the effect on blood and urine of the ingestion of_exp physiol-1968-matthews-399-414

17
Q . J l exp. Phy8iol. (1968) 5 3 , 399-414 THE EFFECT ON BLOOD AND URINE O F THE INGESTION O F SODIUM BICARBONATE. By D . . MATTHEWS* an d W . J . O'CONNOR. From t h e Department o f Physiology, School o f Medicine, University o f Leeds. (Received f o r publication 29th January 1968) 0-145M NaHCO3 given b y stomach tube to conscious dogs caused a fall i n plasma solids (protein), decrease i n plasma C l a n d increase i n HCO3; p H of t h e arterial blood increased but an y increase of arterial Pco, w a s n o t significant; plasma K fell. Th e urine after 0-145M NaHCO3 contained increased amounts o f Na with only a small increase i n C l . Th e increased excretion o f Na + w a s mainly accompanied b y a large excretion o f HCO -, a n d th e urine became a n d contained little NH+. Changes i n t h e excretion o f inorganic P04, S 0 4 a n d K were small. Comparison w a s made with th e effects of t h e same doses o f Na given a s 0-122M NaCl+0023M NaHCO3. This caused a n equal fall i n plasma solids b u t n o change i n plasma C l , HCO3 a n d K . Th e urinary excretion o f N a + increased to rates approxi- mately th e same a s those produced b y NaHCO3 b u t t h e main urinary anion w a s Cl-, th e excretion o f which w a s greatly increased. There w a s a small excretion o f HCO- with larger doses. It i s concluded that a n important agent determining increased excretion o f N a i s dilution o f t h e plasma protein, which i s common t o both types o f experiment. Th e changes i n plasma C l a n d HCO3 appear t o be t h e factor which determines whether t h e increased excretion of N a + is accompanied mainly by HC O o r Cl-. USUALLY when sodium bicarbonate h a been given t o ma n o r experimental animals [e.g. Pitts a n d Lotspeich, 1946; Pitts, Ayer a n d Schiess, 1949] t h e purpose ha s been t o investigate 'metabolic alkalosis' a n d the main attention h a s been given t o changes i n HCO3 plasma a n d urine; there i s indeed n o systematic description of the changes i n t h e urinary excretion o f N a , Cl a n d other ions. I n order t o achieve considerable increases i n plasma HCO3, large amounts o f NaHCO3 have usually been given i n hypertonic solutions. Th e first purpose o f this paper i s t o describe the changes i n urine a n d plasma pro- duced b y t h e ingestion o f small amounts of NaHCO3 i n 0145M solution, approximately isotonic with t h e body fluids. T h e experiments were identical i n design t o those of O'Connor [1955 a n d 1958] i n which 0145M NaCl w a s given, a n d considerable similarities i n t h e urinary changes were immediately apparent. Comparison h a s therefore been made between t h e effects o n t h e plasma a n d urine o f doses o f sodium either a s NaHCO3 o r mainly a s NaCl. This comparison, which seems n o t t o have been made previously, indicates t h e roles o f some o f t h e agents which determine t h e urinary excretion o f Na , C l a n d HCO3. * Present address: D e r artment o f Physiology, Royal Free Hospital School o f Medicine, London W.C. 1 . 3 9 9 ) by guest on December 5, 2010 ep.physoc.org Downloaded from Exp Physiol (

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Page 1: The Effect on Blood and Urine of the Ingestion Of_exp Physiol-1968-Matthews-399-414

8/8/2019 The Effect on Blood and Urine of the Ingestion Of_exp Physiol-1968-Matthews-399-414

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Q . J l e x p . P h y 8 i o l .( 1 9 6 8 )5 3 ,3 9 9 - 4 1 4

THE EFFECT ON BLOOD AND URINE OF THE INGESTION OFSODIUMBICARBONATE. By D . L . MATTHEWS*a n dW . J . O ' C O N N O R .From t h e D e p a r t m e n to f P h y s i o l o g y ,S c h o o lo f M e d i c i n e ,U n i v e r s i t yo fL e e d s .

( R e c e i v e df o r p u b l i c a t i o n2 9 t hJ a n u a r y1 9 6 8 )

0 - 1 4 5 MNaHCO3 g i v e nb y s tomach t u b e t o c o n s c i o u sd o g sc a u s e da f a l li n p l a s m as o l i d s( p r o t e i n ) ,d e c r e a s ei n p l a s m aCl and i n c r e a s ei n H C O 3 ;pH o f t h e a r t e r i a lb l o o di n c r e a s e db u t an y i n c r e a s eo f a r t e r i a lP c o ,was not s i g n i f i c a n t ;p l a s m aK f e l l . Th eu r i n e a f t e r 0 - 1 4 5 MNaHCO3 c o n t a i n e di n c r e a s e da m o u n t s o f Na w i t h o n l y a s m a l li n c r e a s ei n C l . Th e i n c r e a s e de x c r e t i o no f Na + was m a i n l ya c c o m p a n i e db y a l a r g ee x c r e t i o no f HCO - , and t h e u r i n ebecame a l k a l i n eand c o n t a i n e dl i t t l eNH+. C h a n g e si n t h e e x c r e t i o no f i n o r g a n i cP 0 4 , S 0 4an d K were s m a l l .

C o m p a r i s o nwas m a d e w i t h t h e e f f e c t so f t h e s a m e d o s e so f Na g i v e na s 0 - 1 2 2 MNaCl+0023M NaHCO3. T h i sc a u s e dan e q u a lf a l li n p l a s m as o l i d s b u t n o c h a n g ei n p l a s m aC l ,HCO3an d K . Th e u r i n a r ye x c r e t i o no f Na+ i n c r e a s e dt o r a t e s a p p r o x i -m a t e l yt h e same a s t h o s ep r o d u c e db y NaHCO3b u t t h e main u r i n a r ya n i o nwas C l - ,t h e e x c r e t i o no f w h i c hwas g r e a t l yi n c r e a s e d . T h e r ewas a s m a l le x c r e t i o no f HCO-w i t h l a r g e rd o s e s .

I t i s c o n c l u d e dt h a t an i m p o r t a n ta g e n t d e t e r m i n i n gi n c r e a s e de x c r e t i o no f Na i sd i l u t i o no f t h e p l a s m ap r o t e i n ,w h i c hi s c o m m o n t o b o t ht y p e so f e x p e r i m e n t .Th ec h a n g e si n p l a s m aCl and HCO3 a p p e a rt o b e t h e f a c t o r w h i c hd e t e r m i n e sw h e t h e rt h e i n c r e a s e de x c r e t i o no f Na+ i s a c c o m p a n i e dm a i n l yby HCO o r C l - .

USUALLYw h e n s o d i u mb i c a r b o n a t eh a s b e e ng i v e nt o m a n o r e x p e r i m e n t a la n i m a l s[ e . g .P i t t sa n d L o t s p e i c h ,1 9 4 6 ; P i t t s ,Ay e ra n d S c h i e s s ,1 9 4 9 ]t h ep u r p o s eh a s b e e nt o i n v e s t i g a t e' m e t a b o l i ca l k a l o s i s 'a n d t h e main a t t e n t i o nh a s b e e ng i v e nt o c h a n g e si n HCO3 o f p l a s m aa n d u r i n e ;t h e r e i s i n d e e dn os y s t e m a t i cd e s c r i p t i o no f t h ec h a n g e si n t h e u r i n a r ye x c r e t i o no f N a , C la n do t h e ri o n s . I n o r d e rt o a c h i e v ec o n s i d e r a b l ei n c r e a s e si np l a s m aH C O 3 ,l a r g ea m o u n t so f NaHCO3 h a v eu s u a l l yb e e ng i v e ni n h y p e r t o n i cs o l u t i o n s .Th e

f i r s tp u r p o s eo f t h i sp a p e ri s t o d e s c r i b et h e c h a n g e si n u r i n e a n d p l a s m ap r o -d u c e db y t h e i n g e s t i o no f s m a l l a m o u n t so f NaHCO3 i n 0145M s o l u t i o n ,a p p r o x i m a t e l yi s o t o n i cw i t h t h e b o d yf l u i d s .

T h ee x p e r i m e n t sw e r ei d e n t i c a li n d e s i g nt o t h o s eo f O ' C o n n o r[ 1 9 5 5a n d1 9 5 8 ]i n w h i c h0145M N a C lw a s g i v e n ,a n d c o n s i d e r a b l es i m i l a r i t i e si n t h eu r i n a r y c h a n g e sw e r e i m m e d i a t e l ya p p a r e n t . C o m p a r i s o nh a s t h e r e f o r eb e e nmade b e t w e e nt h e e f f e c t so n t h e p l a s m aa n d u r i n e o f i d e n t i c a ld o s e so fs o d i u me i t h e ras NaHCO3 o r m a i n l yas N a C l . T h i s c o m p a r i s o n ,w h i c hs e e m sn o t t o h a v eb e e nmade p r e v i o u s l y ,i n d i c a t e st h e r o l e so f s o m eo f t h ea g e n t sw h i c hd e t e r m i n et h e u r i n a r ye x c r e t i o no f N a , C la n d H C O 3 .

* P r e s e n ta d d r e s s : D e ra r t m e n to f P h y s i o l o g y ,R o y a lF r e eH o s p i t a lS c h o o lo f M e d i c i n e ,L o n d o n W. C .1 .

3 9 9

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4 0 0 M a t t h e w sa n d O ' C o n n o r

METHODS

T h ee x p e r i m e n t sw e r e p e r f o r m e do n f o u r t r a i n e d c o n s c i o u sb i t c h e s ,w e i g h i n g1 3 ,1 5 ,1 8 a n d 2 8 k g . A t p r e l i m i n a r ya s e p t i co p e r a t i o n st h ep e r i n e u mw a s s p l i tt o e x p o s et h e u r e t h r af o re a s y c a t h e t e r i z a t i o na n d e a c h c a r o t i d a r t e r y w a s e n c l o s e di n a s k i n

l o o p . Th ea n i m a l sw e r ef e d 2 0 0 - 3 0 0g .

f r e s hs t e a ka n d 1 0 0 - 1 5 0g . d o gb i s c u i t se a c h

d a y a t a b o u t5P. M . , a n d h a d f r e ea c c e s st o w a t e re x c e p ti m m e d i a t e l yb e f o r ea n dd u r i n ga n e x p e r i m e n t ;t h e yw e r ea l l o w e da p e r i o di n t h e e x r e c i s ey a r de a c hm o r n i n g .E a c hd o gw a s w e l l a c c u s t o m e dt o t h e e x p e r i m e n t a lp r o c e d u r e ,l y i n g q u i e t l yo n t h et a b l ew i t ht h e p u l s er a t e b e t w e e n5 0 a n d 9 0 b e a t s / m i n . ;p u l s er a t eo v e r9 0 i n d i c a t e dt h a t t h e a n i m a lw a sn o t p r o p e r l ya t r e s t .

U r i n e c o l l e c t i o n .- T h e b l a d d e r w a s c a t h e t e r i z e db y a s e l f - r e t a i n i n gc a t h e t e r .D u r i n gt h e l a s t2 m i n .o f e a c hc o l l e c t i o np e r i o d t h eb l a d d e rw a sw a s h e do u t b y t h r e ev o l u m e s ,e a c h 1 0 m l . ,o f d i s t i l l e dw a t e r m e a s u r e df r o ma b u r e t t e .T h ev o l u m eo fu r i n e w a s r e c o r d e das t h e d i f f e r e n c eb e t w e e nt h e t o t a lv o l u m ei n t h e c o l l e c t i n gc y l i n d e ra n d t h e v o l u m eo f t h ew a s h o u t s . T h em i x t u r ei n t h e c y l i n d e rw a su s e df o rt h e u r i n a r ya n a l y s i sd e s c r i b e db e l o w.

A r t e r i a lb l o o ds a m p l e sw e r eo b t a i n e db y p u n c t u r eo f t h e c a r o t i da r t e r y c o n t a i n e di na s k i nl o o pb y a N o . 1 5n e e d l e ; t h i sc a u s e dt h e d o gn o d i s t r e s s .T h ea r t e r i a lb l o o ds a m p l e so f 5 m l . w e r ed r a w ni n t o a l l - g l a s ss y r i n g e sl u b r i c a t e dw i t hs i l i c o n eg r e a s ea n dw i t h t h e d e a ds p a c eo f 0 4 1 3m l . f i l l e dw i t hh e p a r i ns o l u t i o n( 5 , 0 0 0i . u . / m l . )t h e f i n a lh e p a r i nc o n c e n t r a t i o ni n t h e b l o o d( 1 3 0i . u . / m l . )c a u s e so n l ya s m a l lf a l li n t h e b l o o dpH [ A n d e r s e n ,1 9 6 1 ]o r p l a s m ap o t a s s i u m[ B e r l i n e r ,Kennedy a n d H i l t o n , 1 9 5 0 ] ;i n t h e r e s u l t sa c o r r e c t i o nh a s b e e na p p l i e df o rt h e s ma l ld i l u t i o nb y t h e h e p a r i ns o l u t i o n .B l o o df r o mt h e s y r i n g ew a s i m m e d i a t e l yp a s s e di n t o t h e e l e c t r o d e sf o rd e t e r m i n a t i o no f i t s pH a n d P c o 2( s e eb e l o w ) . By t h e m e t h o do f G a b a r d ia n dD a v e n p o r t[ 1 9 4 9 ] ,t h e s y r i n g e sw e r et h e ns e a l e da n d c e n t r i f u g e da t 7 0 0g t o o b t a i nt r u ep l a s m a . Two s a m p l e so f p l a s m ae a c ho f 0 - 2m l . w e r ep i p e t t e df r o mt h e s y r i n g ea n d t r a n s f e r r e di n t o t h e V an S l y k ea p p a r a t u sf o rd e t e r m i n a t i o no f t h e t o t a lC O 2 .A n a e r o b i ct e c h n i q u e sw e r et h e na b a n d o n e da n d s a m p l e so f t h e p l a s m au s e df o rt h eo t h e ra n a l y s e s .

A n a l y t i c a lm e t h o d s .- p H a n d C O 2t e n s i o no f b l o o dw e r e m e a s u r e db y g l a s se l e c t r o d e sas d e s c r i b e db y N o r m a n , L e d s o m ea n d L i n d e n[ 1 9 6 5 ] .I n e a c h c a s e as i n g l em e a s u r e m e n tw a s made o n b l o o da t 3 8 °C . i n t e r p o s e db e t w e e nr e a d i n g so f as t a n d a r dp h o s p h a t eb u f f e r ,pH 7 - 4 1 6at 3 8 °C . [ S e m p l e ,M a t t o c ka n d U n c l e s ,1 9 6 2 ]o r a g a sm i x t u r ea b o u t4 0m m . H g P c o 0a c c u r a t e l yd e t e r m i n e di na H a l d a n ea p p a r a t u s .From t h e p a i r e dr e a d i n g s o n t h e s t a n d a r d s , t h e s t a n d a r d d e v i a t i o no f a s i n g l ed e t e r m i n a t i o n ,e . g .t h o s eo nb l o o d ,w a s0 0 0 3pH u n i t sa n d0 3 m m . H g P c o 0 ,c a l c u l a t e das d e s c r i b e db y K i m b a l l[ 1 9 5 2 ] .

P l a s m as o l i d s .- S a m p l e so f a b o u t0 ' 3 m l . o f p l a s m aw e r e w e i g h e d ,d r i e d at

1 0 5 °C . f o r2 h r . a n d r e w e i g h e d ;t h e r e s u l t sar e e x p r e s s e das g . o f s o l i d s / 1 0 0g .w a t e r .S o d i u ma n d p o t a s s i u mw e r ed e t e r m i n e db y e x t e r n a ls t a n d a r df l a m ep h o t o m e t e r

( E . E . L . )o n s u i t a b l ed i l u t i o n so f p l a s m aa n d u r i n e .C h l o r i d ew a sd e t e r m i n e di nu r i n ea n d i n0 1 m l . s a m p l e so f p l a s m ab y t h e p o t e n t i o -

m e t r i cm e t h o do f S a n d e r s o n[ 1 9 5 2 ] .I n o r g a n i cp h o s p h a t ew a sd e t e r m i n e db yt h em e t h o do fL o w r ya n d L o p e z[ 1 9 4 6 ]

u s i n gp l a s m as a m p l e so f 0 - 1 5m l .B i c a r b o n a t ei np l a s m a . a n du r i n e .- T o t a lc a r b o nd i o x i d ec o n t e n to fd i l u t e du r i n e

a n d o f p l a s m aw a sd e t e r m i n e db y t h e m e t h o do f P e t e r sa n d V an S l y k e[ 1 9 3 2 ]u s i n g0 - 2m l . o f p l a s m at r a n s f e r r e da n a e r o b i c a l l yi n t ot h e b u r e t t ea n d s u i t a b l ev o l u m e so ft h e d i l u t e d u r i n e . B o t hp l a s m aa n d u r i n e c o n t a i n i n gHCO3 h a v e pH o f 7 - 3o r

g r e a t e ra n ds o9 5 - 9 9p e rc e n to f' t o t a lC O 2 'i sH C O 3 .T h er e s u l t sa r eg i v e nas H C O 3 ,w h i c hw a sc a l c u l a t e df r o mt h ed e t e r m i n a t i o n so f ' t o t a lC O 2 'b y m e a n so ff i g .4 2 o fP e t e r sa n d Van S l y k e[ 1 9 3 2 ] .

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E x c r e t i o no f B i c a r b o n a t e 4 0 1

S u l p h a t ei n u r i n e w a s d e t e r m i n e db y a m o d i f i c a t i o no f t h em e t h o do f B e r g l u n da n d S o r b o[ 1 9 6 0 ] .

A m m o n i u mi n u r i n ew a sd e t e r m i n e db y t h e m e t h o do f C o n w a y[ 1 9 5 7 ] .E s t i m a t i o n so n p l a s m aw e r ea l w a y si n d u p l i c a t e .W i t he a c ha n a l y t i c a lm e t h o d

a t l e a s t5 0 s u c hd u p l i c a t e sw e r ec a r r i e do u t i n c o n n e x i o nw i t ht h e s eo r o t h e re x p e r i -m e n t s . From t h i sd a t a t h e s t a n d a r de r r o r o f t h e m e a n o f a s i n g l ed u p l i c a t ep a i rwas

c a l c u l a t e db y t h e p r o c e d u r er e c o m m e n d e d b yK i m b a l l[ 1 9 5 2 ] ;w i t h e ac ha n a l y t i c a l

TABLE I . TH E EXPERIMENTALPROTOCOL.

0 9 . 3 0 Th e d o gwas c a t h e t e r i z e dan d b r o u g h tt o r e s t l y i n gon i t s s i d eon t h e t a b l e ;t h eb l a d d e rwas washed o u t .

1 0 . 0 0 B l a d d e rwashed o u t t o b e g i nu r i n e c o l l e c t i o n .1 0 . 1 0 F i r s t b l o o ds a m p l edrawn f r o mc a r o t i da r t e r y.1 0 . 3 0 B l a d d e rwashed o u t t o c o m p l e t ef i r s tu r i n e c o l l e c t i o n .1 0 . 3 2 1 5 0 - 2 5 0m l . o f t h e t e s ts o l u t i o ng i v e nb y s t o m a c ht u b ean d t h e d o gr e t u r n e dt o

i t s c a g e ,w i t hno a c c e s st o f o o do r w a t e r .1 1 . 3 0 C a t h e t e r i z e dan d b r o u g h tt o r e s to n t h e t a b l e .1 2 . 0 0 -1 2 . 3 0 C o l l e c t i o n ,a s a b o v e ,o f s e c o n du r i n e .1 2 . 1 0 S e c o n db l o o ds a m p l ef r o mt h e c a r o t i da r t e r y.1 2 . 3 2 2 5 0 - 3 5 0m l . o f s o l u t i o ng i v e nb y s t o m a c ht u b e an d d o g a g a i n r e t u r e dt o i t s

c a g e .1 3 . 3 0 C a t h e t e r i z e dan d b r o u g h tt o r e s t o n t h e t a b l e .1 4 . 0 0 -

1 4 . 3 0 C o l l e c t i o n ,a s a b o v e ,o f t h i r d u r i n e s a m p l e .1 4 . 1 0 T h i r db l o o ds a m p l ef r o mc a r o t i da r t e r y.

m e t h o di t w a s0 5 - 1 p e rc e n to f t h e a b s o lu t ev a l u e .T h eo b s e r v e dc h a n g e si np l a s m as o l i d s ,c h l o r i d ea n d b i c a r b o n a t ew e r eu s u a l l yl e s st h a n 1 0 p e r c e n t o f t h e a b s o l u t e

v a l u e sa n d t h e na n a l y t i c a le r r o r i s a s i g n i f i c a n tc a u s eo f t h e s c a t t e r o f r e s u l t s .W i t hu r i n a r ye x c r e t i o n ,h o w e v e r ,a n a l y t i c a le r r o r i s n e g l i g i b l ei nc o m p a r i s o nw i t ht h e l a r g ec h a n g e sd e s c r i b e db e l o w.

E x p e r i m e n t a lp r o t o c o l .- T h e m a j o r i t yo f t h e e x p e r i m e n t sw e r e c a r r i e do u t ac -c o r d i n gt o t h e p r o t o c o lo f Ta b l eI u s i n go n eo f t h et e s ts o l u t i o n so f Ta b l eI I . S o l u t i o n1 , r e f e r r e dt o i n t h e t e x t a s 0 - 1 2 2 MN a C l ,0 - 0 2 3 MNaHCO3, w a s d e s i g n e dt o b e o f

TABLE I I . TH E C O M P O S I T I O NOF S O L U T I O N SGIVEN BY STOMACHTUBE.

S o l u t i o n1 ( r e f e r r e dt o a s 0 - 1 2 2 MN a C l ,0 - 0 2 3 MNaHCO3)NaCl 1 2 2m - m o l e / l .NaHCO3 2 3 m - m o l e / l .

K CI 4 m - m o l e / l .S o l u t i o n2 ( r e f e r r e dt o a s0 - 1 4 5 MN a H C O 3 )

NaHCO3 1 4 5m - m o l e / l .K CI 4 m - m o l e / l .

s i m i l a ri o n i cc o m p o s i t i o nt o p l a s m a( s e ec o l u m n1 o f Ta b l eI I I ) . S o l u t i o n2 , r e f e r r e dt o a s 0 - 1 4 5 MNaHCO3, h a d t h e s a m ec o n t e nt o fNa a n d K b u t d i f f e r e di n t h a t i tc o n t a i n e d1 4 5 m - e q u i v / l .HCO3 a n d p r a c t i c a l l yn o C l . Th e t e s t s o l u t i o n sw e r ewarmed t o 3 8 °C .a n d g i v e nb y s t o m a c ht u b e .

I n some e x p e r i m e n t st h e t i m ec o u r s eo f t h e c h a n g e swas f o l l o w e db y k e e p i n gt h ed o go n t h e t a b l ea n d c o l l e c t i n gb l o o da n d u r i n e s a m p l e sf o r2 h r .a f t e rt h e t e s td o s e s .

I n t wo e x p e r i m e n t ss o l u t i o n2 , made up a s e p t i c a l l y ,w a s i nf u s e d a ta b o u t3 8 ° C.t h r o u g ha c a t h e t e ri n s e r t e di n t o a m a l l e o l a rv e i na n d t h r e a d e df o r w a r ds o t h a t i t s t i pl ay i n t h e f e m o r a lo r i l i a cv e i n[ H o l g a t ea n d O ' C o n n o r ,1 9 5 8 ] .

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4 0 2 M a t t h e w sa n d O ' C o n n o r

R E S U L T S

C h a n g e si n t h ep l a s m aa n d b l o o d .- T h ef i r s tc o l u m no f T a b l eI I I s h o w st h emean a n d s t a n d a r dd e v i a t i o ni n t h e a n a l y s e so f b l o o ds a m p l e sd r a w nf r o mt h e c a r o t i d a r t e r y o f o n e d o g w h i l e a t r e s ta t 1 0 . 1 0 ;c o l u m n1 i n c l u d e so b s e r v a t i o n smade o v e r a p e r i o do f two y e a r s i n c o n n e x i o nw i t h t h e s e a n do t h e re x p e r i m e n t s .S i m i l a rv a l u e sa n d s c a t t e r w e r ef o u n dw i t h t h r e e o t h e rd o g s . I n c o n t r o le x p e r i m e n t sw h e r en o d o s e sw e r eg i v e nt h e c o m p o s i t i o no fb l o o da n d p l a s m aa t 1 2 . 1 0a n d 1 4 . 1 0d i d n o td i f f e rs i g n i f i c a n t l yf r o m1 0 . 1 0 .

Th e m a j o re f f e c t so f t h e d o s e sw e r eo np l a s m as o l i d s ,c h l o r i d ea n db i c a r b o n -a t e . A sw a se x p e c t e df r o mt h e f a c tt h a t e a c ht e s ts o l u t i o nc o n t a i n e dn e a r l yt h e same c o n c e n t r a t i o no f Na as p l a s m an e i t h e r0 - 1 4 5 MNaHCO3n o r 0 - 1 2 2 MN a C l , 0 - 0 2 3 MNaHCO3 c h a n g e ds i g n i f i c a n t l yt h e p l a s m ac o n c e n t r a t i o no fN a , e i t h e ri n Ta b l eI I I o r i n t e n e x p e r i m e n t so n two o t h e ra n i m a l s . B o t h0 - 1 4 5 M

NaHCO3a n d 0 - 1 2 2 MN a C l ,0 - 0 2 3 M

NaHCO3c a u s e da f a l li n p l a s m a

s o l i d s ,i . e .d i l u t i o no f t h e p l a s m ap r o t e i n ,t h e e x t e n to f t h e f a l ld e p e n d i n go nt h e do s ew h i c hwas g i v e n .I n f i g .2 t h e r e s u l t sf r o mf o u r d o g sa r e p l o t t e da n d t h e r e w a s n o s i g n i f i c a n td i f f e r e n c eb e t w e e nt h e f a l l i n p l a s m as o l i d sp r o d u c e db y e q u a l d o s e so f t h e t w o s o l u t i o n s . I ts e e m st h a t t h e r e a r e n ol a r g ed i f f e r e n c e si n t h e a b s o r p t i o na n d d i s t r i b u t i o ni n t h e b o d yo f Na g i v e nas b i c a r b o n a t eo r m a i n l yas t h e c h l o r i d e .

T h e s o l u t i o n0 - 1 2 2 MN a C l ,0 - 0 2 3 MNaHCO3 c o n t a i n e dC la n d HCO3 i nn e a r l y t h e same c o n c e n t r a t i o na s p l a s m aa n d p r o d u c e dn o c h a n g ei n t h ep l a s m ac o n c e n t r a t i o n so f t h e s ei o n s . T h ee x p e r i m e n t si nTa b l eI I I a r e t y p i c a l

o f e i g h to n t h r e e o t h e rd o g s .I n c o n t r a s td o s e so f 0 - 1 4 5 MNaHCO3p r o d u c e di n c r e a s ei n p l a s m aHCO3 a n d a d e c r e a s eo f a b o u t t h e same m a g n i t u d ei np l a s m aC l ; t h e f i g u r e si n t h e s e c o n da n d t h i r d c o l u m n so f Ta b l eI I I w e r ec o n f i r m e db y t e n e x p e r i m e n t so n two o t h e rd o g s .I n e f f e c tt h e N a C lc o n -t a i n e d i n t h e e x t r a c e l l u l a rf l u i db e c o m e sd i l u t e d b y a d m i x t u r ew i t h t h ea d d e d 0 - 1 4 5 MNaHCO3 c a u s i n gn o c h a n g ei n p l a s m as o d i u m ,r i s ei n HCO3a n d f a l li n C l . A c o n s e q u e n c eo f t h e i nc re as e dHCO3 i n p l a s m aw a s t h e r i s ei n t h e pH o f t h e b l o o d ,s i m i l a rc h a n g e st o t h o s ei n Ta b l eI I I b e i n gf o u n di nt wo o t h e ra n i m a l s . Th e c l a s s i c a ls e c o n d a r ye f f e c to f r a i s e d pH i s d e c r e a s e dr e s p i r a t i o nw i t hi n c r e a s ei n t h e C O 2t e n s i o no f a l v e o l a ra i ra n d b l o o d[ D a v i e s ,H a l d a n e a n dK e n n a w a y ,1 9 2 0 ] ,b u t i n G i n a( Ta b l eI I I ) ,a n d i n t h e t w oo t h e rd o g s ,a n y s u c he f f e c twas t o o s m a l lt o b e e s t a b l i s h e db y o u r d i r e c tm e a s u r e -ment o f P c oo f a r t e r i a lb l o o d .

M e a s u r e m e n t sw e r emade o f t h e p l a s m ac o n c e n t r a t i o n so f t w oo t h e ri o n s .I n o r g a n i cP 0 4i n t h r e ed o g sa t 1 0 . 1 0was a b o u t2 - 3m - m o l e / l .a n d t h e e f f e c to fe i t h e rd o s ewas s m a l l ; a m e a n f a l lo f a b o u t0 - 1m - m o l e / l .was n o t s i g n i f i c a n t .P l a s m ap o t a s s i u r na t 1 0 . 1 0was a b o u t41 m - m o l e / l . At 1 2 . 1 0a n d 1 4 . 1 0a f t e rd o s e so f 0 - 1 2 2 MN a C l ,0 - 0 2 3 MN a H C O 3 ,p l a s m aK a p p e a r e dt o b e a l i t t l el o w e r e d ,t h e mean f a l l sb e i n g01 + 0 4 1( S . D . ,5 ) m - m o l e / l . However a f t e rt h e d o s e so f 0 - 1 4 5 MNaHCO3s i g n i f i c a n tf a l l sw e r eo b s e rv e d, t h ef a l la t 1 2 . 1 0b e i n g0 4 + 0 - 1 5( 9 )m - m o l e / l .a n d a t 1 4 . 1 0 ,0 6 + 0 4 1 5( 5 )i n t h e t h re e a n i ma l s .I n e a c h c a s e ,t h e s o l u t i o na d m i n i s t e r e dc o n t a i n e dK i n a p p r o x i m a t e l yt h e

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4 0 4 M a t t h e w s a n dO ' C o n n o r

s a m ec o n c e n t r a t i o nas i n p l a s m a( Ta b l eI I ) . F a l l i n p l a s m aK a f t e ri n f u s i o no f NaHCO3i n a n a e s t h e t i z e dd o g sh a s b e e nd e s c r i b e db y R o b e r t s ,M a g i d aa n dP i t t s[ 1 9 5 3 ]a n d K e a t i n ge ta l . [ 1 9 5 3 ] .

T h eu r i n a r yc h a n g e sp r o d u c e db y 0 4 1 2 2 MN a C l ,0 023M NaHCO3 a n d b y0 - 1 4 5 MNaHCO3. - T h eu r i n e c o l l e c t e da t t h e b e g i n n i n go f e a c he x p e r i m e n ta t a b o u t1 0 * 0 0w a so f s m a l lv o l u m ea n d c o n t a i n e do n l yt h e s m a l lamounts o fNa a n d C l s h o w ni n Ta b l e I V , c o l u m n1 . T h i s u r i n e was a c i d a n d NH+4p r o v i d e da b o u t as m u c h c a t i o n as Na+ a n d K + t o g e t h e r .O f a n i o n s i tc o n t a i n e dn o HCO-; H2PO ( a b o u t 1 0 p t - m o l e / m i n . )a n d SO - ( a b o u t5 , u - m o l e / m i n . )p r o v i d e dmuc h more a n i o nt h a n Cl - ( a b o u t6 , u - m o l e / m i n . ) .

TABLE I V . TH E C O M P O S I T I O NOF TH E URINE OF GINA ( 1 3 K G . ) .

Column 1 i s t h eu r i n a r y c o m p o s i t i o na t 1 0 . 0 0 - 1 0 . 3 0 . C o l u m n s2 , 3 a r e t h eu r i n e c o m p o s i t i o n sa t 1 2 . 0 0 - 1 2 . 3 0a n d 1 4 . 0 0 - 1 4 . 3 0o n d a y swhen 1 5 0 - 2 0 0m l .

o f0 -145M N a H C O 3w a sg i v e nb ys t o m a c ht u b ea t 1 0 . 3 0a n d 2 5 0 - 3 5 0m l .a t 1 2 . 3 0 .C o l u m n s4 , 5 a r e t h eu r i n e c o m p o s i t i o non d a y swhen t h esame d o s e so f 0-122MN a C l ,0-023M NaHCO3w e r eg i v e n .In e a c hc o l u m nt h en u m b e ro f e x p e r i m e n t si s g i v e na t t h et o p and t h ev a l u e sa r e t h em ean an d s t a n d a r dd e v i a t i o n .

1 2 3 4 5A f t e rNaHCO3 A f t e rN a C l ,NaHCO3

1 0 . 0 0 - 1 0 . 3 01 2 . 0 0 - 1 2 . 3 01 4 . 0 0 - 1 4 . 3 01 2 . 0 0 - 1 2 . 3 01 4 . 0 0 - 1 4 . 3 0( 3 3 ) ( 5 ) ( 4 ) ( 4 ) ( 4 )

Volume ( m l . / m i n . ) 0 - 1 0 ± 0 - 0 50 - 2 7 ± 0 - 1 3 1 - 4 ± 0 - 5 0 - 1 2 ± 00 5 0 - 9 ± 0 - 8Na ( M - m o l e / m i n . ) 3±3* 58±26 261±68 34±23 211±115C l ( c u - m o l e / m i n . ) 6 ± 3 * 16±17 49±23 40±20 169±93HCO3 ( , u - m o l e / m i n . ) 0 25±21 189±43 0 2 7± 21NH 4 ( U - m o l e / m i n . ) 14±5 4 ± 3 2± 1 12±5 6 ± 2K ( , u - m o l e - m i n . ) 4±2* 5 ± 2 1 8 ± 7 6 ± 2 14±11

* Mean an d s t a n d a r dd e v i a t i o nc a l c u l a t e du s i n gl o g a r i t h m s .

T h eu r i n e i n Ta b l eI V , c o l u m n1 i s t y p i c a lo f d o g sf e d a d i e to f f r e s hmeata n d b i s c u i t ss u f f i c i e n tt o m a i n t a i nt h e i rw e i g h t s . On t h i r t y o f t h e t h i r t y -t h r e e m o r n i n g si n c o l u m n1 , Na e x c r e t i o nw a s l e s st h a n 1 0 , - m o l e / m i n .a n do n t h e o t h e r t h r e e was 4 8 ,4 0 a n d 2 4 , u - m o l e / m i n .T h e r e a s o nf o r t h e s ee x a m p l e so f h i g hNa e x c r e t i o n ,o b s e r v e dw i t h a b o u tt h i sf r e q u e n c yi n o t h e rd o g sa l s o ,i s n o t o b v i o u s ; t h ea c c o m p a n y i n ga n i o nw a s C l - . S i m i l a rl a r g ee x c r e t i o n so f K a n d p h o s p h a t ew e r eo c c a s i o n a l l ys e e n .

With t h r e e d o g si n n i n e c o n t r o le x p e r i m e n t swhen n o d o s ewas g i v e n ,t h eu r i n e s a t 1 2 . 0 0a n d a t 1 4 . 0 0w e r e f o u n dt o b e l i t t l ed i f f e r e n tf r o mt h o s eat1 0 . 0 0 ; a l t e r a t i o n si n c o m p o s i t i o na n d v o l u m eo f t h e u r i ne s a t 1 2 . 0 0a n d1 4 . 0 0i n T a b l eIV w e r ed u e t o t h e a d m i n i s t e r e dd o s e s .

T h ee f f e c to f 0 - 1 2 2 MN a C l ,0 - 0 2 3NaHCO3 w a s t h e s a m eas t h e e f f e c to f0 - 1 4 5 MN a C ld e s c r i b e db y O ' C o n n o r[ 1 9 5 5a n d 1 9 5 8 ] ,t h e m a i ne f f e c tb e i n gi n c r e a s e de x c r e t i o n o fNa a n d C l . Ta b l eI V , c o l u m n s4 , 5 s h o w st h e mean o ff o u r e x p e r i m e n t so n G i n aa n d t h e r e s u l t so f s e v e ne x p e r i m e n t so n t w o o t h e rd o g sw e r es i m i l a r .I n t h e e x p e r i m e n t so n G i n a ( Ta b l eI V ) , a t 1 2 . 0 0a f t e rt h e f i r s td o s e ,Na e x c r e t i o nh a d i n c r e a s e df r o ma b o u t3 , u - m o l e / m i n .t o 7 - 6 0

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E x c r e t i o no f B i c a r b o n a t e 4 0 5

, u - m o l e / m i n .a n d Cl e x c r e t i o nf r o ma b o u t6 t o 1 6 - 6 4, u - m o l e / m i n . ;a t 1 4 . 0 0a f t e rt h e s e c o n dd o s e ,Na e x c r e t i o nh ad r i s e n t o 1 4 0 - 3 8 0, u - m o l e / m i n . ,andCl e x c r e t i o nt o 1 0 0 - 3 0 0, t - m o l e / m i n .Th e u r i n e a t 1 2 . 0 0 ( c o l u m n4 ) wasu s u a l l ys t i l la c i d a n d c o n t a i n e dno H C O 3 ,w h e r e a sa t 1 4 . 0 0a f t e r t h e s e c o n dd o s e i t was a l w a y s a l k a l i n e and c o n t a i n e dH C O 3 ,t h e r a n g e b e i n g 7 - 5 6

, u - m o l e / m i n .O ' C o n n o r[ 1 9 5 5a n d 1 9 5 8 ]f o u n dt h a t a f t e rdo s e s o f0145MN a C lt h e u r i n e c o n t a i n e dmore Na t h a n C l ,b u t d i d n o t measure t h e H C O 3 .P i t t sand L o t s p e i c h[ 1 9 4 6 ]r e p o r t e dt h a t t h e u r i n e became a l k a l i n e an dc o n t a i n e dHCO3 a f t e rl a r g ed o s e so f N a C l .

Ta b l eI V , c o l u m n s2 , 3 s h o w st h e a v e r a g eo f f o u rt o f i v ee x p e r i m e n t sonG i n ai n w h i c ht h e same d o s e so f Na w e r eg i v e na s 0 - 1 4 5 MN a H C O 3 ,a n d t h e s ew e r e c o n f i r m e db y n i n e e x p e r i m e n t so n t wo o t h e r d o g s .T h e i n c r e a s e si nNa e x c r e t i o ni n Ta b l e I V , c o l u m n s2 , 3 w e r e o f t h e s a m e o r d e r a s t h o s ep r o d u c e db y 0 - 1 2 2 MN a C l ,0 - 0 2 3 MNaHCO3 ( c o l u m n s4 , 5 ) . By c h a n c e ,t h em e a n so f t h e e x p e r i m e n t so n t h e t h r e e d o g sw e r ep r a c t i c a l l yi d e n t i c a l :a f t e rNaHCO3Na e x c r e t i o nwas 5 4, u - m o l e / m i n .a t 1 2 . 0 0a n d 2 0 3a t 1 4 . 0 0 ,w h e r e a sa f t e rN a C l ,NaHCO3 t h e means w e r e 5 6 a n d 2 0 7 . A f t e r 0 - 1 4 5 MNaHCO3t h e r e w a s , h o w e v e r ,o n l y a s m a l l i n c r e a s ei n C le x c r e t i o nt h e r a n g e i n G i n a( Ta b l eI V ) a t 1 2 - 0 0b e i n g3-44 , and a t 1 4 . 0 03 0 - 8 0, - m o l e / m i n . Ta b l eI V ,c o l u m n s2 , 3 s h o w st h e v e r y l a r g ee x c r e t i o no f H C O 3 ;a l lo f t h e u r i n e sa f t e rt h e f i r s td o s e c o n t a i n e db i c a r b o n a t e ,t h e r a n g e i n t h e e x p e r i m e n t so n G i n ab e i n g 2 - 5 6 , u - m o l e / m i n .a t 1 2 . 0 0 a n d 1 3 0 - 2 3 5a t 1 4 . 0 0 a f t e rt h e s e c o n dd o s e .

T a b l eIV s h o w st h a t t h e l a r g e rd o s e so f 0 - 1 4 5 MNaHCO3o r 0 - 1 2 2 MN a C l ,0 - 0 2 3 MNaHCO3 p r o d u c e ds m a l l i n c r e a s e s

i nt h e

e x c r e t i o no f K as w a s a l s or e c o r d e db y O ' C o n n o r[ 1 9 5 8 ]a f t e rdo s e s o f0 - 1 4 5 MN a C l . On i n f u s i n gl a r g ea m o u n t so f NaHCO3 i n t oa n a e s t h e t i z e dd o g s ,R o b e r t se t a l . [ 1 9 5 3 ]o b s e r v e da s u b s t a n t i a li n c r e a s ei n K e x c r e t i o nw h i c ht h e yr e g a r d e da ss p e c i f i c a l l yd u et o H C O 3 . Ta b l eIV a n d t h e e x p e r i m e n t so n t h e o t h e rd o g sf a i l e dt o e s t a b l i s ha g r e a t e re f f e c to n K e x c r e t i o no f NaHCO3 as c o m p a r e dt o N a C l .

Th e amount o f P04 i n t h e u r i n e a t 1 0 . 0 0d i f f e r e dg r e a t l yf r o md a y t o d a yw i t h i nt h e r a n g e1 - 3 0, u - m o l e / m i n . ,mean 1 0 ,a n d b o t hi n c r e a s e sa n d d e c r e a s e sw e r eo b s e r v e di n t h e u r i n e sa t 1 2 . 0 0a n d 1 4 . 0 0w h e t h e ro r n o d o s e sh a db e e ng i v e n . W i t hs u c hl a r g ea n d a p p a r e n t l yr a n d o mv a r i a t i o n si t w a sn o t p o s s i b l et o e s t a b l i s ha n y e f f e c to f t h e d o s e s ;c e r t a i n l yt h e r e w a sn o i n c r e a s ec o m p a r -a b l e t o t h e i n c r e a s e si n t h e e x c r e t i o no f N a , C la n d H C O 3 . S i m i l a r l yS 0 4e x c r e t i o no f a b o u t5 F L - m o l e / m i n .w a sn o t o b v i o u s l yi n c r e a s e db y t h e d o s e s .

Th e u r i n e sa t 1 2 . 0 0a n d 1 4 . 0 0i n c o l u m n s2 , 3 a n d a t 1 4 . 0 0i n c o l u m n5 o fT a b l eIV c o n t a i n e ds u b s t a n t i a la m o u n t so f HCO3a n dh a dt h e u s u a lc h a r a c t e r -i s t i c so f a l k a l i n eu r i n e s .pH w a s n o t a c c u r a t e l ym e a s u r e d ; t e s t e d b yi n d i c a t o r p a p e r s t h e d i l u t e d u r i n e w h i c hr e s u l t e d f r o m t h e c o l l e c t i o nb yb l a d d e rw a s h o u th a di n t h e s ei n s t a n c e spH o f a b o u t8 as c o m p a r e dt o 5 - 5 - 6 . 0i n t h e c o n t r o lu r i n e sc o l l e c t e da t 1 0 . 0 0 .A l t h o u g ht h e amount o f P04 i n t h eu r i n e sw a s n o t g r e a t l y c h a n g e db y t h e d o s e s ,c h a n g ei n i t s a n i o nv a l e n c yi sd e t e r m i n e db y t h e pH o f t h e u r i n e s .I n t h e u r i n e sa t 1 0 . 0 0i t w o u l dh a v eb e e nm a i n l yi n t h e f o r mo f H2PO w h e r e a si nt h e a l k a l i n eu r i n e so f c o l u m n s2 ,

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E x c r e t i o no f B i c a r b o n a t e 4 0 7

1 9 5 8 ]as 0 - 1 4 5 MN a C l . W h e n 0 - 1 4 5 MNaHCO3was g i v e n ,t h e r i s ei np l a s m aHCO3 a n d f a l li n C lo c c u r r e da t t h e s a m e t i m e a s t h e f a l li n p l a s m as o l i d s .Th e u r i n a r y e x c r e t i o no f s o d i u mr o s e t o i t s p e a k 1 - 1 k 1h r . a f t e rd o s e s o fe i t h e rs o l u t i o na n d was i m m e d i a t e l ya c c o m p a n i e db y r i s ei n HCO3 o r C le x c r e t i o n .

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Fall in plasma so l ids ( g / 1 0 0 g )F I G . 2 . Th e r a t e o f e x c r e t i o no f Na p l o t t e da g a i n s t t h e f a l li n p l a s m as o l i d s .

A b s c i s s a :f a l li n p l a s m as o l i d sb e l o wv a l u ea t 1 0 - 1 0 .O r d i n a t e : r a t e o f e x c r e t i o no f N a . A d i f f e r e n ts h a p e ds y m b o li s u s e df o r e a c h o f f o u r

d o g s ; t o a l l o wf o r d i f f e r e n ts i z e so f t h e d o g s ,Na e x c r e t i o ni s p l o t t e da s M - m o l e / m i n . 1 1 5k g .o f b o d yw e i g h t . Open s y m b o l sr e f e r t o e x p e r i m e n t si n w h i c h0 - 1 4 5 MNaHCO3 was g i v e n ;c l o s e ds y m b o l st o e x p e r i m e nt s w i t h0 122M N a C l ,0 - 0 2 3 MNaHCO3e x c e p tf o r S k e w b a l d( V )where 0 - 1 4 5 MNaCl was g i v e n . Each p o i n t i s t h e m e a n o f t wo t o f i v ee x p e r i m e n t s ,t h el e n g t ho f t h e c r o s s l i n e si n d i c a t i n gone s t a n d a r de r r o r o f t h e mean.

Th e d e t a i l e dt i m e c o u r s ec o u l db e more c l e a r l ys e e ni n t h e e x p e r i m e n to ff i g .1 when 0 - 1 4 5 MNaHCO3 w a s i n f u s e di n t r a v e n o u s l y . Th e d i l u t i o n o fp l a s m as o l i d s ,r i s ei n p l a s m aHCO3a n d f a l li n C lw e r eg r e a t e s ta t t h e e n d o ft h e i n f u s i o n ;t h e r a t e s o f e x c r e t i o no f N a , C la n d HCO3 w e r eh i g h e s ti m -m e d i a t e l ya f t e rt h e e n do f t h e i n f u s i o n .An y t i m ed e l a yb e t w e e nt h e c h a n g e si n t h e p l a s m a w h i c hs i g n a lt h e a b s o r p t i o no r i n f u s i o no f t h e s o l u t i o n sa n dt h e c h a n g e si n t h e u r i n e was n o m o r et h a n 1 0 m i n .

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4 0 8 M a t t h e w sa n d O ' C o n n o r

T h ea m m o n i u mc o n t e n to f t h e u r i n ea l s of e l las s o o nas t h e u r i n e c o n t a i n e dH C O 3 . I n f i g .1 t h e u r i n e s a m p l ef r o m4 3 - 5 6m i n . was t h e f i r s tt o c o n t a i nHCO3a n d i t s NH 4 c o n t e n twas 3 u - m o l e / m i n .a s c o m p a r e dt o 1 1 , u - m o l e / m i n .i n t h e p r e c e d i n g s a m p l e .

C o r r e l a t i o nb e t w e e nt h er a t eo fe x c r e t i o no f s o d i u ma n d c h a n g e si n p l a s m as o l i d s .- O ' C o n n o r[ 1 9 5 8 ]p l o t t e dt h e r a t e o f e x c r e t i o n o fs o d i u ma g a i n s tt h ef a l lo f p l a s m as o l i d si n e x p e r i m e n t si n w h i c hd i f f e r e n td o s e so f 0 4 1 4 5 MN a C lw e r eg i v e n . F i g .2 i s t h e s a m ep l o t t i n go f t h e d a t a o b t ai ne don f o u r d o g swhen 0 - 1 4 5 MNaHCO3 ( t h eo p e ns y m b o l s )o r 0 4 1 2 2 MN a C l ,0 - 0 2 3 MNaHCO3( c l o s e ds y m b o l s )w a s g i v e n . I t i s o b v i o u st h a t t h er a t e o f s o d i u me x c r e t i o nw a s r e l a t e d t op l a s m as o l i d si n a s i m i l a rway w h e t h e rt h e s o d i u mwas g i v e nas t h e b i c a r b o n a t eo r as t h e c h l o r i d e .I n f i g .2 t h e p o i n t st o t h e l e f to f t h ed o t t e dl i n er e f e rt o o b s e r v a t i o n sa t 1 2 . 0 0 - 1 2 . 3 0a f t e rt h e f i r s td o s e ,s o t h a ti n t h e p o i n t s p l o t t e dw i t ho p e n s y mb o l st h e r eh a db e e na r i s eo f p l a s m aHCO3

a n d a f a l lo f p l a s m aC lb y a b o u t3 m - e q u i v / l .( Ta b l eI I I )a n d t h e main a n i o n

w h i c h a c c o m p a n i e dt h e e x c r e t e dNa + was HCO- r a t h e r t h a n C l - ( Ta b l eI V ) .T h ep o i n t st o t h e r i g h to f t h ed o t t e dl i n ew e r er e c o r d e da t 1 4 . 0 0 - 1 4 . 3 0a n ds o t h e p l a s m aHCO3 h a d r i s e na n d t h e C lf a l l e nb y a b o u t7 m - e q u i v / l .whent h e do s e sh a d b e e ng i v e na s N a H C O 3 .

F a l l i np l a s m as o l i d si s c o m m o nt o b o t ht y p e so f e x p e r i m e n ta n d s o m e t h i n ga s s o c i a t e dw i t hi t s e e m st o b e t h e m a i nd e t e r m i n a n to f Na + e x c r e t i o n . T h ep l o t t i n go f f i g .2 s h o w st h a t a n y a d d i t i o n a le f f e c to n Na e x c r e t i o np r o d u c e db y g i v i n gNaHCO3r a t h e r t h a n N a C lwas s m a l l .

R e l a t i o n s h i p sb e t w e e nt h er a t eo fe x c r e t i o no fC l a n dHCO3a n d t h ec o m p o s i t i o n

o f t h ep l a s m a .- T h e q u a n t i t a t i v ea s p e c t so f HCO3 e x c r e t i o nh a v e u s u a l l yb e e ns t u d i e db yp l o t t i n gs o m ef u n c t i o no f u r i n a r yHCO3a g a i n s tp l a s m aH C O 3 .F o re x a m p l eP i t t sa n d L o t s p e i c h[ 1 9 4 6 ]i n f u s e dNaHCO3i n d o g sa n d p l o t t e dHCO3 e x c r e t i o np e r 1 0 0m l . o f g l o m e r u l a rf i l t r a t ea g a i n s tp l a s m aH C O 3 . I nt h e p r e s e n te x p e r i m e n t si t w o u l db e s i m i l a r l yp o s s i b l et o p l o t a r e l a t i o n s h i pb e t w e e ne x c r e t i o no f HCO3 a n d i t s p l a s m ac o n c e n t r a t i o n ,i f t h e e x p e r i m e n t sw i t h 0 . 1 4 5 MNaHCO3 o n l y w e r ec o n s i d e r e d ;HCO3 e x c r e t i o na f t e rd o s e s o f0 - 1 2 2 MN a C l , 0 - 0 2 3 MNaHCO3 w o u l dn o t f a l l o n t h e s a m e p l o t t e d l i n e .N e i t h e rw o u l di t b e p o s s i b l et o p l o ta l l o f t h e o b s e r v a t i o n so n t h e r a t e o fe x c r e t i o no f C la g a i n s tp l a s m aC lc o n c e n t r a t i o n .

C o r r e l a t i o nb e t w e e nt h e r a t e o f e x c r e t i o no f HCO3 o r C la n d t h e p l a s m ac o m p o s i t i o nr e q u i r e st h a t t w of a c t o r ss h o u l d b et a k e ni n t o a c c o u n t .

F i r s t l y ,i n a l lo f t h e s ee x p e r i m e n t st h e s u m o f t h e u r i n a r yCl - a n d H C O 3i s a p p r o x i m a t e l ye q u a lt o t h e N a + . T h i sm u s tb e t r u e s i n c et h e r e w e r eo n l ys m a l l c h a n g e si n t h e r a t e o f e x c r e t i o no f o t h e rc a t i o n s( K + ,N H + )a n d o t h e ra n i o n s( H P O - , S O j - ) . T h a tt h e s um o f C l - a n d HCO- i n t h e u r i n e c an b ec o r r e l a t e dw i t h d i l u t i o no f t h e p l a s m ap r o t e i n( s o l i d s )i s s e e n i n t h e b l o c kd i a g r a m so f f i g .3 , w h e r et h e h e i g h to f t h eC l+ HCO3 c o l u m ni n e a c hc a s e i sn e a r l y e q u a l t o t h e s o d i u mc o l u m n . Th e d a t a p l o t t e d i n f i g .3 i s t h a t o fT a b l eIV a n d a f u r t h e rg r o u po f f o u re x p e r i m e n t si n w h i c h G i n aw a s g i v e n3 5 0 m l . o f 0 - 0 7 3 MN a C l ,0 - 0 7 3 MN a H C O 3 .

S e c o n d l y ,t h e p r o p o r t i o n so f Cl - a n d HCO- w h i c hmake u p t h e s um o f

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E x c r e t i o no f B i c a r b o n a t e 4 0 9

t h e s ea n i o n sc a n b e r e l a t e d t o p l a s m aC la n d H C O 3 . W h e n t h e p l a s m aC la n d HCO3 r e m a i n e du n c h a n g e db y t h e d o s e ,t h e u r i n a r y a n i o n was p r e -d o m i n a n t l yC l - w i t h a s m a l l i n c r e a s eo n l y i n HCO. W h e n p l a s m aC lf e l la n d HCO3r o s e ,H CO b e c a m ea l a r g e ra n d C1 -a s m a l l e rf r a c t i o no f t h e t o t a la n i o n .

PlasmasolidsC lHCO3

- 0 * 7 0g / 1 0 0 g- 3 m - m O 1/ l .

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0 * 0 7 3 MN a C I0 * 0 7 3 MN a H C O 3

( 6 )F I G . 3 . G i n a , 1 3 k g . E x c r e t i o no f i o n s a f t e r d o s e so f N a C lan d N a H C O 3 .

Th e h e i g h to f t h e o p e n ,h a t c h e dan d s o l i db l o c k ss h o w st h e mean r a t e o f e x c r e t i o no fN a , C l ,HCO3 i n f o u r t o f i v ee x p e r i m e n t s ;t h e b a r s show o n e s t a n d a r de rr o r o ft h e m e a n .C h a n g e si n t h e p l a s m aa r e s h o w n a b o v e . Column 1 , u r i n a r ye x c r e t i o na t 1 0 . 0 0( c o l u m n1 ,T a b l eI V ) ; c o l u m n s2 , 3 a t 1 2 . 0 0an d 1 4 . 0 0a f t e r d o s e so f 0 - 1 4 5 MNaHCO3 ( c o l u m n s2 , 3 ,T a b l e sI I I , I V ) ; c o l u m n s4 , 5 a t 1 2 . 0 0 an d 1 4 . 0 0 a f t e r d o s e s o f 0 - 1 2 2 MN a C l , 0 - 0 2 3 MNaHCO3 ( c o l u m n s4 , 5 , T a b l e sI I I , I V ) ; column 6 , 6 0 - 9 0m i n . a f t e r 3 5 0 m l . o f 0 - 0 7 3 MNaHCO3, 0 - 0 7 3 MNaCl ( f o u re x p e r i m e n t s ) .

To p l o tr a t e o f e x c r e t i o no f HCO3 o r C l a g a i n s t p l a s m ac o m p o s i t i o nr e q u i r e sa t h r e e d i m e n s i o n a lg r a p ho f w h i c hf i g .4 i s o n e e x a m p l e . H e r eHCO3 e x c r e t i o ni s p l o t t e da g a i n s t p l a s m aHCO3 w i t h f a l li n p l a s m as o l i d sf o r m i n ga t h i r d d i m e n s i o nt o g i v e a f a m i l yo f c u r v e so f w h i c ht w o c a n b edrawn f r o mt h e s ee x p e r i m e n t s .F o re a c hc u rv e am a x i m u mr a t e o f e x c r e t i o no f H CO i s s e tb y t h e r a t e o f Na+ e x c r e t i o na s s o c i a t e dw i t he a c hd i l u t i o no fp l a s m as o l i d s .A p l o t t i n go f t h i st y p e s e e m sb e t t e r t h a n t h a t u s e db y P i t t sa n d L o t s p e i c h[ 1 9 4 6 ,f i g .1 ] i n t h a t i t a v o i d st h e i m p l i c a t i o nt h a t r i s ei np l a s m aHCO3i s t h e s o l em a j o rd e t e r m i n a n to f t h e r a t e o f HCO3e x c r e t i o n .

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4 1 0 M a t t h e w s a n dO ' C o n n o r

D I S C U S S I O N

O ' C o n n o r[ 1 9 5 5 ,1 9 5 8a n d 1 9 6 2 ]h a s g i v e nr e a s o n sf o rr e g a r d i n gd i l u t i o no fp l a s m ap r o t e i nas a n i m p o r t a n ta g e n tw h i c ha c t s o n t h e k i d n e y st o d e t e r m i n ei n c r e a s e de x c r e t i o no f N a . T h ep r e s u m e dm e c h a n i s mi s t h a t f a l li n p l a s m ap r o t e i nc a u s e si n c r e a s e dg l o m e r u l a rf i l t r a t i o na n d W e s s o n[ 1 9 5 7a n d 1 9 6 4 1

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F i G . 4 . G i n a , 1 3 k g . R a t e o f e x c r e t i o no f HCO3 p l o t t e da g a i n s t p l a s m aHCO3 a t t wo d i f f e r e n tf a l l si n p l a s m as o l i d s .

HCO3e x c r e t i o ni s p l o t t e da s o r d i n a t e ,p l a s m aHC03 a s a b s c i s s a . Plasmas o l i d sa r e i n d i c a t e da s f o r m i n ga f a m i l y o f c u r v e so f w h i c ht wo c a n b ei n d i c a t e df r o mt h e d a t a - f a l lo f p l a s m as o l i d s0 - 7 - 0 - 8an d 0 3 5 - 04 5 g . / 1 0 0g .Th e h o r i z o n t a ll i n e s ,N a + ,show t h e r a t e o fe x c r e t i o no f Na w i t hf a l lo f p l a s m as o l i d so f 0 - 7- 0- 8an d 0 3 5 - 0 4 5g . / 1 0 0g .

h a s e m p h a s i z e dt h e c o r r e l a t i o n sw h i c hd o e x i s tu n d e rm a n y c i r c u m s t a n c e sb e t w e e nt h e r a t e o f e x c r e t i o no f Na a n d i n u l i no r c r e a t i n i n ec l e a r a n c e ,s o f a ra s t h e s em e a s u r e m e n t sa r e a c c u r a t ee n o u g ht o a l l o wc o r r e l a t i o n st o b e m a d e .O ' C o n n o r[ 1 9 6 2 ,C h a p .X V I I ]h a s p o i n t e do u t t h a t u n d e rt h e c o n d i t i o n so ft h e s ee x p e r i m e n t s ,w i t h s m a l la n d c h a n g i n gu r i n e f l o w s ,i t i s n o t p o s s i b l et om e a s u r e t h ec l e a r a n c eo f i n u l i no r c r e a t i n i n e w i t h s u f f i c i e n ta c c u r a c yt od i r e c t l yd e t e r m i n et h e r e a b s o r p t i o no f N a , C l ,H C O 3 . C h a n g e si n g l o m e r u l a rf i l t r a t i o nr a t e c a n o n l y b e i n f e r r e db y e x t r a p o l a t i o nf r o mp u b l i s h e dd a t a ,w h i c hi n d i c a t e st h a t i n d o g sa f a l lo f 0 . 1g . / 1 0 0g . i n p l a s m as o l i d ss h o u l dp r o d u c ea n i n c r e a s eo f 1 m l . / m i n .i n g l o m e r u l a rf i l t r a t i o n[ O ' C o n n o r ,1 9 6 2 ] .

T h u sa f t e rt h e f i r s td o s ei n Ta b l eI V , t h e r e w o u l dh a v eb e e na n i n c r e a s eo f4 m l . / m i n .i n t h e v o l u m ea n d a n i n c r e a s eo f 6 0 0, u - m o l e / m i n .i n t h e amount o fNa f i l t e r e d ;u r i n e v o l u m ei n c r e a s e db y o n l y 0 . 1m l . / m i n .a n d Na e x c r e t i o n

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E x c r e t i o no f B i c a r b o n a t e 4 1 1

b y o n l y5 0 , - e q u i v / m i n .Even a f t e rt h e s e c o n dd o s ewhen t h e r ewas p r o b a b l ya n i n c r e a s eo f 8 n l l . / m i n .i n t h e v o l u m ea n d 1 2 0 0 u - m o l e / m i n .i n t h e Na o ft h e g l o m e r u l a rf i l t r a t e ,u r i n ev o l u m ei n c r e a s e db y o n l y1 m l . / m i n .a n d u r i n a r yNa b y a b o u t 2 0 0 p , - m o l e / m i n .I n t h e s e e x p e r i m e n t s ,a s i n m a n y o t h e ri n v e s t i g a t i o n so f Na e x c r e t i o n ,i t s e e m st h a t i n c r e a s ei n g l o m e r u l a rf i l t r a t i o ni s a c c o m p a n i e db y i n c r e a s e dr e a b s o r p t i o no f Na a n d w a t e r . S i m i l a rc a l c u l -a t i o n s i n d i c a t e t h a t i n e a c h o f t h e s e e x p e r i m e n t st h e r e was a l s oi n c r e a s e dr e a b s o r p t i o no f C l a n d H C O 3 . R e c e n t l y ,m i c r o p u n c t u r eo f t h e p r o x i m a lt u b u l e si n r a t s a n dd o g sh a s b e e nu s e dt o i n v e s t i g a t et h i sr e l a t i o n s h i pb e t w e e ng l o m e r u l a rf i l t r a t i o na n d Na r e a b s o r p t i o n[ e . g .R e c t o r ,B r u n n e ra n d S e l d i n ,1 9 6 6 ] .

C u r r e n tc o n c e p t i o n so f t h e r e a b s o r p t i o no f N a + ,C 1 - ,HCO- a r e d e s c r i b e db y P i t t s [ 1 9 6 3 ] .T h er e a b s o r p t i o no f Na + i s r e g a r d e das an a c t i v ep r o c e s s ,w h i c hs e t sup a n e l e c t r o c h e m i c a lg r a d i e n tw h i c hc a u s e st h e t r a n s f e r e n c eo f

C l - a n d HCO- o u t o f t h el u m e n . T h em o d e so f t r a n s f e ra l o n gt h e e l e c t r i c a lg r a d i e n t a r e d i f f e r e n t ,t h a t o f C l - c o n s i s t i n gi n s i m p l ed i f f u s i o n ,w h e r e a sp a s s a g eo f HCO- i n v o l v e sm o v e m e n t o f H + , f o r m a t i o no f H 2 C 0 3a n d i t sb r e a k d o w ni n t o C O 2a n d w a t e rw i t h t h e i n v o l v e m e n to f c a r b o n i ca n h y d r a s e[ R e c t o r ,C a r t e ra n dS e l d i n ,1 9 6 5 ] .I f ,a f t e rdo s e s o fN a H C O 3 ,t h o s ec h a r a c t e r -i s t i c so f t h e r e n a l t u b u l a rc e l l sw h i c ha l l o wt h e p a s s i v et r a n s f e r o f Cl - a n dHCO- w e r eu n c h a n g e d ,t h e n as r e ab s o rp t i o n o fNa + p r o c e e d s ,t h e a n i o nl e f ti n t h e u r i n ew o u l db e Cl - o r HCO- a c c o r d i n gt o t h e c o n c e n t r a t i o no f t h e s ei o n si n t h e g l o m e r u l a rf i l t r a t e .I t s h o u l db e n o t e dt h a t t h i se x p l a n a t i o ni n v o l v e so n l yc h a n g e si n t h e v o l u m ea n d c o m p o s i t i o no f t h e g l o m e r u l a rf i l t r a t e ;f r o mt h e s ee x p e r i m e n t st h e r e i s n o r e a s o nt o p o s t u l a t ec h a n g e si n t h e p r o p e r t i e so ft h e t u b u l a rc e l l sd u e t o a l k a l k e m i ao r i n c r e a s e dC O 2t e n s i o n .

I n e x i s t i n gw o r ko n t h e e f f e c t so f t h e i n g e s t i o no f N a H C O 3 ,o n l y HCO3e x c r e t i o nh a s b e e nm e a s u r e d[ e . g .P i t t sa n d L o t s p e i c h ,1 9 4 6 ; R e c t o re t a l . ,1 9 6 0 ; G u i g n a r d ,1 9 6 6 ] ,i t b e i n ga s s u m e dt h a t Na + w a s t h e c a t i o n a c c o m -p a n y i n gt h e i n c r e a s e du r i n a r y HCO-; t h i sh a s n o w b e e nd e m o n s t r a t e db yd i r e c tm e a s u r e m e n t .A l s o b y c o m p a r i n gt h e e f f e c t so f t h e i n g e s t i o no fNaHCO3a n d N a C l ,i t h a s n o w b e e nf o u n dt h a t i n c r e a s ei n p l a s m aHCO3 h a sn o o b v i o u se f f e c ti n i n c r e a s i n gNa e x c r e t i o nb e y o n dt h e r a t e t o b e e x p e c t e df r o mc o n c o m i t a n td i l u t i o no f t h ep l a s m ap r o t e i n( f i g .2 ) . T h i so b s e r v a t i o nh a s t w o i m p o r t a n tc o r o l l a r i e s .

F i r s t l y ,i n c r e a s e i n p l a s m aHCO3 a p p e a r so f i t s e l fu n a b l et o d e t e r m i n em u c h i n c r e a s ei n t h e e x c r e t i o no f H C O 3 ;t h e r em u s tb e a c o n c o m i t a n tc h a n g ew h i c hc a u s e si n c r e a s e de x c r e t i o no f a c a t i o n ,i n t h i sc a s e N a + . T h e r ea r ema ny c o m p l e xs i t u a t i o n sw h e r ei t s e e m st h a t a h i g hp l a s m aHCO3 d o e sn o tr e s u l ti n t h e u r i n a r ye x c r e t i o no f HCO3u n t i la s u f f i c i e n tu r i n a r ye x c r e t i o no fNa o r K i s s u p p l i e d : o n e e x a m p l ei s t h e e f f e c to f l o s so f g a s t r i cj u i c e[ e . g .Van S l y k ea n d E v a n s ,1 9 4 7 : N e e d l e ,K a l o y a n i d e sa n d S c h w a r t z ,1 9 6 4 ] .

S e c o n d l y ,o n c e t h e r e i s s u f f i c i e n ti n c r e a s e i n p l a s m aHCO3 a n d f a l l i np l a s m aC lt o e n s u r et h a t HCO- r a t h e rt h a nCl - a c c o m p a n i e sNa + i n t h e

u r i n e ,t h e r a t e o f e x cr e t i o n o fHCO- d e p e n d so n Na + e x c r e t i o na n d i n t h e s ee x p e r i -m e n t si s t h u s r e l a t e d t od i l u t i o no f t h e p l a s m ap r o t e i n( f i g .4 ) . W h e n P i t t s

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4 1 2 M a t t h e w sa n d O ' C o n n o r

a n d L o t s p e i c h[ 1 9 4 6 ]b y i n f u s i n gl a r g eq u a n t i t i e so f NaHCO3 c a u s e dp l a s m aHCO3 i n d o g s t o r i s et o o v e r 5 0 m - e q u i v / l .a n d t h e e c x r e t i o no f HCO3 t oa b o u t2 0 0 0/ u - e q u i v / m i n . ,t h e r e w o u l da l s oh a v eb e e np r o g r e s s i v ed i l u t i o no fp l a s m ap r o t e i na n d p r o g r e s s i v ei n c r e a s ei n t h e r a t e o f e c x r e t i o no f N a . T h es h a p eo f

t h e i rc u r v er e l a t i n g

HCO3e x c r e t i o nt o p l a s m a

HCO3was n o t t h e r e -

f o r ed e t e r m i n e db y t h e c a p a c i t yo f t h e t u b u l a r c e l l st o r e a b s o r bHCO3;r a t h e r i t p r o b a b l yr e f l e c t st h e r e l a t i o n s h i pb e t w e e nNa e x c r e t i o na n d c h a n g e si n p l a s m ap r o t e i nw h i c ho c c u r r e dc o n c o m i t a n t l yw i t h t h e c h a n g e si n HCO3a n d w h i c hw e r en o t m e a s u r e d .

T h ep l o t t i n go f HCO3 e x c r e t i o np e r 1 0 0 m l . o f g l o m e r u l a rf i l t r a t ea g a i n s tp l a s m aHCO3 h a s r e s u l t e di n t h e u s e o f t w o e x p r e s s i o n sa s m e a s u r e so f t h et u b u l a r h a n d l i n go f H C O 3 ,n a m e l y' t h r e s h o l df o r HCO3' a n d ' m a x i m u mt u b u l a r r e ab s o rp t i o no f HCO3 p e r 1 0 0 m l . o f g l o m e r u l a rf i l t r a t e ' .I n o u re x p e r i m e n t st h e t h r e s h o l df o rHCO3o b v i o u s l yd e p e n d so n t h e r a t e o f e x c r e t i o n

o f Na a n d c a n b e r e l a t e d t o t h e d i l u t i o no f p l a s m ap r o t e i n( f i g .4 ) . F i n d i n g ss u c h as t h o s eo f R e c t o re t a l . [ 1 9 6 0 ]a n d G u i g n a r d[ 1 9 6 6 ]t h a t i n a n i m a l sl o a d e dw i t h NaHCO3 ' m a x i m a lHCO3 r e a b s o r p t i v ec a p a c i t yp e r 1 0 0 m l . o ff i l t r a t e 'c a n b e a l t e r e db y l a r g ec h a n g e si n P c o 2o r b y a c e t a z o l a m i d ed o n o tn e c e s s a r i l ymean t h a t t h e t u b u l a rh a n d l i n go f HCO3 i s s p e c i f i c a l l ya l t e r e d ;t h e yc o u l de q u a l l yb e d u e t o c h a n g e si n t h e e x c r e t i o no f Na o r C lw h i c hw e r en o t m e a s u r e d .

E x i s t i n gw o r ko n HCO3 e x c r e t i o ns u c h as t h a t o f P i t t sa n d L o t s p e i c h[ 1 9 4 6 ] ,R e c t o re t a l . [ 1 9 6 0 ] ,h a s i n v o l v e dt h e a d m i n i s t r a t i o no f l a rg e d o s e so fNaHCO3 a n d c h a r a c t e r i s t i c so f HCO3 e x c r e t i o nh a v eb e e nd e f i n e da t r a t e s2 0 0 - 2 0 0 0, u - e q u i v / m i n .i nc o n s c i o u so r a n m e s t h e t i z e dd o g s . Even t h e e x c r e t i o no f Na a t 5 0 a n d 2 0 0 , u - e q u i v / m i n .o n w h i c ht h e d i s c u s s i o n so f t h i sp a p e ra r eb a s e di s m u c h h i g h e rt h a ni s n o r m a l l ye n c o u n t e r e di no u rd o g s .On c a t h e t e r -i z a t i o n ,t h e e x c r e t i o no f Na i s o n l yr a r e l yh i g h e rt h a n 2 0 , u - e q u i v / m i n .a n d i su s u a l l yl e s st h a n 6 ( c o l u m n1 , Ta b l eI V ) ; t h e d a i l ye x c r e t i o no f o u rd o g si sa b o u t5 - 1 0 m - e q u i v / d a y,e q u a l t o 3 - 7 , u - e q u i v / m i n .T h ei n v e s t i g a t i o n so ft h i sp a p e rd o n o t t h e r e f o r en e c e s s a r i l yi n d i c a t e t h e m e c h a n i s m sb y w h i c he l e c t r o l y t eb a l a n c ei s m a i n t a i n e di n o u r d o g s ; t h e y w o u l db e m o r ed i r e c t l ya p p l i c a b l et o d o g sf e d a d i e tr i c h e ri n N a , w h i c hm ay b e t h e c a s e when d o g s

a r e f e d c a n n e dm e a t .

ACKNOWLEDGMENT

O u r t h a n k sa r e d u e t o M r . J . B r o o ka n d M r s . C . Tw i t c h e t tf o r t h e i rt e c h n i c a la s s i s t a n c e .Some o f t h e a p p a r a t u su s e dt o t h i sw o r kw a sp r o v i d e db y a g r a n t f r o mt h e M e d i c a lR e s e a r c hC o u n c i l .

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E x c r e t i o no f B i c a r b o n a t e 4 1 3

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d o g ,and t h e e f f e c to f o c c l u s i o no f t h e

c a r o t i d a r t e r i e s ' ,Q u a r t . J . e x p . P h y s i o l .4 0 ,2 3 7 - 2 5 7 .O ' C O N N O R ,W . J . ( 1 9 5 8 ) .' T h ee f f e c to n u r i n a r yv o l u m ean d c o m p o s i t i o no f t h e i n g e s t i o n

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t u b u l a r b a l a n c e . I . E f f e c t o f a o r t i c c o n s t r i c t i o n an d e l e v a t e d u re t e ro p e lv i cp r e s s u r eo n g l o m e r u l a rf i l t r a t i o nr a t e ,f r a c t i o n a lr e a b s o r p t i o n ,t r a n s i t t i m ean d t u b u l a rs i z ei n t h e p r o x i m a lt u b u l eo f t h e r a t ' ,J . c l i n .I n v e s t .4 5 ,5 9 0 - 6 0 2 .

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