r a n i n f u s i o n i n i n t a c t , TX, and TX sheep t r e a t e d w i t h salmon c a l c i t o n i n (2 X 50 U ) . Changes from b a s e - l i n e c o n t r o l v a l u e s a r e i n d i c a t e d . (Mean v a l u e s a r e shown; f o r n see T a b l e X X I V ) .  89 TABLE XXIV Changes i n u r i n a r y e l e c + r o l y + e e x c r e t i o n f o l l o w i n g d e x + r a n i n f u s i o n i n i n t a c t , T X , a n d TX + CT s h e e p * Time a f t e r of dextran  AU V  start infusion (hr)  0 - I  - 2  2 - 3  (meq/hr)  N g  Intact (4)  3.27+0.74  4.92+1.84  3.03+1.42  TX ( 6 )  3.23+1.24  4.88+1.64  3.65+1.02  TX t CT ( 3 )  6.10+3.64  10.74+3.94  6.44+1.82  0.50+0.I 3  0.77+0.60  0.25+0.19  -0.02+0.10  -0.09+0.13  -0.09+0.I I  0.33+0.37  0.19+0.20  -0.19+0.16  AU V  (mg/hr)  C g  Intact (5) IX (6) TX + CT ( 3 ) £  I n t a c t v s TX  AU V  <0.025  (mg/hr)  M g  Intact (5)  2.02+0.73  2.32+1.22  0.45+0.61  TX ( 6 )  I.21+0.54  0.94+0.68  0.20+0.42  T X + C T (3)  2.47+1.37  I.78+0.23  -0.98+0.13  0.14+0.15  -0.34+0.14  -0.35+0.29  TX ( 6 )  -0.15+0.13  -0.47+0.20  -0.85+0.28  TX + CT ( 3 )  -0.06+0.18  -0.83+0.18  -I.64+0.08  AU V K  (meq/hr)  Intact (5)  £  I n t a c t v s TX+CT  ^Changes i n o u t p u t from b a s e l i n e c o n t r o l v a l u e s a r e shown. D e x t r a n i n f u s e d o v e r a p e r i o d o f 15 m i n u t e s f r o m t i m e 0 h o u r . Mean + SEM; n = number i n p a r e n t h e s i s .  <0.025  90  Decreases i n U^V  were o b s e r v e d  i n a l i t h r e e groups of sheep  d u r i n g t h e p e r i o d of u r i n e c o l l e c t i o n . The f o l l o w i n g the dextran IL  t r a n s i e n t increase in  U^V  i n f u s i o n p a r a l l e l e d the t r a n s i e n t increase in  V o b s e r v e d a t t h i s t i m e as  i s seen i n F i g  25.  91  TX  TX  Intact  + Calcitonin  => "5 cr =3,  r  500 n  •500 <3  I I I  I  I  I  I  I  Calcitonin  ft £  ^  Dextran  —t  +1  Time  F i g 25.  in  Dextran  -  -1 Hours  Changes i n U^V (upper t r a c e ) and l - ' r ; V (lower t r a c e ) f o l l o w i n g a 15-minute d e x t r a n i n f u s i o n i n i n t a c t , TX, and TX sheep t r e a t e d w i t h salmon c a l c i t o n i n (2 X 50 U ) . Changes from b a s e - l i n e c o n t r o l v a l u e s a r e i n d i c a t e d . (Mean v a l u e s a r e shown: f o r n see T a b l e XXIV.) r e a+  + i  92  DISCUSSION  I.  EXOGENOUS C A L C I T O N I N ADMINISTRATION A. The  Chronic  Studies  f i n d i n g o f a potent n a t r i u r e t i c  salmon c a l c i t o n i n  i n young r a t s d u r i n g  hormone was o f c o n s i d e r a b l e  interest.  chronic  been r e p o r t e d ,  c a l c i t o n i n could  effect of  administration ofthe  At that time,  u r i n a r y changes t h a t o c c u r f o l l o w i n g c h r o n i c had  and d i u r e t i c  no s t u d i e s o n t h e  treatment with  calcitonin  a n d no e v i d e n c e was a v a i l a b l e t o show t h a t  exert  such profound a l t e r a t i o n s i n u r i n a r y  salmon excretory  patterns.  The  n a t r i u r e t i c and d i u r e t i c  output of other the  e l e c t r o l y t e s which  hormone, b e s i d e s  They found t h a t every three  included  i n a d d i t i o n t o the increased  C a , P, a n d Mg, s u g g e s t e d  that  i t s known e f f e c t o n b o n e , may be e x e r t i n g a r e n a l  e f f e c t which p e r s i s t s with Recent s t u d i e s  response,  continued  a d m i n i s t r a t i o n o f t h e hormone.  i n r a t s by S ^ r e n s e n a n d H i n d b e r g porcine  calcitonin  hours f o r t h r e e  (68) support these f i n d i n g s .  i n a d o s e o f 100  mU/100 g body  days caused a p r o g r e s s i v e  increase  weight  in urine  v o l u m e , a n d t h e e x c r e t i o n o f N a , C a , P, a n d Mg. T h e y a t t r i b u t e d t h e s e e f f e c t s t o a d i r e c t a c t i o n o f c a l c i t o n i n on t h e renal  B i j v o e t e t a]_. ( 6 9 ) calcitonin  showed t h a t t h e c o n t i n u a l  i n man ( 6 3 MRC U / d a y ) d u r i n g  a period  tubules.  infusion of  o f 6 t o 39 d a y s r e s u l t e d  i n a t r a n s i e n t d i u r e s i s a n d n a t r i u r e s i s w h i c h was a c c o m p a n i e d loss  inthe first  two days.  secretion  by w e i g h t  I t w o u l d a p p e a r t h a t t h e h o r m o n e was  e x e r t i n g a c o n t ? nued e f f e c t o n Na a n d v o l u m e , h o w e v e r , that aldosterone  porcine  since  r a t e s and plasma r e n i n a c t i v i t y  i t was o b s e r v e d  were a b o v e normal  93  during could  t h e experimental  period. This  obscure a continued  action  increase  o f t h e hormone o n t h e k i d n e y .  e t a_l_.also o b s e r v e d a n i n c r e a s e  i n e x c r e t i o n o f cAMP was o b s e r v e d .  I t would appear from t h e s e c h r o n i c  the  i s capable of causing  hormone i s b e i n g  in order  In man  which  (69) a n d p o s s i b l y  that  rats,  condition.  hormone o n u r i n a r y Na a n d v o l u m e  chronic administration of calcitonin,  loss of other e l e c t r o l y t e s  i n c l u d e s C a , P, a n d Mg c a n a l s o o c c u r a n d t h e s e e f f e c t s a p p e a r  t o be l e s s r e a d i l y c o m p e n s a t e d  B. I. Plasma  for.  A c u t e Stud i e s changes  The  hypocalcemic e f f e c t of c a l c i t o n i n  basis f o r t h e bioassay and  i n r a t a n d man  t o compensate f o r t h i s  In a d d i t i o n t o t h e e f f e c t s o f t h i s during  studies  a volume s t r e s s which p e r s i s t s a s long a s  administered.  m e c h a n i s m s may be e v o k e d  Bijvoet  i n Ca a n d F e x c r e t i o n a n d r u l e d o u t t h e  i n t e r v e n t i o n o f PTH s i n c e no i n c r e a s e  calcitonin  i n compensatory mechanisms  of t h i s  (62).  In T a b l e  documented and i s t h e  hormone (59). T h e r e s p o n s e  i s r e l a t e d t o t h e age o f t h e animal  bone t u r n o v e r  i s well  a n d more d i r e c t l y  I I I , a progressive  drop  six-hour  (jp<0.00l).  r e s p o n s e was f o u n d a t t h e d o s e o f hormone u s e d f o r many o f t h e  urinary studies  ( 1 0 0 mll/100 g body w e i g h t ) ,  hypocalcemic state during  The  to the rate of  i n plasma Ca l e v e l s  i s shown f r o m 0 t o 3 h o u r s w h i c h was h i g h l y s i g n i f i c a n t Since t h i s  i s dose-dependent  the periods  of urine  highly s i g n i f i c a n t decrease  h o u r s a s shown i n T a b l e  t h e r a t s were i n a  collection.  i n plasma P a t o n e and t h r e e  I I I (p_<0.00l) i s c o n s i s t e n t with t h e hypophosphatemic  e f f e c t of c a l c i t o n i n observed  by o t h e r  workers  ( 7 0 , I I , 7 1 ) . The  94  hypophospha+ernic  effect  i s a p p a r e n t l y not a b o l i s h e d  by n e p h r e c t o m y o r  p a r a t h y r o i d e c t o m y a s shown by Kennedy e t a I . ( 7 1 ) , and a d i r e c t e f f e c t o f t h e hormone on  Table i n plasma  Mg  been found  by o t h e r w o r k e r s . S t u d i e s i n man  i n plasma  Mg.  patients than  a l s o found a decrease  Mg  (70-110 g) as d i d P a l m i e r i  p o r c i n e c a l c i t o n i n . These f i n d i n g s were e t a I.(16) u s i n g salmon using  synthetic  calcitonin  human and  salmon  Negative  Nielsen et a l . ( l 5 ) using hypomagnesemic  effect  et a I.(4) using p a r t i a l l y  purified  in contrast to those of Aldred  i n 220-250 g r a t s .  calcitonin also  in response to c a l c i t o n i n  W i l l jams e t a I.(18)  r e p o r t e d no  response t h r e e hours f o l l o w i n g t h e s t a r t o f a one-hour These d i f f e r e n c e s  in  Haas e t a I . ( 5 0 )  in hypoparathyroid patients.  porcine c a l c i t o n i n observed a s i g n i f i c a n t  in young r a t s  hypo-  more pronounced  patients.  r e s u l t s w e r e r e p o r t e d by B i j v o e t e t a I . ( 7 3 ) . synthetic  treatment  by S«5rensen e t a I. ( 7 2 ) r e v e a l e d a  i n normocaIcemic  i n plasma  be  C o n s i s t e n t decreases  following calcitonin  m a g n e s e m i c e f f e c t w i t h p o r c i n e c a l c i t o n i n w h i c h was hypercalcemic  to  bone.  I I I a l s o shows a d e c r e a s e have not a l w a y s  thus appears  hypomagnesemic  infusion of  t r e a t m e n t may  hormone.  be r e l a t e d  to  t h e age o f t h e a n i m a l and  t h u s t h e r a t e o f bone r e m o d e l l i n g , a  e f f e c t b e i n g more o b v i o u s  i n t h o s e a n i m a l s where bone t u r n o v e r i s o c c u r r i n g  at a faster  rate.  taken following data  in Table  In a d d i t i o n , t h e t i m e a t w h i c h t h e b l o o d s a m p l e i s  hormone a d m i n i s t r a t i o n may  I I I were d e r i v e d  from  ( c a . 4 0 g body w e i g h t ) f r o m w h i c h after  a single  hypomagnesemic  be a n  studies  samples  in three-week-old  were t a k e n a t one and  i n j e c t i o n o f hormone. O n l y a t one  decrease s i g n i f i c a n t  (p < 0 . 0 2 5 ) .  important f a c t o r .  h o u r was  The  rats three  t h e plasma  hours Mg  95  S i g n i f i c a n t decreases  i n plasma  Na o r K i n r e s p o n s e t o c a l c i t o n i n  t r e a t m e n t have n o t been c o n s i s t e n t l y o b s e r v e d w i t h d a t a shown  The accounted  and t h i s  i n Table I I I .  decrease  i n plasma  l e v e l s o f C a , P, a n d Mg c o u l d  readily  f o r by t h e i n h i b i t i o n o f b o n e r e s o r p t i o n w h i c h o c c u r s  c a l c i t o n i n a d m i n i s t r a t i o n . The l o w e r i n g o f plasma be a r e s u l t o f a g e n e r a l movement o f t h i s been s u g g e s t e d  by T a I m a g e a n d A n d e r s o n  ions from t h e kidney changes  i s i n agreement  P could,  be  following  in addition,  i o n i n t o s o f t t i s s u e s a s has  (74). An i n c r e a s e d  i n response t o c a l c i t o n i n could  loss o f these  enhance t h e plasma  found.  2. U r i n e c h a n g e s Young r a t s t r e a t e d exhibited  a marked  with  single  i n j e c t i o n s o f salmon  n a t r i u r e t i c and d i u r e t i c  response.  calcitonin  Increases i n P  e x c r e t i o n w e r e a l s o o b s e r v e d a t t h i s t i m e . H o w e v e r , C a a n d Mg o u t p u t s w e r e found t o d e c r e a s e , a l t h o u g h d e c r e a s e was p r e c e d e d changes  by a t r a n s i t o r y  in the excretion of urinary  of c a l c i t o n i n and  i n some f r a c t i o n a l - c o l l e c t i o n  electrolytes  decrease  single  doses  i n F i g 5.  i n U_ V a n d U,, V w h i c h was o b s e r v e d Ca Mg  s t u d i e s was a t v a r i a n c e w i t h f i n d i n g s a  following  The  o f some o f t h e c h a n g e s t h a t o c c u r r e d was r e l a t e d t o  t h e d o s e o f hormone g i v e n a s i s s e e n  U^ V  i n LL^V and U ^ V .  this  were found t o o c c u r w i t h i n t h e range o f a s i x - h o u r p e r i o d ,  t h e magnitude  The  increase  studies,  a n d L)^ V i n c r e a s e d .  from t h e c h r o n i c  in the acute  studies  where  I t i s p o s s i b l e t h a t t h e n e t changes found i n  t h e a c u t e s t u d i e s w e r e s e c o n d a r y t o t h e e f f e c t s o f t h e hormone o n b o n e .  96  The decreased plasma Ca  l e v e l , as a r e s u l t o f decreased bone r e s o r p t i o n ,  would r e s u l t i n a decreased f i l t e r e d  l o a d * of Ca  (assuming GFR  unchanged).  T h i s would mask any d e c r e a s e s i n t u b u l a r r e a b s o r p t i o n o f Ca t h a t occur.  If d e c r e a s e s i n t h e f i l t e r e d  might  load o f Ca were s m a l l e r , t h e c a l c i u r i c  e f f e c t o f t h e hormone would become e v i d e n t as was suggested by t h e f i n d i n g s o f S«5rensen and Hindberg  (67).  They found t h a t d u r i n g  chronic  a d m i n i s t r a t i o n of porcine c a l c i t o n i n , the hypocalcemic e f f e c t of the hormone was  reduced a f t e r t h e f i r s t day of t r e a t m e n t , and as plasma  levels returned e x c r e t i o n was  Ca  towards normal, t h e i n i t i a l d e c r e a s e i n u r i n a r y C a  replaced  Decreases  by an i n c r e a s e  in the f i l t e r e d  in the excretion of t h i s ion.  load o f Mg c o u l d a l s o mask any  in r e a b s o r p t i o n o f t h i s i o n by t h e r e n a l t u b u l e s . S i n c e Mg  decrease  i s normally  r e a b s o r b e d a t a maximal r a t e ( 2 5 ) , v e r y smaI I d e c r e a s e s i n f i l t e r e d c o u l d be r e f l e c t e d by l a r g e d e c r e a s e s i n U^gV.  The  increase  i n Mg  e x c r e t i o n which was found d u r i n g c h r o n i c c a l c i t o n i n a d m i n i s t r a t i o n be e x p l a i n e d  i n a way  s i m i l a r to that described  be n o t e d , as shown i n F i g 5, t h a t  c a l c i t o n i n tended t o r e v e r s e t h e t r e n d . a bi p h a s i c  in e x c r e t i o n of Ca and Mg  may  In t h i s  in the acute  l a r g e doses o f  In a d d i t i o n , as mentioned  response i n t h e o u t p u t of t h e s e ions v/as o b s e r v e d  fractionaI-col Iection studies.  may  above f o r Ca.  A l t h o u g h t h e net e x c r e t i o n of Ca and Mg was reduced studies, i t will  load  above,  i n some  instance, the t r a n s i t o r y  increase  have r e f l e c t e d a d i r e c t a c t i o n o f c a l c i t o n i n  ^ f i l t e r e d load = t h e amount o f a g i v e n s u b s t a n c e f i l t e r e d t h r o u g h t h e glomerulus in a given time: u I t r a f i I t r a b l e concentration X GFR.  97  on  the renal  decreases  tubules  in decreasing  in filtered  The  load  reabsorption  u r i n a r y e l e c t r o l y t e changes t h a t occurred  since they occurred  no  rats  SgSrensen e t a I . ( 7 2 )  no c h a n g e  H a a s e t a_l_. ( 3 0 ) unaltered  in Q u  r e a  et al.(l8).  in  ^. V which they  e t a I.(16)  (14, 30).  e l e c t r o l y t e e x c r e t i o n observed  increases  It i s likely  in the reabsorptive  o f t h e nephron where t h e s e changes m i g h t have  of i n u l i n o r c r e a t i n i n e , inelectrolyte  were  capacities of  l o c a l i z e any p a r t i c u l a r occurred.  DOCA s t u d i e s d i d s u g g e s t t h a t t h e Na e f f e c t e x e r t e d  c a l c i t o n i n m i g h t - be o c c u r r i n g s i t e of action of t h i s  at a site  i n t h e nephron proximal  synthetic mineralocorticoid.  t h e f i n d i n g s t h a t when c a l c i t o n i n  was g i v e n  by t h e  t h a t t h e changes i n  tubules, although these studies cannot  The  was i n c r e a s e d  following c a l c i t o n i n treatment  p r i m a r i l y a r e f l e c t i o n o f changes renal  when  i n doses  A r d a i l l o u e t a I . (14) and  f o u n d GFR, a s i n d i c a t e d by c l e a r a n c e  by c a l c i t o n i n a d m i n i s t r a t i o n  could  H o w e v e r , when  ^. V, Na e x c r e t i o n  b u t n o t by t h e human p e p t i d e .  e x c r e t i o n were found  found  excretion ( i n  In s t u d i e s o n r a t s , A l d r e d  as d i d Williams  which caused a s i m i l a r r i s e  by  who  e t a I . g a v e e i t h e r s y n t h e t i c human o r s a l m o n c a l c i t o n i n  salmon c a l c i t o n i n  i n GFR  i n f u s i o n o f i n u l i n ) i n response t o c a l c i t o n i n .  i n man a l s o f o u n d  found I L , V elevated Creat.  a~ea  f o r by a n i n c r e a s e  t h e f i n d i n g s o f Rasmussen e t a I . ( 3 1 )  a t t r i b u t e t o c a l c i t o n i n treatment.  the  following a single  i n endogenous c r e a t i n i n e e x c r e t i o n o r i n u l i n  receiving a constant  Williams  before  when e n d o g e n o u s c r e a t i n i n e e x c r e t i o n was u n c h a n g e d .  i s i n agreement w i t h  increase  ions  were s u f f i c i e n t t o o b s c u r e t h e e f f e c t .  i n j e c t i o n o f c a l c i t o n i n c a n n o t be a c c o u n t e d  This  of these  This  was  by to the indicated  t o t h e DOCA-treated  rats,  9a  an  i n c r e a s e i n U..V was found ( T a b l e  to this distal  IV).  An i n c r e a s e d d e l i v e r y o f Na  s i t e c o u l d r e s u l t i n an i n c r e a s e d exchange f o r K (75).  The DOCA s t u d i e s a l s o r e v e a l e d t h a t c a l c i t o n i n can c o u n t e r a c t t h e N a - r e t a i n i n g e f f e c t o f l a r g e doses o f m i n e r a l o c o r t i c o i d . Thus, i t c a n be r u l e d o u t t h a t changes i n m i n e r a l o c o r t i c o i d a c t i v i t y a r e r e s p o n s i b l e f o r t h e changes i n U^gV t h a t were o b s e r v e d . The i n c r e a s e in  V f o l l o w i n g c a l c i t o n i n t r e a t m e n t i n DOCA-treated  o r non-treated  r a t s was v i r t u a l l y t h e same, and t h e changes i n t h e e x c r e t i o n o f C a , P, and Mg were u n a l t e r e d by DOCA p r e t r e a t m e n t .  P a r a t h y r o i d hormone c a u s e s a d e c r e a s e i n t h e r e a b s o r p t i o n o f phosphate from t h e k i d n e y t u b u l e a s demonstrated  by m i c r o p u n c t u r e s t u d i e s  (76) and an i n c r e a s e d r e a b s o r p t i o n o f Ca and Mg (23-25, 77). An i n c r e a s e i n UpV and a d e c r e a s e i n U^ V and U^gV i s s u b s e q u e n t l y o b s e r v e d . I t i s g  u n l i k e l y , however, t h a t changes o b s e r v e d  in intact rats following calcitonin  a d m i n i s t r a t i o n c o u l d be secondary t o s t i m u l a t i o n o f t h e p a r a t h y r o i d g l a n d s as a r e s u l t o f t h e h y p o c a l c e m i a s i n c e an i n c r e a s e i n UpV and a d e c r e a s e i n UQ V and W^V, a  were a l s o found  ' a d d i t i o n t o a n a t r i u r e t i c and d i u r e t i c n  response,  i n a n i m a l s w i t h t h e i r p a r a t h y r o i d g l a n d s removed (TPTX r a t s ) .  In f a c t , an even g r e a t e r n a t r i u r e t i c r e s p o n s e was c o n s i s t e n t l y o b s e r v e d f o l l o w i n g c a l c i t o n i n a d m i n i s t r a t i o n t o TPTX r a t s a s compared t o e i t h e r TX o r i n t a c t r a t s where p a r a t h y r o i d f u n c t i o n was n o r m a l .  It i s p o s s i b l e t h a t t h e decreasing  plasma Ca l e v e l which was  found d u r i n g t h e p e r i o d o f n a t r i u r e s i s f o l l o w i n g c a l c i t o n i n a d m i n i s t r a t i o n might  i n i t s e l f be r e s p o n s i b l e f o r t h e i n c r e a s e i n U^gV-  is i n d i r e c t c o n f l i c t with the f i n d i n g s of others.  However, t h i s  V/olf and B a l l (49)  99  showed t h a t a n i n c r e a s i n g  p l a s m a Ca  i n t h e r a t e o f Na e x c r e t i o n Levitt  e t aj_. (78)  that a f a l l  with  resulted  i n t h e dog. This  a f f e c t Na e x c r e t i o n , t h i s t h e TPTX r a t s w i t h  p l a s m a Ca normal  In T a b l e V I I I , i t i s s e e n t h a t appreciably  have been a p p a r e n t  l e v e l s ranging  V in the three  r a t s were  i n general  e t a I . ( 5 1 ) i n 1967. using  in r a t s .  high  in the studies  period.  g r o u p s o f r a t s was n o t  In a d d i t i o n , altered  c a l c i t o n i n a d m i n i s t r a t i o n , a n a t r i u r e s i s was s t i l l  e l e c t r o l y t e changes  I eve I p e r s e  p l a s m a Ca l e v e l s o f a p p r o x i m a t e l y 10 mg%.  d i f f e r e n t o v e r a 24-hour  The  with an  f r o m 5-7 mg% a s c o m p a r e d  man w h e r e p l a s m a Ca l e v e l s w e r e n o t s i g n i f i c a n t l y  effect  demonstrated  I f a l o w e r e d p l a s m a Ca  would  agreement  with  following  observed  t h a t were o b s e r v e d  in studies in  ( 7 9 , 14, 1 7 ) .  i n the acute  natriuretic  (ca_. 7 0 U/kg b o d y w e i g h t / h o u r ) o f p o r c i n e  A r d a i l l o u e t a I.(14) i n s t u d i e s  i n man  using  porcine  a t much  lower doses  ( c a . 6 m i l / kg body w e i g h t / h o u r ) r e p o r t e d  greater  natriuretic  response  and  studies  t h o s e o b s e r v e d by R a s m u s s e n  However, t h e s e w o r k e r s o b s e r v e d a minimal  doses  increase  was a l s o o b s e r v e d by  i n p l a s m a C a i n d u c e d by Na EDTA was a s s o c i a t e d  t o TX o r i n t a c t r a t s w i t h  with  i n a prompt  i n man a n d m o n k e y . L e v i t t ' e t a_|_. a l s o  i m m e d i a t e d e c r e a s e i n Na e x c r e t i o n . could  level  i n addition t o increases  calcitonin  calcitonin  a much  in V, u  p  U^gV,  U V. C |  Independent o b s e r v a t i o n s calcitonin  substantiated  our findings  e f f e c t t h a t salmon c a l c i t o n i n studies  by W i l l i a m s  human a n d s a l m o n  by A l d r e d  (32) and e s t a b l i s h e d  salmon the dramatic  h a s o n Na a n d w a t e r e x c r e t i o n .  e t a_l_. ( 1 8 ) , c o m p a r i n g  calcitonin  e t aj_. (16) w i t h  the relative  Recent  effects of synthetic  i n r a t s , demonstrated t h e f a r greateer  renal  100  e f f e c t o f t h e salmon p r e p a r a t i o n of  human c a l c i t o n i n .  This  they a t t r i b u t e d t o not only  s t r u c t u r e o f t h e two p e p t i d e s , salmon p r e p a r a t i o n .  on a weight b a s i s as compared t o t h a t  but a l s o t o t h e greater  In l i m i t e d c o m p a r a t i v e s t u d i e s  a l s o d e m o n s t r a t e d a more p r o n o u n c e d calcitonin  than that obtained  with  renal  e f f e c t with  in the urinary  the  renal  specific  activity,  tubules. binding  inner cortex calcitonin tissue  salmon  o r human  peptides.  e x c r e t i o n o f N a , C a , P, a n d Mg.  These  i n GFR, a l d o s t e r o n e  or  a n d may r e f l e c t a d i r e c t a c t i o n o f t h e hormone o n  Recent studies  sites  o r outer  synthetic  that c a l c i t o n i n can cause  changes a r e n o t dependent on c o n c o m i t a n t changes parathyroid  of the  i n r a t s , a n d f r o m t h e many  i n v e s t i g a t i o n s i n b o t h man a n d a n i m a l s ,  profound changes  stability  i n man, H a a s e t a I . ( 3 0 )  e i t h e r the porcine  It would appear from t h e s e s t u d i e s recent  differences in  by M a r x a n d A u r b a c h  f o rc a l c i t o n i n  i n t h e kidney,  (80) l o c a l i z e  concentrated  medulla. These a u t h o r s a l s o found t h a t  had a h i g h e r  affinity  in the  salmon  t h a n t h e mammalian c a l c i t o n i n s f o r t h e s e  receptors.  The  absolute  changes exerted  by c a l c i t o n i n o n t h e r e n a l  excretion  o f c e r t a i n e l e c t r o l y t e s a p p e a r t o be r e l a t e d t o t h e p a r t i c u l a r c a l c i t o n i n used, t h e d u r a t i o n that  i s found, t h e e f f e c t s being  where bone t u r n o v e r an  o f a d m i n i s t r a t i o n , and t o t h e r a t e o f bone  i soccurring  immediate and g r e a t e r  change  more pronounced a t a greater  rate.  i n t h e young r a p i d l y g r o w i n g a n i m a l  hypocalcemic  response which  animals  A s shown  i n T a b l e V,  i n u r i n a r y e l e c t r o l y t e s was o b s e r v e d i n  5-week-old r a t s a s compared t o t h e 28-week-old response  i n younger  turnover  i s a l s o found  be o b s e r v e d , h o w e v e r , t h a t t h e r e n a l  r a t s . This  increased  i sconsistent  i n t h e young  with  r a t (63).  effect in the older  renal  the greater It will  r a t s was m o r e  101  p r o l o n g e d and t h i s tended t o compensate f o r t h e s m a l l e r immediate r e s ponse (as compared t o t h e younger r a t s ) .  102  II.  CALCIUM  INFUSION STUDIES (ENDOGENOUS C A L C I T O N I N R E L E A S E )  Changes observed  i n plasma c o n c e n t r a t i o n s  o f C a , P, a n d Mg  have  been  f o l l o w i n g exogenous a d m i n i s t r a t i o n o f c a l c i t o n i n as w e l l  by  induced  r e l e a s e o f endogenous  Ca  ( 8 1 , 8 2 , 4 7 , 8 3 , 8 4 , 57) o r Mg  correlation  between  calcitonin salts  induced changes  following treatment  (19).  However, a  in the circulating  as  with  possible  levels of  endogenous c a l c i t o n i n and t h e e x c r e t i o n o f u r i n a r y e l e c t r o l y t e s has not  been  i n v e s t i g a t e d . There  r e l e a s e o f t h e a n i m a l ' s own similar  i s some q u e s t i o n w h e t h e r p h y s i o l o g i c a l hormone c a n r e s u l t i n e l e c t r o l y t e c h a n g e s  t o t h o s e f o u n d f o l l o w i n g exogenous hormone a d m i n i s t r a t i o n .  o t h e r w o r d s , does t h e p h y s i o l o g i c a l  release of c a l c i t o n i n  In  have any  real  e f f e c t o n e x c r e t i o n o f s u c h i o n s a s Na, C a , P, a n d Mg v i a t h e k i d n e y i n t h e normal  animal?  Numerous s t u d i e s  have been p e r f o r m e d w h i c h d e m o n s t r a t e t h a t t h e  i n f u s i o n o f Ca s a l t s d o e s r e s u l t i n d r a m a t i c c h a n g e s of c e r t a i n urinary in animals  e l e c t r o l y t e s both  i n f u s i o n i n c l u d e an  i n Na, C a , P, and Mg  increase  f o l l o w i n g an  Deftos et al.(48)  i n u r i n e v o l u m e , and an  e x c r e t i o n . T h e s e c h a n g e s have n o t been  r e l a t i o n t o changes t h a t would o c c u r  calcitonin  ( 5 1 , 85, 86, 53, 87) and  ( 4 9 , 50, 8 8 , 52, 5 4 ) . The u r i n a r y c h a n g e s t h a t a r e f o u n d  f o l l o w i n g Ca  in  i n man  i n the excretion  induced  in circulating  considered  levels of  h y p e r c a l c e m i a . C a r e e t a_l_. ( 4 7 ) a n d  h a v e shown t h a t a p r o p o r t i o n a l  relationship exists  b e t w e e n t h e d e g r e e o f h y p e r c a l c e m i a and t h e r a t e o f s e c r e t i o n o f S i n c e t h e u r i n a r y c h a n g e s t h a t o c c u r f o l l o w i n g Ca animals a r e very administration, changes.  increase  infusion in intact  s i m i l a r t o t h o s e found f o l l o w i n g exogenous i t is possible that calcitonin  calcitonin.  calcitonin  i s p a r t i c i p a t i n g i n such  103  Calcium in p l a s m a  Ca and  increase was  infusion P  i n i n t a c t , c o n s c i o u s sheep produced  levels that  would  i f a concurrent  i n e n d o g e n o u s c a l c i t o n i n had o c c u r r e d . T h a t  f o u n d w h i c h was  i n f u s i o n , and  rapidly corrected  a hypophosphatemia  were a l s o  found  consistent  with  to decrease.  The  included  in the excretion  removal  thyroidectomy  was  urine  an  changes  increased  o f Na, C a ,  i n changes  cessation found  of the  P, and  in the  Mg  levels  i n t a c t sheep were  infusion  i n man  or  and  i n plasma  and  "C"  c e l l s o f t h e sheep  urinary  were d i f f e r e n t from t h o s e found  the  The  w h i c h was  of was  plasma  Ca  However, t h e s e a u t h o r s f a i l e d I t remained  by S a n d e r s o n  1he  released  improved  findings  control  f o r C o p p e t a l _ . i n 1961  following  an  The Ca  infusion  group,  in the thyro-parathyroid  i n t h e p r e s e n c e o f h y p e r c a l c e m i a and of hypercalcemia in animals with  an  impaired control  i . p . Ca g l u c o n a t e  rise  i n plasma  i n t h e TX  suggested  that  sheep  i n dogs.  of  the  gland complex  could  account f o r  intact glands.  l n s k e e p and  hypercalcemia  i n TX  Kenny  These (83)  sheep  load.  P which o c c u r r e d f o l l o w i n g  sheep,  (89)  (90) t o d e m o n s t r a t e  h a v e b e e n c o n f i r m e d by many w o r k e r s a n d  have a l s o observed  control  i n t h e TX  e t a j _ . i n I960  in  to r e a l i z e the s i g n i f i c a n c e of t h e i r  presence of a hypocalcemic f a c t o r w h i c h was  in the  levels f o l l o w i n g the hypercaIcemic s t r e s s  s i m i l a r to that observed  findings.  observed  by  electrolytes  i n f u s i o n which impairment  an  Mg.  i n r e s p o n s e t o Ca i n t a c t sheep.  Ca  following  volume of u r i n e  of the caIcitonin-containing  resulted  i s , a hypercalcemia  a l s o observed. Plasma  f i n d i n g s o f o t h e r s f o l l o w i n g Ca  a n i m a l s . These changes  The  following  similar to that  e x o g e n o u s hormone a d m i n i s t r a t i o n  increase  be e x p e c t e d  alterations  in contrast  endogenous r e l e a s e  to the f a l l  the s t a r t of  the  found  in the  intact  also  affect  of c a l c i t o n i n could  104  plasma  P  levels  i n a s i m i l a r way  hormone t r e a t m e n t . K e n n e d y a n d P  levels  i n TX  rats  bone. a Ca to act  s t r e s s t o an  the  i n h i b i t i o n of P  levels  Since this  Mg  the r i s e  fall  decrease  i n PTH  P  transport  into soft  i n plasma  was  Mg  levels  into c e l l s  i n t o c e l l s and  different  similar,  i n t h e TX  s h e e p was  from t h a t found  the  ion from following  secondary  thus  reduce  in the  w i t h t h e s e o b s e r v a t i o n s . The  i n t a c t and  t h e TX  activity  following  groups  could  intact  a significantly  was  seen which  calcitonin  be a s s o c i a t e d  H o w e v e r , when greater fall  which sheep.  decrease  t h e h y p e r c a l c e m i a , and  g i v e n t o t h e TX  sheep,  observed  i n v o l v e m e n t o f endogenous  was  i n plasma  with  thus  contrast to the  increased  calcitonin  i n plasma  maintained decrease  Accompanying t h i s  v o l u m e o f u r i n e t h a t was  infusion  in the  i n u r i n e v o l u m e was  decrease  i n t h e TX  i n u r i n e volume, s i g n i f i c a n t l y  i n o s m o l a l o u t p u t were a l s o o b s e r v e d  i n t h e TX  Mg hormone.  found  i n t a c t sheep, a  found  the  the  s u g g e s t s a p o s s i b l e hypomagnesemic e f f e c t o f t h i s  f o l l o w i n g t h e s t a r t o f t h e Ca  increases  i n t h e TX a n i m a l s  tissues  (74).  i o n from bone.  In  plasma  TaI mage e t a I . ( 9 1 )  transport  d e c r e a s e d movement o f t h i s  and  in  membranes. T h e y s u g g e s t c a l c i t o n i n c a n c o u n t e r -  phosphate  n o t be a s s o c i a t e d  i n both t h e  i n plasma  impaired phosphate  not s i g n i f i c a n t l y  could  load.  found a r i s e  c a u s e s a g e n e r a l movement o f P  Ca a c c u m u l a t i o n o n c e l l  A fall was  i . p . Ca  exogenous  a s b o n e , i n a d d i t i o n t o s t o p p i n g t h e movement o f t h i s They a t t r i b u t e  plasma  following  TaImage (57) a l s o  f o l l o w i n g an  suggest that c a l c i t o n i n as w e l l  t o t h a t found  significant  animals.  smaller group.  105  In expected  small  Ca  changes  increase in  V  V were reduced output which  changes  i n t h e TX  i n UpV  was  g r e a t e r i n t h e TX g r o u p . s i n c e plasma  TX  and  group  Ca  and  be  observed  in t h i s  V were a l s o  sheep as compared  were m a i n t a i n e d  f a c t , two o f t h e TX  increase  for a  and  to that  seen.  found  Na  control  outputs  a higher absolute level  was  apparent  no  i n t h e TX  increase in  in the renal  V when a  following  t h e Ca  were a l s o o b s e r v e d  in a given animal  i m p o s s i b l e t o pool  r e s u l t s from any one  w h e r e a s LL. V changes,  in the  i n t a c t and  TX  P changes t h a t were seen. P, t h e u r i n a r y  four animals observed. PTH-induced s i n c e PTH  phosphaturia  secretion  been shown by  play a  o f t h e s e two  stress.  from day  not o n l y i n  Variations  t o day.  individual  In t h e  i n UpV  rates diminish  Sherwood e t a I . ( 9 2 ) .  Neverthat plasma  in relation to  the  despite a  i n c r e a s e d i n each o f  t o be t h e c a u s e  with rising  U^V  to r e f l e c t the  S i n c e t h e sheep were h y p e r c a I c e m i c likely  in  indicated  i n t a c t sheep,  P e x c r e t i o n was  i s not  in the  T h u s , i t was  animals  sheep appeared  role  ions.  s e r i e s of experiments.  t h i s d i d not a p p l y t o changes  plasma  control  large  v a l u e s between t h e d i f f e r e n t a n i m a l s , but a l s o  t h e l e s s , a n a l y s i s o f the data from  in the  sheep.  i n t h e sheep were v e r y v a r i a b l e ,  a b s o l u t e changes observed  falling  be  i n LL. V o c c u r r e d . T h i s s u g g e s t s t h a t c a l c i t o n i n may  Phosphate  plasma  i n c r e a s e d LL. V w o u l d  longer period of time. Thus, a  s h e e p showed  in m a i n t a i n i n g a p a r a l l e l i s m  resting  This  l e v e l s reached  d i s s o c i a t i o n o f u r i n a r y Ca  Ca  was  as would  i n t a c t a n i m a l s o c c u r r e d d e s p i t e t h e f a c t t h a t t h e mean o u t p u t  expected  In  in  osmolal  In a d d i t i o n , d e c r e a s e d  in the of  sheep,  from t h e decreased  group. The  t h e TX  plasma  I t i s more l i k e l y  at this  of t h i s Ca  time,  finding  l e v e l s as  that a  the  has  decreased  106  reabsorption filtered found (II, can in  o f P had o c c u r r e d  i n t h e kidney since a decreased  l o a d o f P was i n d i c a t e d .  A phosphaturic  r e s p o n s e has been  by a number o f w o r k e r s f o l l o w i n g a d m i n i s t r a t i o n o f c a l c i t o n i n 14, 3 0 , 1 6 ) , a n d t h e s e e f f e c t s a r e a l s o f o u n d w h e r e PTH i n t e r v e n t i o n  be r u l e d o u t ( 1 2 ,  13, 3 1 , 1 5 ) .  endogenous c a l c i t o n i n  levels could  It i s possible that  induced  cause a phosphaturic  increases  effect similar  t o t h a t s e e n f o l l o w i n g exogenous hormone t r e a t m e n t .  When s a l m o n c a l c i t o n i n  was g i v e n  t o t h e TX s h e e p , t h e p a t t e r n  of  b o t h p l a s m a a n d u r i n a r y c h a n g e s f o l l o w i n g t h e C a i n f u s i o n was r e s t o r e d  in  part t o one s i m i l a r t o that  found  l e v e l s were l i m i t e d i n t h e i r a b s o l u t e l e v e l s was a c c e l e r a t e d . the in  r i s e and t h e r e t u r n t o b a s e - l i n e  Plasma P l e v e l s immediately f e l l  s t a r t o f t h e Ca i n f u s i o n a n d , i n a d d i t i o n , t h e r e p l a s m a Mg t h a n t h a t  Increases  during  found  following  was a g r e a t e r  fall  i n e i t h e r t h e i n t a c t o r TX s h e e p .  i n u r i n e v o l u m e a n d t h e e x c r e t i o n o f N a , P, a n d Mg  were a l s o o b s e r v e d  Ca  i n t h e i n t a c t s h e e p . Plasma Ca  i n t h e TX s h e e p when c a l c i t o n i n was  a n d f o l l o w i n g t h e Ca i n f u s i o n . A d e c r e a s e  administered  in the excretion of  was a l s o f o u n d w h i c h a p p e a r e d t o be s e c o n d a r y t o t h e c a l c i t o n i n -  induced changes  i n p l a s m a Ca l e v e l s . T h e c h a n g e s  e x c r e t i o n o f C a when c a l c i t o n i n was a d m i n i s t e r e d were s i m i l a r t o t h o s e found  The  i n plasma Ca and u r i n a r y t o t h e TX g r o u p  i n t h e i n t a c t sheep.  a l t e r a t i o n s i n both plasma and u r i n a r y  sheep a s compared t o t h o s e found  responses  i n t h e TX  i n t h e i n t a c t (endogenous c a l c i t o n i n )  o r TX+CT ( e x o g e n o u s c a l c i t o n i n ) a n i m a l s s u g g e s t t h a t t h e r e l e a s e o f calcitonin  i n r e s p o n s e t o a Ca s t r e s s a f f e c t s p l a s m a C a , P, a n d p o s s i b l y  Mg, a s w e l l a s u r i n a r y v o l u m e a n d t h e e x c r e t i o n o f N a , C a , P, a n d Mg.  107  III.  EXTRACELLULAR VOLUME EXPANSION The " s t r a i n on volume h o m e o s t a s i s "  following a  calcitonin  significant  role  animals f o l l o w i n g considerable  administration  in the control  isdifficult  to  Na c o n t r o l  in control  to correlate  w i t h o u t such  A. V o l u m e E x p a n s i o n  h o r m o n e may  o f body v o l u m e  glands  loading occurred  has n o t been  studies  in rats  TPTX a n d TX r a t s tissue  hormone i n r e l a t i o n  implicated  calcitonin  i n Na h o m e o s t a s i s . T h i s was n o t i m m e d i a t e l y and d i u r e t i c similar  ( F i g 16).  response  following  O n l y when c a l c i t o n i n  might  saline  in these  natriuretic  response  i n response  natriuresis  be r e s p o n s i b l e f o r t h e d e l a y e d  released  by p a r a t h y r o i d  was f o u n d )  between t h e  t h a t t h e presence of t h e transplanted natriuresis.  s u p p o r t t h i s s u g g e s t i o n i t was h y p o t h e s i z e d t h a t a n y p o s s i b l e exhibited  apparent,  was a b s e n t  volume e x p a n s i o n . The d i f f e r e n c e suggested  could  tissue  in the intact  be a n t a g o n i z e d  i n response t o volume  and t h e  i n magnitude t o t h a t found i n  (TX r a t s ) was a n i n h i b i t i o n o f t h e n o r m a l  evident following  demonstrated.  in Rats  i n TPTX r a t s  intact animals  "C" c e l l s  i n man o r a n i m a l s  evidence.  however, s i n c e a n a t r i u r e t i c  activity  play  h a v e shown t h a t a  the a c t i v i t i e s of t h i s  The volume e x p a n s i o n  thyroid  suggests that t h i s  about  l o s s o f Na a n d v o l u m e o c c u r s a s a r e s u l t o f t h e t r e a t m e n t .  It  animals  i s brought  o f body Na. S t u d i e s i n b o t h man a n d  without the caIcitonin-containing  the  which  exogenous hormone a d m i n i s t r a t i o n  However, an impairment  parathyroid  (93)  expansion.  rats  by t h e a c t i o n  paraTo  antinatriuretic  (where an of  immediate  calcitonin  108  The p o s s i b i l i t y was  responsible  strengthened  f o r the antinatriuretic  load  in a similar  first  three  in t h e i n t a c t  i n C a , P, a n d Mg o u t p u t s  hours f o l l o w i n g t h e s a l i n e load were n o t  r a t s (Table  were n o t a p p r e c i a b l y  the  increases  XIV).  different  However,  in U  C  r  e  a  +  V occurred  hours f o l l o w i n g t h e s a l i n e load  t h e v o l u m e a n d Na  increase  in these animals  i n response t o  I t was  in the f i r s t  that three  8%  parathyroid  i s inhibited  in intact rats  In t h e s e s t u d i e s w h e r e  be r e l e a s e d  concentration  t o occur.  i n response  i s o t o n i c s a l i n e was  t o c a u s e t h e e x t r a c e l l u l a r volume e x p a n s i o n , one m i g h t have the opposite  i n response  i n those animals which a r e "C"-celI  (TX r a t s ) s u g g e s t s t h a t c a l c i t o n i n may  t o volume e x p a n s i o n .  by t h e s a l i n e l o a d w o u l d be e x p e c t e d  used  expected  A d i l u t i o n of the e x t r a c e l l u l a r  r e l e a s e o f c a l c i t o n i n and enhance p a r a t h y r o i d the  found  a l s o have been a f a c t o r .  t o a s a l i n e l o a d and  eoctly  ions  increases  ( T a b l e X I V ) a s compared t o an  The f i n d i n g t h a t a n a t r i u r e s i s o c c u r s  deficient  i n GFR.  i n t h e i n t a c t r a t s . The a b s e n c e o f f u n c t i o n i n g  t i s s u e may  significant,  b e t w e e n t h e i n t a c t a n d TPTX g r o u p s .  s a l i n e load were s e c o n d a r y t o an  a 23? i n c r e a s e  during  in the excretion of these  i s p o s s i b l e t h a t t h e u r i n a r y c h a n g e s i n t h e TPTX r a t s  increase  was  ( F i g 17).  in c o n t r a s t t o the s i g n i f i c a n t  It  i n t h e TX r a t s  i n h i b i t i o n o f Na o u t p u t f o l l o w i n g a  In t h e TPTX r a t s , t h e i n c r e a s e s the  response  tissue  by t h e f i n d i n g t h a t e x o g e n o u s a d m i n i s t r a t i o n o f PTE t o  TPTX r a t s r e s u l t e d saline  that the presence of the parathyroid  Ca  t o decrease the  secretion.  However,  u r i n a r y changes t h a t o c c u r f o l l o w i n g volume e x p a n s i o n w i t h  s a l i n e (44),  109  even when GFR i s reduced  ( 5 3 ) , a r e n o t c o n s i s t e n t w i t h t h e known  u r i n a r y changes t h a t o c c u r f o l l o w i n g PTH i n t e r v e n t i o n . The o n l y renal  r e s p o n s e found t h a t i s c o n s i s t e n t w i t h t h e PTH a c t i v i t y  phosphaturia,  but a p h o s p h a t u r i c  response i s a l s o o b s e r v e d  isa  with  c a l c i t o n i n . The changes t h a t a r e found f o l l o w i n g volume e x p a n s i o n in  i n t a c t animals a r e c o n s i s t e n t with t h e renal responses observed  in a n i m a l s f o l l o w i n g t h e a d m i n i s t r a t i o n o f exogenous c a l c i t o n i n . The  f a c t t h a t t h e s e changes d i d n o t o c c u r i n t h y r o i d e c t o m i z e d  support t o t h i s  rats  lends  hypothesis.  B. PTH and Renal E l e c t r o l y t e Changes In 1929, A l b r i g h t and E l l s w o r t h (27) f i r s t noted t h a t a d e c r e a s e in u r i n a r y e x c r e t i o n o f Ca o c c u r r e d ,  i n a d d i t i o n t o an i n c r e a s e i n  phosphate e x c r e t i o n , f o l l o w i n g t h e a d m i n i s t r a t i o n o f PTE i n a hypoparathyroid patient. serum Ca l e v e l  The d e c r e a s e i n Ca e x c r e t i o n c o n t i n u e d  rose t o a " c r i t i c a l  u r i n a r y Ca i n c r e a s e d . T a l b o t along  until the  v a l u e " o f 8.5 mg%, above which  point  e t a l . ( 2 l ) i n r e - e v a l u a t i n g t h i s data  w i t h t h e i r own f i n d i n g s suggested t h a t PTH a c t s " t o b o o s t t h e lowered  serum Ca c o n c e n t r a t i o n  towards n o r m a l , i n p a r t by i n c r e a s i n g t h e  e f f i c i e n c y o f Ca r e a b s o r p t i o n  by t h e r e n a l  tubules".  Talmage and K r a i n t z (5) o b s e r v e d an i n c r e a s e  i n Ca e x c r e t i o n  in r a t s f o l l o w i n g a c u t e p a r a t h y r o i d e c t o m y which was r e v e r s e d a d m i n i s t r a t i o n o f PTE. S i n c e serum Ca l e v e l s were  falling at this  they c o n c l u d e d t h a t PTH has a d i r e c t e f f e c t on t h e r e n a l enhancing Ca r e a b s o r p t i o n .  by t h e  tubules,  S i m i l a r f i n d i n g s were o b s e r v e d by  time,  I 10  Kleeman e+ aj_. (22) o f Ca  i n man  and  dogs. They s+a+ed t h a t " t h e  i s a f u n c t i o n of t h e f i l t e r e d  load of  i o n i c and  and  the homeostatic f a c t o r s r e g u l a t i n g a c t i v e t u b u l a r  One  of t h e f a c t o r s i n v o l v e d  reabsorption  i s PTH  hyperparathyroid was  in hypoparathyroid  a decreased f i l t e r e d  load of Ca,  increased  t h a t t h e s i t e of a c t i o n of PTH M i c r o p e r f u s ion and  i n PTX  this  on Ca  proximally. Therefore, by PTH  Changes i n Mg w i t h changes i n Ca  Levinsky  i n 1962  reabsorption  was  and  and  (23)  must o c c u r a t a more d i s t a l  reabsorption  reabsorption  U^V.  Studies  indicated  i n the d i s t a l  does not  affect  f o l l o w i n g PTE.  r o s e f o l l o w i n g PTE, reversed.  the  Gill  have a l s o been found i n c o n j u n c t i o n  f o l l o w i n g PTH  administration.  or L i l l y  PTE,  in h y p o p a r a t h y r o i d  man  In  observed d e c r e a s e s by G i l l  initial  d e c r e a s e i n u r i n a r y Ca and Mg increased  filtered  load o f  change i n r e a b s o r p t i v e c a p a c i t y of t h e r e n a l  c e l l s . Peacock e+ a_l_. (95) a l s o s t a t e d t h a t PTH r e a b s o r p t i o n of Ca.  1963,  e t a I . (77) Mg  e t a I.(77) found t h a t as plasma Ca and  They suggested t h a t t h e  ions masked any  of  site.  Haas e t aj_. (30) a l s o showed t h a t d e c r e a s e s i n u r i n a r y Ca and  occurred  tubule.  I965((94)  t h e changes i n r e a b s o r p t i o n  M a c l n t y r e e t a I . ( 2 4 ) , u s i n g p u r i f i e d PTH i n both U^V  dogs, d e s p i t e  m i c r o p u n c t u r e s t u d i e s by F r i c k e t a l . i n  ion m o d i f i e d  C_  i n c r e a s e d . Massry e t a I.(25)  s u b s t a n t i a t e d t h e s e f i n d i n g s by d e m o n s t r a t i n g t h a t PTH reabsorption  In  i n TPTX dogs.  S t o p - f l o w s t u d i e s by Widrow and  Ca  tubular  reabsorption.  patients or was  Ca  reabsorption."  p a t i e n t s , f o r example, t h e y found t h a t t h e  d e c r e a s e d , and  a l s o found an  complexed  i n h o m e o s t a t i c r e g u l a t i o n of  which they found enhanced Ca  excretion  When c a l c i u r i a  is evident  Mg  was these tubule  promotes t u b u l a r in hyperparathyroidism,  it  I 11  is secondary t o the  The years.  increased  phosphaturic  a c t i o n of  that the  decrease  found t o occur  little  by a p a r a l l e l  However, a  n a t r i u r e s i s was attributed  r e a b s o r p t i o n and  decrease not  via  i n Na  Na  proximal  this  that occurred  e x c r e t i o n was  event. be  s i n c e they  reabsorption a t the simply It site  observed  not c o n f i r m  proximal  ( w h e r e PTH  to t h i s  and  nephron.  acting  phosphate hypothesis  increased  s i t e s o t h a t no  was  Na,  Na  net  i n t e r p r e t e d somewhat  a c t i n g d i r e c t l y on Na  reabsorption  phosphate  r e a b s o r p t i o n was  increase the  the  a t a more  increased  n a t r i u r e s i s d i d not  Na was  reabsorption.  r e a b s o r p t i o n o f Ca  counteracting  r e g i o n so t h a t t h e e x p e c t e d  be  A decreased  with a decreased  been found t o  r e a b s o r p t i o n of  t h a t PTH  tubule s i t e .  in conjunction  has  site.  observed.  i s p o s s i b l e t h a t PTH's a c t i o n o n  enhancing the Na  do  initially  in the  i n a more d i s t a l  same  distal  However, t h i s  T h e s e f i n d i n g s by G o l d b e r g e t a 1 . ( 7 6 ) c o u l d differently  was  in the be  the  phosphaturia,  proximal  involved  the  a l s o found t h a t tubule  ion  found  in  reabsorption at this  i n h i b i t i o n of  i n d i c a t e w h a t f a c t o r ( s ) may  i n Na  then excreted  this  PTH  t u b u l e . They  i t s m e d i a t o r cAMP may  that the  f o r many  following  f o u n d t o accompany t h e  i s a consequence of  reabsorption of increase  s i t e was  to a reabsorption of  T h e y s u g g e s t e d t h a t PTH  does not  proximal  f u r t h e r a l t e r a t i o n . These authors  accompanied  reabsorption  been r e c o g n i z e d  that occurred  in phosphate r e a b s o r p t i o n a t the  they  Ca.  i n d o g s by G o l d b e r g e t a I.(76);,  in the  r e j e c t e d phosphate from t h i s  urine with  Na  has  in phosphate r e a b s o r p t i o n  a d m i n i s t r a t i o n was  on  PTH  load of  In a r e c e n t m i c r o p u n c t u r e s t u d y  the decrease  this  filtered  distal (23)),  d e l i v e r y of  occur.  I 12  In many o f t h e s t u d i e s w h e r e a n i n c r e a s e is observed action  f o l l o w i n g PTH a d m i n i s t r a t i o n ,  have n o t a l w a y s  n a t r i u r e s i s which changes  been c o n s i d e r e d .  i s sometimes observed  ( 9 6 ) ; (b) i s i t secondary  may f o l l o w PTH a c t i v i t y release of c a l c i t o n i n  (7);  urine  excretion  f a c t o r s secondary  F o r example,  t o an i n c r e a s e  t o PTH  (a) i s t h e  a r e s u l t of renal  hemodynamic  i n plasma  Na  which  (c) i s t h e n a t r i u r e s i s secondary  i n response t o PTH-induced  S u c h f a c t o r s may be p e r t i n e n t  i n Na  to the  hypercalcemia?  i n i n t e r p r e t i n g t h e Na c h a n g e s  i n the  f o l l o w i n g PTH i n t e r v e n t i o n .  If o n e i s t o a c c e p t t h a t t h e i m m e d i a t e d e c r e a s e u r i n a r y Ca e x c r e t i o n  before  e f f e c t o f PTH i s t o  any changes  i n plasma  Ca o c c u r  w h i c h may o b s c u r e t h e e f f e c t , a c l o s e r e x a m i n a t i o n o f some o f t h e studies  f o l l o w i n g PTH i n t e r v e n t i o n r e l a t i n g  i n Na a n d Ca m i g h t c l a r i f y  t h e problem.  In s t u d i e s o n TPTX d o g s , M a s s r y t o PTE, I L V f e l l ua  o n Day  t h e simultaneous changes  e t a I.(52) found  I of treatment despite  i n U., V w e r e m i n i m a l Na  elevated.  On Day 2 o f t r e a t m e n t , UQ V was i n c r e a s e d  large  u N a  V  o  n  increase  In a s i m i l a r s t u d y treatment with  serum C a .  only  when t h e d o g  Day 2 was r e d u c e d o r m o d e r a t e l y i n s e r u m Na  elevated  concentration.  i n man, Wi I I s e t a_l_. ( 5 3 ) f o u n d  PTE, I L V i n c r e a s e d ua  i n response  when s e r u m Na was  g  was h y p e r c a I c e m i c . a  t i m e even  a rising  Increases  despite  at this  that  with  t h a t o n Day I  no m e a s u r e d c h a n g e  U^gV was a l s o  increased  a t t h e same t i m e b u t was a c c o m p a n i e d  i n s e r u m Na.  On D a y s 2 a n d 3, I L V was s t i l l  elevated  i n serum C a . by a n  increase  b u t serum Ca l e v e l s  I 13  were a l s o e l e v a t e d and  was  not  s e r u m Na  at t h i s time.  significantly  l e v e l s were  d i f f e r e n t from c o n t r o l values  study  by  showed s i m i l a r c h a n g e s  in t h e i r  i n f u s i o n . The  Na  second  r a t i o s of  similar  and  increase  et a I.(26)  excretory  patterns  Ca  outputs first  decreases.  decreased, a s i m i l a r decrease in animals  Paunier  in the  h o u r showed s i m i l a r  such s t u d i e s  i n Na  That  PTH  causes a primary  decrease  Mg  and  in the  Accompanying the e x c r e t i o n and As  i s seen  e x c r e t i o n o f Ca u r i n a r y Ca,  i n F i g . 19, U^ V  loading with  either TCA-precipitated  a g r e a t e r and Lilly  was  observed  PTE.  The  PTE  increasing the  reabsorption of  in  Mg  and  a phosphaturic  and  Mg  changes, a decrease  observed with linearly  PTE,  as  was  related to the  and  Mg  that  Mg  initial  response. in  Na hormone.  log-dose of  responses of  was  e x c r e t i o n was  in  the  in Table XVI.  antinatriuretic activity  from  reabsorption  b o t h hormone p r e p a r a t i o n s ,  i n h i b i t i o n o f Ca  and  i n c r e a s i n g doses of  i s seen  the  response.  P,  P c a u s e s an  and  with  and  are consistent with  h o r m o n e by  or  outputs  natriuretic  s a l i n e d i d not a l t e r t h e  PTH  more p r o l o n g e d  PTE.  marked w i t h  P,  was  g  antinatriuresis  the  the  u r i n e v o l u m e was  Previous to  decreasing  Ca  excretion  i n the e x c r e t i o n o f Ca,  TPTX r a t s f o l l o w i n g a d m i n i s t r a t i o n o f  Ca  PTE  not c o n v i n c i n g l y demonstrate  the changes  Parathyroid  and  and  e x c r e t i o n v/as f o u n d . R e s u l t s  exogenous a d m i n i s t r a t i o n of  In T a b l e X V I I ,  Na  following  i s , when Ca  do  and  3  when n o r m a l  h o u r f o l l o w i n g PTE,  man  o f Ca  D a y s 2 and  i n man,  t o c o n t r o l Na  and  f i n d i n g s of o t h e r s .  during  found.  In a more r e c e n t  showed a  V decreased  PTE.  rats  An  although  observed a l s o more  with  I 14  In  T a b l e XV, t h e a n t i n a t r i u r e t i c  non-loaded  a n d s a I i n e - I o a d e d TPTX r a t s e x h i b i t e d  t h r e e hours f o l l o w i n g a  t r e a t m e n t was f o l l o w e d  t h a t was f o u n d  suggested  following  that during this  during the f i r s t  by a n " e s c a p e "  PTE was a t r a n s i e n t  not always a s s o c i a t e d  In  that decreases  with decreases  i n GFR  a C a - c h e l a t i n g agent which  treatment were found  lowered plasma  i n L l ^ V were  Ca  levels resulted  in similar PTE  (Table X V I I ) . That t o occur  i s , i m m e d i a t e d e c r e a s e s i n U.. V a n d U~ V ' Na Ca i n a d d i t i o n t o a c o n c u r r e n t phosphaturia which  t h a t t h e p h o s p h a t u r i a was s e c o n d a r y  i n response t o hypocalcemia  i n f u s i o n was s t o p p e d . T h e a u t h o r s to stimulated  release  b u t d i d n o t comment o n t h e c a u s e o f  o t h e r u r i n a r y c h a n g e s t h a t o c c u r r e d a t t h e same t i m e .  possible that  r e l e a s e o f e n d o g e n o u s PTH c o u l d  have caused  i n t h e u r i n a r y e x c r e t i o n o f Na a n d C a , a s w e l l  It i s equally the decrease  as being  responsible  the phosphaturia.  Highly U  accompanied  i n t h e TPTX r a t s f o l l o w i n g  suggested  for  increased  i n man a n d m o n k e y , t h e i n f u s i o n  even a f t e r t h e c h e l a t i n g  found  increasing  rea  persisted  PTH  which  i n ^Q ^. V.  s t u d i e s by L e v i t t e t a j _ . ( 7 8 )  e l e c t r o l y t e changes t o those observed  the  to  r e a b s o r p t i o n o f Ca a n d Mg f r o m t h e k i d n e y t u b u l e s , a l s o  t h e s e c h a n g e s c a n n o t be o v e r l o o k e d , a l t h o u g h d e c r e a s e s  of  whereby  inhibition  t i m e p e r i o d , PTE, i n a d d i t i o n  Na r e a b s o r p t i o n . The p o s s i b i l i t y  of  PTE i n  n a t r i u r e s i s and a d i u r e s i s were o b s e r v e d . Thus t h e a n t i n a t r i u r e t i c  activity  the  response t o L i l l y  purified  PTH d i d n o t c a u s e a s i g n i f i c a n t d e c r e a s e i n  V when g i v e n i n g r a d e d  doses  t o TPTX r a t s  (Table X V I I I ) .  However,  I 15  significant  increases  i n U^V  were o b s e r v e d  i n t h e 10 a n d 100 U/100 g  dose range which suggested t h e p o s s i b i l i t y t h a t an increased of  Na  the  i n e x c h a n g e f o r K was o c c u r r i n g .  reabsorption  :thus r e d u c i n g for  reabsorption  PTH a d m i n i s t r a t i o n . an  s i t e . Goldberg  o f Na o c c u r r e d  Since  this  relative  excretion could  in  preference  tubule  that  following  i s t h e major s i t e f o r Na-hydrogen  exchange,  by H e l I m a n e t a j _ . ( 9 7 ) i s  e f f e c t s o f t h e d i f f e r e n t PTH p r e p a r a t i o n s  be a t t r i b u t e d t o c h a n g e s  PTE, f o r example, a d e c r e a s e d  apparent decrease  i n GFR.  In some  i n GFR  parathyroid  for this  transplants)  in saIine-Ioaded  purified distal  the reabsorption  of this  proximal  reabsorption  i o n a t a more d i s t a l  e x c r e t i o n o f K w h i c h was o b s e r v e d PTH ( T a b l e  tubular  XVIII)  reabsorption  substantiated o f Na.  TX r a t s  a s c o m p a r e d t o TPTX r a t s  h a s b e e n shown t o o c c u r f o l l o w i n g v o l u m e e x p a n s i o n  increased  studies  i n some o f t h e s e s t u d i e s c a n n o t be a c c o u n t e d f o r .  t h a t PTH c a n c o m p e n s a t e f o r a d e c r e a s e d  increasing  o n n e t Na  e x c r e t i o n o f endogenous c r e a t i n i n e  f a c t t h a t l l . , V was n o t i n c r e a s e d Na  functioning  vhich  tubule  e t a I.(76) found  was o b s e r v e d when u r i n a r y Na was d e c r e a s e d . T h e r e a s o n  The  alter  unreasonable.  The  with  site)  i n t h e proximal  i n h i b i t i o n o f t h i s mechanism a s p o s t u l a t e d  not  to the distal  ion ( a t a proximal  e x c h a n g e f o r K a t a more d i s t a l  a decreased  I t i s p o s s i b l e t h a t PTH may  s i t e f o r Na f r o m t h e p r o x i m a l  exchange f o r hydrogen  reabsorption  (with  suggests o f Na  ( 7 6 ) by s i t e . The  in the studies with  highly  t h e c o n c e p t t h a t PTH may  enhance  I 16  C. I.  V o l u m e E x p a n s i o n i n Sheep  Plasma The  changes  initial  d i l u t i o n o f t h e plasma volume  as a r e s u l t o f t h e d e x t r a n  infusion  resulted  by a f a c t o r  of  in decreases in the  c o n c e n t r a t i o n s o f t o t a l C a , P, a n d Mg  i n t h e plasma. Since a  of  saline  in the u I t r a f i I t r a b I e  of  Ca a n d Mg a c c o r d i n g t o B l y t h e e t a j _ . ( 4 4 ) ,  only causes small  studies the uItrafiItrabIe "btally  increases  i t is likely  c o n c e n t r a t i o n s o f C a , Mg,  sheep  (Figs.  20 a n d  animals, a similar g r o u p p l a s m a Ca following  found  dilution effect  levels  slowly  the dextran  in these  P (which i s  was  plasma changes  In t h e TX  o b s e r v e d . However, i n t h i s  r e t u r n e d t o normal  in the three-hour  l o a d . The o b s e r v a t i o n t h a t a c a l c i u r i a  handling of t h i s  ion contributed  group  in part to  found.  If c a l c i t o n i n in t h e i n t a c t  electrolyte  period.  i n t h e i n t a c t g r o u p w h i c h d i d n o t o c c u r i n t h e TX  suggests t h a t the renal the  fraction  that  2 1 ) , t h e s e plasma  changes were m a i n t a i n e d t h r o u g h o u t t h e e x p e r i m e n t a l  was  and  dilution  u I t r a f i I t r a b I e) were a l s o d e c r e a s e d .  In t h e i n t a c t  period  23$*  was  released  s h e e p , p l a s m a Ca  *Based on t h e a s s u m p t i o n t h a t body w e i g h t ( 9 8 ) .  i n r e s p o n s e t o volume  levels  i n sheep  would  expansion  be e x p e c t e d t o be  plasma volume  = 3.4$  unaltered  total  117  o r even decreased f u r t h e r f o l l o w i n g t h e dextran  l o a d . C a l c i t o n i n by d e p r e s s i n g  initial  d i l u t i o n with  bone r e s o r p t i o n and  the  by  inducing  a c a l c i u r i a c o u l d c a u s e such plasma changes as were o b s e r v e d . PTH  was  released  i n response t o t h e hypocalcemia i n t h e TX  If  animals,  : unapposed by c a l c i t o n i n , t h e o b s e r v e d changes i n t h e plasma and would a l s o be expected. of the c i r c u l a t i n g  I t i s not p o s s i b l e t o d e t e r m i n e w i t h o u t  l e v e l s o f t h e s e two  what a c t u a l mechanism may were i n v o l v e d a t a l l . u r i n a r y Ca be  PTH, hormones  However, the observed changes i n plasma  and  TX sheep d i d s u g g e s t t h a t c a l c i t o n i n might  s u b s t a n t i a t e d by t h e f i n d i n g t h a t when t h e  sheep were g i v e n c a l c i t o n i n , a p r o g r e s s i v e and  sustained f a l l  plasma Ca o c c u r r e d .  In a d d i t i o n , a c a l c i u r i a was  o f the  level.  low plasma Ca  knowledge  hormones, c a l c i t o n i n and  have been o p e r a t i n g , i f indeed t h e s e  i n t h e i n t a c t and  i n v o l v e d . T h i s was  urine  observed  TX  in  in s p i t e  2. U r i ne Changes The  i n f u s i o n o f a s a l i n e load w i t h t h e a d d i t i o n of t h e macro-  molecule dextran  i n c r e a s e s t h e c o l l o i d o s m o t i c p r e s s u r e o f t h e plasma  so t h a t t h e i n c r e a s e d volume i s m a i n t a i n e d . glucose  polymer w i t h an average m o l e c u l a r  D e x t r a n (Gentran  75)  w e i g h t o f 75,000 and  is a  is  o n l y s l o w l y degraded t o g l u c o s e which can t h e n be e l i m i n a t e d from v a s c u l a r space. As a r e s u l t , of dextran  the  i n f u s i o n o f a s a l i n e load w i t h t h e a d d i t i o n  i n c r e a s e s t h e v a s c u l a r volume f o r a l o n g e r p e r i o d of t i m e  than t h a t o f s a l i n e a l o n e . N i z e t (99)  found t h a t the  f o l l o w i n g a s a l i n e load depressed t h e  i n c r e a s e i n Na and  e x c r e t i o n that occurred  i n f u s i o n of  dextran  volume  w i t h s a l i n e a l o n e . T h i s he a t t r i b u t e d t o a  measured i n c r e a s e i n plasma c o l l o i d o s m o t i c p r e s s u r e which may  have been  I 18  r e s p o n s i b l e f o r a simultaneous decrease  i n GFR.  However, N i z e t  c o u l d not r u l e o u t haemodynamic i n t r a - r e n a l changes a s a l s o being involved  i n t h e response.  Howards e t a I.(100) i n m i c r o p u n c t u r e  s t u d i e s i n t h e dog found t h a t d e x t r a n decreased p r o x i m a l t u b u l e but n e t Na e x c r e t i o n was s t i l l it  Na r e a b s o r p t i o n by t h e depressed.  Therefore,  i s p o s s i b l e t h a t t h e d e p r e s s i o n o f Na e x c r e t i o n f o l l o w i n g  dextran  i n f u s i o n a s compared t o s a l i n e e x p a n s i o n a l o n e c a n be a t t r i b u t e d t o haemodynamic changes w i t h i n t h e k i d n e y enhancing in s i t e s d i s t a l is simply  from t h e p r o x i m a l t u b u l e .  m o d i f y i n g t h e changes found  r e a b s o r p t i o n o f Na  I t would appear t h a t d e x t r a n  i n response t o s a l i n e l o a d i n g  and o f f e r s some advantages i n such s t u d i e s by compensating f o r t h e d i l u t i o n o f plasma p r o t e i n s a n d , t h e r e b y , r e d u c i n g t h e degree o f e l e c t r o l y t e l o s s which c o u l d be secondary  t o a s h i f t of the " S t a r l i n g  e q u i l i b r i u m " i n the kidney. If d e x t r a n a f f e c t s t h e a b s o l u t e changes t h a t a r e found i n response t o volume e x p a n s i o n ,  i t does n o t a l t e r t h e d i r e c t i o n o f  e l e c t r o l y t e changes t h a t n o r m a l l y o c c u r s f o l l o w i n g s a l i n e l o a d i n g i n normal a n i m a l s . were found  I n c r e a s e s i n u r i n a r y volume, Na, C a , P, and Mg e x c r e t i o n  i n t h e i n t a c t sheep f o l l o w i n g t h e d e x t r a n  n a t r i u r e t i c and d i u r e t i c responses were a l s o found to t h i s  which o c c u r r e d  load.  The  i n t h e i n t a c t sheep  i n t h e TX sheep. Only when salmon c a l c i t o n i n was g i v e n  l a t t e r group was an a l t e r e d response f o u n d . A t t h i s t i m e ,  exogenous c a l c i t o n i n a d m i n i s t r a t i o n doubled volume e x c r e t i o n f o l l o w i n g d e x t r a n  t h e i n c r e a s e i n Na and  infusion.  The most s i g n i f i c a n t d i f f e r e n c e s t h a t o c c u r r e d t h e s e t h r e e groups o f sheep were t h o s e Whereas t h e changes i n U  M  in the urine of  i n r e l a t i o n t o Ca e x c r e t i o n .  V i n t h e i n t a c t and TX sheep were o f a s i m i l a r  I 19  magni+ude, a c a l c i u r i a  d i d n o t accompany t h e n a + r i u r e s i s  s h e e p a s was f o u n d  in the intact animals.  decreased  animals  values  i n these  a s shown  In f a c t ,  f o l l o w i n g the dextran  i n T a b l e XXII  although  these  intact animals. Ca  This could  inflation  increased.  decreased  in studies  increases  K  found  by t h e g r e a t e r  fall  i n plasma  salmon  t h e decrease  ions excreted  Ca and Na, B I y t h e  calcitonin.  in the urine  etaj_.suggested  B u t , whatever t h e mechanism, an p a r t " o f t h e kidneys  by  i n GFR, t h e  r e a b s o r p t i o n o f e i t h e r Ca o r Na m i g h t c o n s e q u e n t l y  e x c r e t i o n o f Ca i s a n " i n t e g r a l  inthe  V when GFR was r e d u c e d  load o f a l l t h e s e  reabsorption of the other.  increased  i n U., V a n d I L V a n d Na Ca  in the aorta. Despite  In r e l a t i n g  and an  i n dogs f o l l o w i n g volume  i n U V , UpV, a n d  fraction of the f i l t e r e d was  be e x p l a i n e d  s a l i n e observed  of a balloon  clearance  by a c a l c i u r i a  i n t h e TX s h e e p t r e a t e d w i t h  B l y t h e e t aj_. (44)  i n c o n s i s t e n t changes  l o a d , and  changes were n o t as g r e a t a s t h o s e  l e v e l s which occurred  expansion with  U"Q V a c t u a l l y  i n d i c a t e d no s i g n i f i c a n t c h a n g e . C a l c i t o n i n  a d m i n i s t r a t i o n t o t h e TX s h e e p was f o l l o w e d C'Ca'  i n t h e TX  that  affect the increased  response t o volume  expansion. Antoniou clearances loading.  e t a_l_. ( 4 5 )  o f Na, C a , a n d Mg o c c u r r e d  (43). Since these  a r e caused  by some o t h e r  pass through t h e nephron.  increase  inthe  in response t o s a l i n e by W a I s e r  ion changes occur  i n GFR, m i n e r a l o c o r t i c o i d o r ADH a c t i v i t y  t h a t they as they  i n dogs  S i m i l a r changes were p r e v i o u s l y o b s e r v e d  D u a r t e and Watson changes  found t h a t a p r o g r e s s i v e  i r r e s p e c t i v eof  (44),  factor(s) affecting  (41) and  i t would their  appear  reabsorption  120  The was  a t variance  parallel  since  with  t h e many o b s e r v a t i o n s  r e l a t i o n s h i p o f t h e s e two ions  kidney.  was  d i s s o c i a t i o n b e t w e e n Ca a n d Na e x c r e t i o n  This  d i s s o c i a t i o n could  i t was o n l y  present,  clearance  found  by  e x c r e t i o n o f Mg was a l s o  sheep.  When  calcitonin  changes  f o l l o w i n g t h e dextran  inthis  reduced  i o n . M a s s r y e t aj_. (25)  the percent of f i l t e r e d  Mg e x c r e t e d  reabsorption  i n t h e e x c r e t i o n o f C a a n d Mg  If t h i s a r g u m e n t should  load  i n t h e TX s h e e p a s c o m p a r e d  Plasma changes c o u l d  t h e i n t e r v e n t i o n o f PTH u n o p p o s e d  results  by t h e  increased.  t h a t PTH c a n e n h a n c e t u b u l a r observed  excretion  be a t t r i b u t e d t o t h e l a c k o f c a l c i t o n i n  o f Ca w e r e f o u n d t o i n c r e a s e  excretory  decreased  in their  i n thyroidectomized  t o t h e i n t a c t a n d TX+CT a n i m a l s . the  t h a t demonstrate t h e  e i t h e r endogenously o r exogenously, both e x c r e t i o n and  when Na e x c r e t i o n was  The  i n t h e TX s h e e p  i scontinued  not account f o r f o u n d t h a t PTE  which supports t h e concept  o f Mg.  The c h a n g e s t h a t  were  i n t h e TX s h e e p c o u l d a I s o b e m o d i f i e d  by c a l c i t o n i n  in relation  indicate s i m i l a r patterns  i n these  animals.  to P excretion, the  of P excretion  in the three  o f a n i m a l s s i n c e b o t h c a l c i t o n i n a n d PTH c a n c a u s e a p h o s p h a t u r i a . increases (Table  a n d d e c r e a s e s o r no c h a n g e a t a 11  in P excretion  groups Both  were o b s e r v e d  XXI 11).  C a l c i t o n i n a p p e a r e d t o h a v e no d i r e c t i n f l u e n c e o n K e x c r e t i o n i n these studies.  In p r e l i m i n a r y  control  i n s h e e p w h e r e no  i n f u s i o n was g i v e n ,  U^V  of  i n a way s i m i l a r t o t h a t o b s e r v e d  urine collection  infusion studies. This  was f o u n d  studies  t o decrease over a period  dextran  o f 4-5 h o u r s  i n t h e dextran  i s probably a r e f l e c t i o n o f dietary  input  121  s i n c e t h e a n i m a l s were s t a r v e d . diurnal  It could  be r e l a t e d  to the  p a t t e r n o f a l d o s t e r o n e s e c r e t i o n . O n l y when t r a n s i e n t i n c r e a s e s  i n UQ _|_ V w e r e o b s e r v e d rea  increases  following the dextran  load were  small  i n U^V o b s e r v e d . T h e s e c h a n g e s a r e p r o b a b l y d i r e c t l y  to transient  i n c r e a s e s i n GFR. E v i d e n c e  i s not c o n c l u s i v e that  has a n y d i r e c t e f f e c t o n K m e t a b o l i s m . mineral  also  Potassium  and a l l o f t h e K i n bone i s r e a d i l y  e x c r e t i o n , a p a r t from changes  in dietary  the distal  where K i s s e c r e t e d .  nephron  and  saline  i n t h e TX r a t s  i n t h e TX s h e e p showed c e r t a i n  response t h a t  i n 4/6  diuretic  significant  r e s p o n s e , t h i s was n o t o b s e r v e d  i n t h e Na a n d v o l u m e r e s p o n s e s c o u l d used  f o r volume e x p a n s i o n  a species difference.  not present.  similarities to  in the calciuretic  impairment  in the natriuretic  i n t h e sheep.  This  disparity  be a r e s u l t o f t h e d i f f e r e n t  N e v e r t h e l e s s , i t was a p p a r e n t  following  this  i n these animals.  i n t h e two a n i m a l s , o r then a g a i n  t h e sheep s t u d i e s t h a t a l t e r a t i o n s body e l e c t r o l y t e s  i n response t o  a n d i n t h e TX s h e e p  of t h e s t u d i e s performed  W h e r e a s t h e r a t s showed a h i g h l y and  g r a d i e n t (75).  n o r m a l l y f o l l o w s v o l u m e e x p a n s i o n . In  t h e TX r a t s , a p h o s p h a t u r i a was n o t o b s e r v e d was t h e f i n d i n g  portion  i n response t o volume e x p a n s i o n w i t h an  l o a d . B o t h a n i m a l s showed a n i m p a i r m e n t  magnesuric  t o the  c a n i n c r e a s e t h e p a s s i v e movement o f K i n r e s p o n s e  volume e x p a n s i o n w i t h d e x t r a n i n f u s i o n  i.p.  in K  I n c r e a s e d c o n c e n t r a t i o n s o f Na i n  u r i n a r y e l e c t r o l y t e changes  t h e changes found  bone-seeking  ion i n the d i s t a l  t o t h e e s t a b l i s h m e n t o f a more f a v o u r a b l e e l e c t r o - c h e m i c a l  The  calcitonin  exchangeable. Changes  input, are related  movement o f Na a n d t h e c o n c e n t r a t i o n o f t h i s o f t h e nephron  i s not a  related  i n t h e normal  i t may  methods be  i n both t h e r a t and  e x c r e t i o n of c e r t a i n  v o l u m e e x p a n s i o n o c c u r when c a l c i t o n i n i s  This suggests that t h i s  h o r m o n e may p l a y some r o l e  inthe  e l e c t r o l y t e changes t h a t o c c u r f o l l o w i n g e x t r a c e l l u l a r expansion.  volume  123  SUMMARY AND CONCLUSIONS  I.  E x o g e n o u s C a I c i+on i n Admi n i s t r a t i o n  1.  The a d m i n i s t r a t i o n o f s a l m o n c a l c i t o n i n  concentration  o f c e r t a i n e l e c t r o l y t e s i n t h e plasma. These  in a d d i t i o n t o Ca, inorganic of and Mg  these  ions  P a n d Mg.  following calcitonin  Decreases  in the  included, concentrations  t r e a t m e n t were observed  i n the r a t  t h e s h e e p . The p i a s m a - l o w e r i n g e f f e c t o f c a l c i t o n i n o n C a , P, a n d i s a t t r i b u t e d t o the decrease  following  i n bone r e s o r p t i o n w h i c h  a d m i n i s t r a t i o n o f t h e hormone.  in t h e renal  excretion of these  piasma-lowering  ions could  e f f e c t . I t has a l s o  However, c o n c u r r e n t changes also contribute t o the net  (91).  C a l c i t o n i n appears t o decrease the reabsorption  Mg f r o m t h e k i d n e y t u b u l e magnesuria a r e found  occurs  been s u g g e s t e d t h a t c a l c i t o n i n c a n  e n h a n c e t h e movement o f P i n t o c e l l s  2.  lowered t h e  so t h a t a c a l c i u r i a ,  o f C a , P, a n d  phosphaturia,  f o l l o w i n g hormone t r e a t m e n t . The m a g n i t u d e o f t h e  u r i n a r y c h a n g e s may be d e p e n d e n t o n t h e p l a s m a c h a n g e s t h a t Where c a l c i t o n i n Ca,  and  i s causing  decreases  occur.  i n t h e plasma c o n c e n t r a t i o n s  P, a n d Mg, s e c o n d a r y t o i t s a c t i o n o n b o n e , t h e s u b s e q u e n t  in f i l t e r e d  load o f t h e s e  e f f e c t s of a decrease  ions could  in tubular  decrease  modify o r even obscure t h e  reabsorption  a t t h e renal  of  site.  124  3. Mg  Accompanying the  changes  excretion  a l s o o b s e r v e d . C a l c i t o n i n a l s o c a u s e d an  in r a t s p r e - t r e a t e d  with  DOCA, w h i c h d i d  differ  not  non-DOCA t r e a t e d this  large doses of from the  rats. This  Since  increases  the  in the  changes  urinary  5.  increases  excretion  e l e c t r o l y t e changes  The  were not  renal  of  i n Na  excretion  natriuretic effect  dose o f  n a t r i u r e t i c response  the  parathyroid  TPTX r a t s  ( i n t a c t and  TX  rats),  t i s s u e can  alter  6.  urinary  The  following the r a t as  the  in the  found  in rats with  magnitude of  older  the  parathyroid  the  of  following  presence of  given tissue  parathyroid  n a t r i u r e t i c response.  immediately  c a l c i t o n i n were g r e a t e r  animal.  in i n t a c t  intact parathyroid  e l e c t r o l y t e changes t h a t occurred  compared t o the  for  glands.  i n response to a  i t would appear t h a t t h e  administration  were  d i u r e t i c responses,  (without  TPTX r a t s  consistently greater  hormone t h a n t h a t  of  activity.  endogenous c r e a t i n i n e  n a t r i u r e t i c and  in  following c a l c i t o n i n treatment  s t i m u l a t i o n of  c a l c i t o n i n t r e a t m e n t was  found  were p r i m a r i l y r e s p o n s i b l e  calcitonin administration,  Since the  excretion  mineralocorticoid,  t i s s u e ) showed s i m i l a r e l e c t r o l y t e c h a n g e s t o t h o s e f o u n d rats.  and  found.  responses observed  secondary to  Following  i n GFR  the  P,  natriuretic effect  synthetic i n Na  Ca,  in m i n e r a l o c o r t i c o i d  c o n s i s t e n t l y found t o accompany t h e is unlikely that  of  increase  increase  suggests that  hormone i s i n d e p e n d e n t o f  4.  it  renal  f o l l o w i n g c a l c i t o n i n t r e a t m e n t , a d i u r e t i c and  was  not  in the  in the  young  125  II.  Calcium  Infusion Studies  (Endogenous C a I c i t o n i n R e l e a s e )  1.  P l a s m a Ca l e v e l s i n i n t a c t s h e e p w e r e  normal  values  f o l l o w i n g t h e c o m p l e t i o n o f a o n e - h o u r Ca i n f u s i o n .  P l a s m a P l e v e l s showed Ca  rapidly restored t o  an immediate f a l l  following the start of the  i n f u s i o n . T h e s e a f f e c t s o n p l a s m a Ca a n d P a r e a t t r i b u t e d t o a n  increased  endogenous  release of calcitonin  following a hypercaIcemic stress This  i s substantiated  impairment  induced  by t h e o b s e r v a t i o n  by t h e i n f u s i o n o f C a that  salts.  i n t h e TX s h e e p , a n  and f o l l o w i n g t h e Ca  s a l m o n c a l c i t o n i n was a d m i n i s t e r e d  found  i s known t o o c c u r  i n t h e c o n t r o l o f p l a s m a C a was o b s e r v e d , a n d p l a s m a P  l e v e l s were found t o r i s e d u r i n g  t h e Ca  which  i n f u s i o n , t h e changes  infusion.  t o t h e TX s h e e p d u r i n g  When  and f o l l o w i n g  i n p l a s m a Ca a n d P were s i m i l a r t o t h o s e  i n i n t a c t sheep.  2.  An i n c r e a s e d  endogenous  f o r some o f t h e c h a n g e s f o l l o w i n g Ca increase  r e l e a s e o f c a I c i t o n i n may b e  in urinary  electrolyte excretion  i n f u s i o n i n i n t a c t sheep. These changes  was i n d i c a t e d by t h e o b s e r v a t i o n  were  significantly  e x c r e t i o n were f o u n d . S m a l l e r  changes  occurred an  in urine  t h a t t h e changes  r e d u c e d i n t h e TX s h e e p when l a r g e  that  included  i n Na, P, a n d Mg, i n a d d i t i o n t o a n i n c r e a s e  This  responsible  i n Na  volume.  excretion  increases  i n Ca  i n t h e e x c r e t i o n o f P a n d Mg i n  t h e TX s h e e p w e r e a l s o o b s e r v e d , i n a d d i t i o n t o a d e c r e a s e i n u r i n e volume.  I t would appear t h a t a d i s s o c i a t i o n i n t h e r e n a l  Ca a n d Na c a n o c c u r  i n s h e e p when c a l c i t o n i n  i s not  excretion of  present.  126  III.  CaIcitonin  1.  An  and  Homeostasis  in the  normal  impairment  l y t e s was  observed  when t h e  Volume  no  the  caIcitonin-containing  excretion  of  c e r t a i n body  i n response to volume expansion  a n i m a l s , volume expansion and  excretion  of  Na,  "C"  cells  is followed K,  s i g n i f i c a n t increases  by  i n r a t s and  were removed. increases  Mg.  Ca,  P,  and  i n any  of  these parameters  intact  in urine  volume  Thyroidectomized in the  In t h e  excretion  o f Ca  v o l u m e e x p a n s i o n and  increases  in the  excretion  of  by Mg  TX  rats  showed  first  sheep, both the  were o b s e r v e d as  sheep  In  hours f o l l o w i n g volume e x p a n s i o n . were u n a l t e r e d  electro-  C^  only  three and  g  the  small  compared t o t h e  intact  sheep.  2.  The  dextran  f i n d i n g of  infusion  a maintained  in the  in the  response t o volume  3.  The  lack of  the  release  administration  t o TPTX r a t s  diuretic  Na  It is postulated  in addition  t o t h a t of  postulated  that  calcitonin  (in addition  Ca,  Mg)  P,  and  following  may  that Ca  tissue  i n h i b i t i o n of  following  following  in the be  TX  involved  in these rats  PTH  and  Mg  may  in a d d i t i o n  from the  Exogenous  natriuretic  and  following  volume  enhance the renal  reabsorption tubule.  volume e x p a n s i o n , endogenous r e l e a s e  to decreasing  antagonize the  proximal  action  of  PTH  to  normal  volume e x p a n s i o n .  prevented the  responses which were found  expansion. of  rats  in the  i n TX  PTE  observed  c a l c i t o n i n may  parathyroid  implicated  electrolyte excretion of  of  not  levels  expansion.  functioning  c a l c i t o n i n was  i n p l a s m a Ca  i n t a c t s h e e p , w h i c h was  sheep, suggested f u r t h e r t h a t  presence of  reduction  It is of  reabsorption  of  a t a more  distal  Na,  further  127  site.  T h u s , an  increased  u r i n e v o l u m e and  electrolyte excretion  is  observed.  The  e v i d e n c e from the  i m p l i c a t e d c a l c i t o n i n and found. would of  the  However, t h i s  PTH  volume e x p a n s i o n s t u d i e s in the  e v i d e n c e was  be a c o n c u r r e n t e v a l u a t i o n circulating  l e v e l s of  e l e c t r o l y t e changes t h a t  indirect.  by means o f  the  two  hormones a r e  S t o p - f l o w and of  the  of  Na  at various  whether the other  involved  micropuncture studies  at the  t o what e x t e n t  sites  a c t i o n of renal  in the  PTH  PTH  were  experiment  r e l i a b l e assay  methods  in response  approach would c l a r i f y  should tubular  enable a level.  is affecting tubular  n e p h r o n , and  e i t h e r hormone c a n  site.  definitive  sheep  to to  i n volume c o n t r o l .  s i t e of a c t i o n of c a l c i t o n i n a t the  would a l s o c l a r i f y  The  b o t h c a l c i t o n i n and  volume e x p a n s i o n o r volume d e p l e t i o n . 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