Diuretic Agents - ACS Publications - American Chemical Society

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Prostaglandins and Renal Function: Implications for the Activity of Diuretic Agents J. C. McGIFF and P. Y - K WONG

Downloaded by 117.255.233.93 on March 3, 2016 | http://pubs.acs.org Publication Date: June 1, 1978 | doi: 10.1021/bk-1978-0083.ch001

Department of Pharmacology and Department of Medicine, University of Tennessee Center for the Health Sciences, Memphis, T N 38163

Prostaglandins are primarily local or tissue hormones which act at or near their sites of synthesis and are synthesized on demand as they are not stored (1). In the kidney, as in other tissues, prostaglandins serve primarily a defensive function, although they may contribute to the maintenance of renal function under physiological conditions. Furosemide, ethacrynic acid and bumetanide, the most potent of the diuretic agents, can cause a precipitous decline in renal function, particularly in the sodium depleted subject; a prostaglandin response evoked i n response to the "loop diuretic" may maintain renal function in the face of this challenge (2). The capacity of the kidney to respond to a stimulus which depresses renal function by increasing prosta glandin synthesis was f i r s t shown during administration of a vasoconstrictor agent such as angiotensin or norepinephrine (3). Release of prostaglandins coincided with restoration of renal blood flow and urine flow despite continued administration of either angiotensin II or norepinephrine. STRESS EVOKED RENAL PROSTAGLANDIN RESPONSE A prostaglandin mechanism seems important to the regulation of the renal circulation when the latter i s compromised by an acute insult or chronic disease. For example, activation of the renin-angiotensin system by either hemorrhage , laparotomy (5.) or a "loop diuretic" can increase synthesis of prostaglandins by the kidney; the concentration of PGE^ i n renal venous blood increased by as much as fifteen-fold during surgical stress and was closely correlated with the level of plasma renin activity (5). Thus, under acute stress the a c t i v i t i e s of the reninangiotensin and prostaglandin systems within the kidney appear to be coupled. The contribution of a prostaglandin mechanism to the support of the renal circulation in the acutely stressed dog may be uncovered by administration of indomethacin, an inhibitor of prostaglandin synthesis (5). A large reduction i n renal blood flow oceurred rapidly i n response to indomethacin, despite an 0-8412-0464-0/78/47-083-001$05Ό0/0 © American Chemical Society In Diuretic Agents; Cragoe, Edward J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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attendant increase i n r e n a l p e r f u s i o n pressure. There was a simultaneous d e c l i n e i n r e n a l e f f l u x o f PGEp which was proport i o n a l to the r e d u c t i o n i n r e n a l blood flow. T h i s study demons t r a t e d that i n the animal subjected t o acute s t r e s s , the r e n a l c i r c u l a t i o n was supported by a major p r o s t a g l a n d i n component, withdrawal o f which r e s u l t e d i n decreased r e n a l blood flow, p a r t i c u l a r l y that f r a c t i o n to the inner cortex and medulla ( 7 ) .


PROSTAGLANDIN RELATED EFFECTS ON RENAL BLOOD FLOW The pattern o f d i s t r i b u t i o n o f blood flow w i t h i n the kidney may a f f e c t s a l t and water e x c r e t i o n ; f o r example, increased blood flow to the medulla can lower the t o n i c i t y o f the medullary i n t e r s t i t i u m and, thereby, diminish the c a p a c i t y to concentrate u r i n e , r e s u l t i n g i n increased water e x c r e t i o n . Changes i n p r o s t a g l a n d i n s y n t h e s i s , whether r e s u l t i n g from i n h i b i t i o n by a s p i r i n - l i k e drugs, o r i n c r e a s e s induced by e i t h e r acute s t r e s s (5_), i n f u s i o n o f a r a c h i d o n i c a c i d (8), or a d m i n i s t r a t i o n o f a loop d i u r e t i c (2), a r e l i k e l y t o be r e f l e c t e d p r i m a r i l y by a l t e r a t i o n s o f that p o r t i o n o f r e n a l blood flow which s u p p l i e s the medulla and w i l l be r e f l e c t e d by decreased o r increased blood flow t o the i n n e r and mid cortex, as measured by the d i s t r i b u t i o n of r a d i o a c t i v e microspheres w i t h i n the cortex. T h i s e f f e c t o f a l t e r e d p r o s t a g l a n d i n s y n t h e s i s on zonal d i s t r i b u t i o n o f r e n a l blood flow a r i s e s from two f a c t o r s . F i r s t , s t r a t i f i c a t i o n o f prostaglandin synthetase i n t r a r e n a l l y i s opposite t o that o f r e n i n ; the g r e a t e s t p r o s t a g l a n d i n s y n t h e t i c c a p a c i t y i s i n the p a p i l l a and medulla, the l e a s t i n the r e n a l cortex (£). I t should be noted that the apparent d i f f e r e n c e i n p r o s t a g l a n d i n b i o s y n t h e t i c c a p a c i t y between the r e n a l cortex and medulla may be r e l a t e d , i n p a r t , to the presence w i t h i n the cortex o f an i n h i b i t o r o f cyclooxygenase (10). Second, the inner c o r t i c a l and medullary c i r c u l a t i o n s are continuous, as the a f f e r e n t a r t e r i o l e s of the inner cortex extend i n t o the medulla, g i v i n g r i s e t o the vasa r e c t a (11). Therefore, changes i n p r o s t a g l a n d i n s y n t h e s i s i n the inner medulla w i l l have secondary e f f e c t s on blood flow to the outer medulla and inner and mid cortex because o f the morphol o g i c a l u n i t y o f these v a s c u l a r s t r u c t u r e s . A p o s s i b l e c l i n i c a l c o r r e l a t i o n o f these f i n d i n g s i s the nephropathy o f a n a l g e s i c abuse. Nanra e t a l have proposed that "analgesic-nephropathy" i s due to medullary ischemia secondary to reduced s y n t h e s i s o f one or more v a s o d i l a t o r p r o s t a g l a n d i n ( s ) (12), such as PGE or PGI F u r t h e r , elevated t i s s u e l e v e l s o f PGE , the presumed agent o f enhanced renomedullary blood flow, should r e s u l t from i n h i b i t i o n of PGE-9-ketoreductase. Furosemide and e t h a c r y n i c a c i d have been shown t o i n h i b i t t h i s enzyme and should thereby promote increased r e n a l blood flow to the medulla (13). The evidence f o r a p r o s t a g l a n d i n mechanism p a r t i c i p a t i n g i n the r e g u l a t i o n o f the i n t r a r e n a l d i s t r i b u t i o n o f blood flow was f i r s t obtained i n the i s o l a t e d blood-perfused kidney o f the dog 2

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In Diuretic Agents; Cragoe, Edward J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Prostaglandins and

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(14) - and l a t e r i n the conscious r a b b i t (15). One or more r e n a l p r o s t a g l a n d i n ( s ) , p r i m a r i l y PGE , i s r e s p o n s i b l e f o r mediating i n c r e a s e s i n blood flow to the r e n a l medulla i n response to s t i m u l i as d i v e r s e as s u r g i c a l trauma (5), hemorrhagic hypot e n s i o n (4), s a l t l o a d i n g (16), and loop d i u r e t i c agents (17). Those i n t e r v e n t i o n s which i n c r e a s e p r o s t a g l a n d i n production, even though they may reduce t o t a l r e n a l blood flow, can increase blood flow to the r e n a l medulla. A balanced mechanism seems to regul a t e the d i s t r i b u t i o n of r e n a l blood flow: a p r o s t a g l a n d i n mechanism i n c r e a s e s blood flow to the inner cortex and medulla, and one of the components of the r e n i n - a n g i o t e n s i n system, a n g i o t e n s i n I , probably has a major i n t r a r e n a l r o l e e f f e c t i n g decreases i n blood flow to the medulla (18). T h i s a c t i o n on the i n t r a r e n a l d i s t r i b u t i o n of blood flow may be unique f o r angiot e n s i n I , as a n g i o t e n s i n I I u s u a l l y r e s u l t s i n r e d u c t i o n i n r e n a l blood flow to a l l zones (18). I t should be noted that high doses of a n g i o t e n s i n I I , which can stimulate p r o s t a g l a n d i n s y n t h e s i s , may cause an i n c r e a s e i n medullary blood flow despite a d e c l i n e i n t o t a l r e n a l blood flow. As d i u r e t i c agents have the c a p a c i t y to a c t i v a t e the r e n i n - a n g i o t e n s i n system consequent to r e d u c t i o n of e x t r a c e l l u l a r f l u i d volume, some of the e f f e c t s on r e n a l hemodynamics may operate through t h i s mechanism. In c o n t r a s t to i t s e f f e c t on the s u r g i c a l l y - s t r e s s e d anest h e t i z e d dog, indomethacin d i d not a f f e c t r e n a l blood flow i n the conscious r e s t i n g dog, even i n doses having major t o x i c e f f e c t s ( 5 ) . T h i s f i n d i n g supports the proposal t h a t , under physiol o g i c a l c o n d i t i o n s , those mechanisms i n v o l v i n g r e n a l p r o s t a glandins are quiescent, r e q u i r i n g a noxious stimulus to be a c t i v a t e d . T h i s proposal a l s o i s i n agreement with the general c o n c l u s i o n that prostaglandins subserve a defensive f u n c t i o n , and that t h e i r r e l e a s e from an organ represents s y n t h e s i s on demand, as prostaglandins are not s t o r e d (1). Although t h i s c o n c l u s i o n appears v a l i d f o r many t i s s u e s , i t f a i l s to e x p l a i n the b a s a l e f f l u x , a l b e i t low, of prostaglandins from kidneys of the cons c i o u s r e s t i n g dog, which i s unaffected by high doses of indomethacin C5). Further, i n the conscious r a b b i t (15) and perhaps i n r e s t i n g man (19), i n h i b i t i o n of p r o s t a g l a n d i n s y n t h e s i s has been shown to r e s u l t i n increased v a s c u l a r r e s i s t a n c e . In the conscious r a b b i t , indomethacin increased r e n a l v a s c u l a r r e s i s tance two-fold, a s s o c i a t e d with a s h i f t of r e n a l blood flow to the outer cortex (15). Thus, the a c t i v i t y of i n t r a r e n a l p r o s t a g l a n d i n mechanisms i n the conscious animal under p h y s i o l o g i c a l c o n d i t i o n s may vary with the s p e c i e s . N a s j l e t t i et a l (20) have obtained evidence that the r e l e a s e of prostaglandins from the kidney under r e s t i n g c o n d i t i o n s i s determined, i n l a r g e p a r t , by the a c t i v i t y of the r e n a l k a l l i k r e i n - k i n i n system. 2


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PROSTAGLANDIN BIOSYNTHETIC CAPACITY OF RENAL TISSUES An a l t e r n a t i v e explanation f o r the f a i l u r e of indomethacin



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to a f f e c t r e n a l blood flow i n the conscious r e s t i n g dog d e r i v e s from p o s s i b l e d i f f e r e n c e s i n a c c e s s i b i l i t y of a s p i r i n - l i k e compounds to p r o s t a g l a n d i n synthetase, perhaps r e f l e c t i n g v a r i a t i o n i n metabolism or d i s t r i b u t i o n of the i n h i b i t o r . Another explanation i s that the cyclooxygenase v a r i e s i n i t s suscep t i b i l i t y to a s p i r i n - l i k e drugs depending on the t i s s u e and species; t h i s seems l e s s l i k e l y (21). Thus, the question of access of indomethacin to i t s s i t e of a c t i o n , as w e l l as s p e c i e s and t i s s u e d i f f e r e n c e s i n the e f f e c t s of indomethacin on the p r o s t a g l a n d i n s y n t h e s i z i n g machinery, must be kept i n mind. T h i s c o n s i d e r a t i o n leads to an important observation; v i z . , the c a p a c i t y to s y n t h e s i z e p r o s t a g l a n d i n s i s d i s t r i b u t e d widely among the c e l l u l a r elements of the kidney. Cyclooxygenase i s present i n at l e a s t three d i f f e r e n t t i s s u e s i n the kidney. The i n t e r s t i t i a l c e l l s of the r e n a l medulla were the f i r s t to be shown to have the c a p a c i t y to synthesize prostaglandins (21). A l s o , cyclooxygenase was shown to be l o c a l i z e d i n the c e l l s l i n i n g the d i s t a l nephron and c o l l e c t i n g ducts (22); t h i s l o c a t i o n accords with the known i n t e r r e l a t i o n s h i p s of p r o s t a g l a n d i n s and ADH (23). (Figure 1). For example, i n c r e a s e d u r i n a r y c o n c e n t r a t i n g a b i l i t y i n response to ADH occurred a f t e r treatment with indomethacin (24). P r o s t a g l a n d i n s of the Ε s e r i e s have been shown to b l u n t the e f f e c t s of ADH (23) and favor the e x c r e t i o n of f r e e water. A p r o s t a g l a n d i n mechanism may c o n t r i b u t e to the a c t i o n of those d i u r e t i c agents which i n c r e a s e l e v e l s of PGE i n the r e n a l medulla. The l a t t e r could be e f f e c t e d by an a c t i o n of the d i u r e t i c agent e i t h e r on s y n t h e s i s of p r o s t a g l a n d i n s , or on the enzyme 15-hydroxyprostaglandin dehydrogenase which degrades PGE or by i n h i b i t i o n of PGE-9-ketoreductase which transforms PGE to PGF- . Indeed, furosemide may have e f f e c t s on each of these mechanisms; i t i n c r e a s e s p r o s t a g l a n d i n s y n t h e s i s by promoting a r a c h i d o n i c a c i d d e l i v e r y to the cyclooxygenase (25) and i n h i b i t s both the dehydrogenase and reductase (13). The NADP -dependent form of the dehydrogenase has been suggested to be i d e n t i c a l to the PGE-9-ketoreductase (26). 2

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POSSIBLE CIRCULATING PROSTAGLANDINS There i s l i t t l e evidence that prostaglandins f u n c t i o n as c i r c u l a t i n g hormones. An exception to t h i s was thought to be PGA which, when i n f u s e d i n t r a v e n o u s l y , was not destroyed on passage across the pulmonary c i r c u l a t i o n (31). However, i n a l l p r o b a b i l i t y , PGA i s an a r t i f a c t r e s u l t i n g from spontaneous breakdown of PGE during e x t r a c t i o n and p u r i f i c a t i o n of t i s s u e s or plasma; recent s t u d i e s based on h i g h l y s e n s i t i v e and s p e c i f i c mass spectrometric methods d i d not detect PGA i n the blood (32). Recently, P G I has been suggested to f u n c t i o n as a c i r c u l a t i n g hormone because i t s vasodepressor a c t i v i t y i s undiminished by passage across the lung (33)• 2

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Prostaglandins and Renal Function

Figure 1.

Prostaglandin-kinin interaction in the nephron.

The generation of kinins in the distal nephron and collecting ducts results in the release of prostaglandins which inhibit the effect of ADH and thereby participate in the excretion of solute-free water. Prostaghndin-15-hydroxydehydrogenase (PGHD), PGE-9-ketoreductase (9 KR).


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Although cyclooxygenase i s present i n many t i s s u e s w i t h i n the kidney, the major products o f a r a c h i d o n i c a c i d metabolism, be they P G I , PGE , PGD , P G F , o r TXA (Figure 2), may be t i s s u e s p e c i f i c and, consequently, t h e i r e f f e c t s may be p r i m a r i l y r e s t r i c t e d to one compartment, such as the v a s c u l a r , tubular or interstitial. Thus, p r o s t a c y c l i n , a major product of arachidonic a c i d metabolism w i t h i n the blood v e s s e l w a l l (j$4), which together with other prostaglandins may a f f e c t the a c t i v i t y o f the r e n i n a n g i o t e n s i n system, i s p o s s i b l y destroyed l o c a l l y by the abundant p r o s t a g l a n d i n dehydrogenases o f the v a s c u l a r t i s s u e s (27). The r e n i n - a n g i o t e n s i n system i s p r i m a r i l y r e s t r i c t e d to the v a s c u l a r compartment as i s p r o s t a c y c l i n . T h i s i s i n c o n t r a s t to k a l l i k r e i n - k i n i n and PGE which are mainly a s s o c i a t e d with the u r i n a r y and i n t e r s t i t i a l compartments. Thus, the presence o f p r o s t a g l a n d i n synthetase w i t h i n one or more c e l l u l a r elements l i n i n g the u r i n a r y compartment, p a r t i c u l a r l y the d i s t a l nephron and c o l l e c t i n g ducts (22), f a c i l i t a t e s the i n t e r a c t i o n o f p r o s t a glandins with k i n i n s and ADH. For example, entry o f k a l l i k r e i n i n t o the d i s t a l tubules, and subsequent formation o f k i n i n s , r e s u l t s i n r e l e a s e o f one or more prostaglandins by k i n i n s from s i t e s o f p r o s t a g l a n d i n generation along the c o l l e c t i n g ducts. I n h i b i t i o n o f the e f f e c t s o f ADH can occur, then, i n response to the kinin-mediated generation o f prostaglandins i n the d i s t a l nephron; t h i s r e s u l t s i n the e x c r e t i o n o f s o l u t e - f r e e water. A recent study by Weber et a l (J36) i n d i c a t e s that the a c t i v i t y o f a major p r o s t a g l a n d i n metabolizing enzyme (37), PGE-9-ketoreductase, which converts PGE t o PGF , i s i n f l u e n c e d by s a l t i n t a k e . Thus, reabsorption o f water i s f a c i l i t a t e d by increased a c t i v i t y of t h i s enzyme, which has the e f f e c t o f lowering l e v e l s o f PGE i n t r a r e n a l l y by f a v o r i n g formation o f P G F . As P G F , u n l i k e PGE , does not i n h i b i t ADH, increased a c t i v i t y o f PGE-9-ketoreductase w i l l f a c i l i t a t e reabsorption i n water. The "loop d i u r e t i c " agents have already been noted to be capable o f i n h i b i t i n g the a c t i v i t y o f t h i s enzyme. I t should be noted that k i n i n s , i n a d d i t i o n to promoting p r o s t a g l a n d i n s y n t h e s i s , are a l s o capable o f i n c r e a s i n g the a c t i v i t y o f PGE-9-ketoreductase (38), and that these e f f e c t s may be c r u c i a l to the a b i l i t y o f k i n i n s to a l t e r e x c r e t i o n o f s o l u t e - f r e e water as a f f e c t e d by the s t a t e o f sodium balance. As i n h i b i t i o n o f p r o s t a g l a n d i n synt h e s i s has been shown to prevent increased f r e e water generation induced by b r a d y k i n i n (39), a p r o s t a g l a n d i n mechanism appears t o be necessary f o r t h i s e f f e c t o f the k i n i n (Figure 1). 2


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The concept o f segregation o f cyclooxygenases w i t h i n s e v e r a l f u n c t i o n a l compartments o f the kidney and d i f f e r e n t p r o s t a glandins a r i s i n g from these compartments i s u s e f u l f o r



Metabolism of arachidonic acid by the prostaglandin synthetase complex. t

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Major products of vascular tissues are prostacyclin (PGI ) and PGE ; a major product of blood platelets is thromboxane A

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i n t e r p r e t i n g the v a r i a b l e e f f e c t s of one or more p r o s t a g l a n d i n mechanisms on s a l t e x c r e t i o n . The n a t r i u r e t i c e f f e c t of e i t h e r the p r i n c i p a l r e n a l p r o s t a g l a n d i n , PGEp, or i t s precursor, a r a c h i d o n i c a c i d , cannot be d i s s o c i a t e d e a s i l y from i t s e f f e c t s on the r e n a l c i r c u l a t i o n . In the only i n vivo study which examined the e f f e c t of PGE on t u b u l a r f u n c t i o n uncomplicated by v a s c u l a r e f f e c t s , Kauker, u s i n g m i c r o - i n j e c t i o n techniques, demonstrated that i n t r a l u m i n a l i n j e c t i o n o f PGEp i n r a t s r e s u l t e d i n i n h i b i t i o n of sodium r e a b s o r p t i o n (40). F u r t h e r , Stokes and Kokko demonstrated an i n h i b i t o r y e f f e c t o f PGE on sodium t r a n s port i n i s o l a t e d perfused r e n a l c o l l e c t i n g tubules of r a b b i t s p r e t r e a t e d with m i n e r a l o c o r t i c o i d s (41). In conscious r a t s , N a s j l e t t i et a l (20) demonstrated that m i n e r a l o c o r t i c o i d t r e a t ment not only increased k a l l i k r e i n e x c r e t i o n , but a l s o enhanced e x c r e t i o n of PGEp by two- to t h r e e - f o l d . Augmented e x c r e t i o n o f k a l l i k r e i n and PGE i n these r a t s was a s s o c i a t e d with escape from the s a l t and water r e t a i n i n g e f f e c t s of m i n e r a l o c o r t i c o i d s . In the r a t , i n h i b i t i o n of p r o s t a g l a n d i n s y n t h e s i s a l s o r e s u l t s i n i n c r e a s e d concentration of sodium c h l o r i d e i n the r e n a l medulla (42). The l a t t e r suggests that exaggerated t u b u l a r r e a b s o r p t i o n of sodium i n the ascending limb of the loop of Henle r e s u l t s from e l i m i n a t i n g a p r o s t a g l a n d i n mechanism which promotes s a l t excret i o n . On the other hand, i n the conscious dog undergoing a water-induced d i u r e s i s , both indomethacin and meclofenamate have been reported to increase sodium e x c r e t i o n (43). A possible p r o s t a g l a n d i n mechanism which prevents demonstration of the d i r e c t n a t r i u r e t i c a c t i o n of b r a d y k i n i n was described by McGiff et a l i n the blood-perfused i s o l a t e d canine kidney (39). Thus, a n a t r i u r e t i c a c t i o n of b r a d y k i n i n was not shown u n t i l p r o s t a g l a n d i n s y n t h e s i s was i n h i b i t e d by indomethacin. These seemingly d i s c r e p a n t s t u d i e s may be r e c o n c i l e d i f i t i s recognized that the experimental c o n d i t i o n s determine not only the l e v e l of p r o s t a g l a n d i n a c t i v i t y , but a l s o the major s p e c i e s of p r o s t a g l a n d i n s produced w i t h i n the u r i n a r y compartment. As these vary, the e f f e c t s o f indomethacin, which a l s o a l t e r s p r o s t a g l a n d i n metabol i z i n g enzymes (13), w i l l depend on the l e v e l and p r o f i l e of prostaglandins produced under a given set of c o n d i t i o n s . T h i s , i n t u r n , i s r e l a t e d to the s t a t e of s a l t and water balance, the degree of s t r e s s occasioned by a n e s t h e s i a and surgery, the a c t i v i t y of other hormonal systems, the " i n t r i n s i c " a c t i v i t y o f the cyclooxygenase as determined by n a t u r a l i n h i b i t o r s and a c t i v a t o r s , and, f i n a l l y , the s p e c i e s being s t u d i e d . These general c o n s i d e r a t i o n s f o r c e the c o n c l u s i o n that the products of cyclooxygenases i n the v a r i o u s compartments w i t h i n the kidney may vary with experimental c o n d i t i o n s , as w e l l as i n h e a l t h and i n d i s e a s e . For example, thromboxane, a powerful vasoconstrictor; i s not normally synthesized by the kidney. However, when r e n a l f u n c t i o n i s d i s t u r b e d , as by acute u r e t e r a l l i g a t i o n , thromboxane s y n t h e s i s may occur (44). I t s production may c o n t r i b u t e to the l a t e i n c r e a s e i n r e n a l v a s c u l a r r e s i s t a n c e i n response to 2


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ureteral obstruction (45 ). Changes in extracellular potassium concentration can also affect renal prostaglandin synthesis (46 ). As urinary k a l l i k r e i n concentrations have been positively correlated with excretion of potassium, but not sodium (47), the possibility of a potassiumdependent interaction of prostaglandins with kallikrein-kinins should be considered. Thus, induction of potassium deficiency has been shown to result i n enhanced renal prostaglandin synthesis (48). Hyposthenuria associated with potassium deficiency, then, may be related to inhibition of the effects of ADH (23) consequent to increased production of PGE^ or a related prostaglandin. SUMMARY Those diuretic agents such as furosemide which have as their primary sites of action the ascending limb of the loop of Henle and the cortical collecting ducts, where they have a primary effect on chloride transport (j\9), can be shown to have major effects not only on the renin-angiotensin system (6), but also on the k a l l i k r e i n - k i n i n (50) and prostaglandin systems (13). There i s evidence suggesting that their diuretic action may be related partially to an effect on the vasodilator-diuretic system of the kidney, the kallikrein-kinin-prostaglandin system. Thus, aspirin-like compounds have been shown to blunt the diuretic action of furosemide (j51), although this effect of antiinflammatory acids is complicated by their inhibition of the organic acid secretory system. Integrity of the latter may be required for access of these diuretic agents to their active sites. Further, furosemide and ethacrynic acid have been shown to inhibit two of the major prostaglandin catabolizing enzymes, prostaglandin-15-hydroxydehydrogenase and PGE-9-ketoreductase (13). Their effects on these enzymes may result in increased levels of PGE and PGI which may then contribute to vasodilator-diuretic mechanisms. The design of agents which have major effects on prostaglandin metabolism is well underway and has already resulted in novel diuretic agents (52). Acknowledgments - We thank Mrs. Cathy Reynolds and Mrs. Sue Hatton for assistance in typing the manuscript. This study was supported by USPHS Grants HL-18845 and HL-22075 and American Heart Association Grant 77-987. Literature Cited 1. Änggard, Ε . , Bohman, S. O., G r i f f i n , J . Ε., III, Larsson, C., and Maunsbach, A. B . , Acta Physiol. Scand. (1972), 84, 231-246. 2. Olsen, U. B . , Acta Pharmacol. Toxicol. (1977), 41, 1-31. 3. McGiff, J . C., Crowshaw, Κ., Terragno, Ν. Α . , and Lonigro, Α . , Nature (1970), 227, 1255-1257. 4. Vatner, S. F., J . C l i n . Invest. (1974), 54, 225-235. 5. Terragno, Ν. Α . , Terragno, D. A. and McGiff, J . C. Circ. Res. (1977), 40, 590-595. 2

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6. B a i l i e , M.D., Davis, L . E . and Loutzenhiser, R . , Am. J . Physiol (1973), 224, 425-430. 7. Itskovitz, H. D . , Terragno, N. A. and McGiff, J. C . , Circ. Res. (1974), 34, 770-776. 8. Chang, L . C. T., Splawinski, J . Α . , Oates, J. A. and Nies, A. S., C i r c . Res. (1975), 36, 204-207. 9. Larsson, C. and Änggard, E., Eur. J. Pharmacol. (1974), 21, 30-36. 10. Terragno, Ν. Α . , McGiff, J. C. and Terragno, Α . , C l i n . Res. (1978), 26, 545A (abstract). 11. Fourman, J. and Moffat, D. B . , "Blood Vessels of the Kidney", p. 58, Oxford, Blackwell Scientific Publications, Oxford, England, 1971. 12. Nanra, R. S., Chirawong, P. and Kincaid-Smith, P . , Aust. N. Z. Med. (1973), 3, 580-586. 13. Stone, K. J. and Hart, Μ., Prostaglandins (1976), 12, 197-207. 14. Itskovitz, H. D . , Stemper, J., Pacholczyk, D. and McGiff, J. C., C l i n . S c i . (1973), 45, 321s-324s. 15. B e i l i n , L . J. and Bhattacharya, J., J. Physiol. (1977), 269, 395-405. 16. Papanicolaou, N . , Safar, Μ., Hornych, Α . , Fontaliran, F., Weiss, Υ . , Bariety, J. and M i l l i e z , P . , C l i n . S c i . Molec. Med. (1975), 49, 459-463. 17. Olsen, U. B. and Ahnfelt-Ronne, I . Acta Physiol. Scand. (1976), 97, 251-257. 18. Itskovitz, H. and McGiff, J. C., Circ. Res. (1974), 34-35, (Suppl I ) , 65-73. 19. Wennmalm, Α . , IRCS (1974), 2, 1099. 20. Nasjletti, Α . , McGiff, J . C. and Colina-Chourio, J., Circ. Res., i n press. 21. Pong, S. S. and Levine, L., J. Pharmacol. Exp. Ther. (1976), 196-197, 226-230. 22. Smith, W. L . and Wilkin, G. P . , Prostaglandins (1977), 13, 873-892. 23. Grantham, J. J. and Orloff, J., J. C l i n . Invest. (1968), 47, 1154-1161. 24. Berl, P . , Raz, Α . , Wald, H . , Horowitz, J. and Czaczkes, W., Am. J. Physiol. (1977), 232, F529-F537. 25. Weber, P. C., Scherer, B. and Larsson, C., Eur. J . Pharmacol. (1977), 41, 329-332. 26. Hassid, A. and Levine, L., Prostaglandins (1977), 13, 503-516. 27. Wong, P. Y - K . , Sun, F . F . and McGiff, J . C., J. B i o l . Chem. (1978), i n press. 28. Larsson, C., Weber, P. and Änggard, E., Eur. J. Pharmacol. (1974), 28, 391-394. 29. Gerber, J. G . , Branch, R. Α . , Nies, A. S., Gerkens, J. F., Shand, D. G . , H o l l i f i e l d , J. and Oates, J. Α . , Prostaglandins (1978), 15, 81-88.



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30. Terragno, D. Α . , Crowshaw, K., Terragno, N. A. and McGiff, J. C . , C i r c . Res. (1975), 36-37, (Suppl I ) , 76-80. 31. McGiff, J. C., Terragno, Ν. Α . , Strand, J. C., Lee, J. B . , Lonigro, A. J. and Ng, Κ. K. F., Nature (1969), 223, 742-745. 32. F r o l i c h , J. C., Sweetman, B. J., Carr, Κ., H o l l i f i e l d , J. W. and Oates, J. Α . , Prostaglandins (1975), 10, 185-195. 33. Armstrong, J. Μ., Lattimer, N . , Moncada, S. and Vane, J. R . , Br. J. Pharmac. (1978), 62, 125-130. 34. Moncada, S., Gryglewski, R. J., Bunting, S. and Vane, J. R., Prostaglandins (1976), 12, 715-737. 35. Carretero, O. A. and Scicli, A. G . , Fed. Proc. (1976), 35, 194-198. 36. Weber, P. C., Larsson, C. and Scherer, B . , Nature (1977), 266, 65-66. 37. Leslie, C. A. and Levine, L., Biochem. Biophys. Res. Commun. (1973), 52, 717-724. 38. Wong, P. Y-K, Terragno, D. Α . , Terragno, N. A. and McGiff, J. C., Prostaglandins (1977), 13, 1113-1125. 39. McGiff, J. C., Itskovitz, H. D. and Terragno, Ν. Α . , C l i n . S c i . Molec. Med. (1975), 49, 125-131. 40. Kauker, M. L., Proc. Soc. Exp. B i o l . Med. (1977), 154, 272-277. 41. Stokes, J. B. and Kokko, J. P . , J. C l i n . Invest. (1977), 59, 1099-1104. 42. Ganguli, M . , Tobian, L., Azar, S. and O'Donnell, Μ., Circ. Res. (1977), 40, (Suppl I ) , 135-139. 43. Kirschenbaum, M. A. and Stein, J. Η . , J. C l i n . Invest. (1976), 57, 517-521. 44. Morrison, Α . , Nishikawa, K. and Needleman, P . , Nature (1977), 267, 259-260. 45. Yarger, W. E . and G r i f f i t h , L . D . , Am. J. Physiol. (1974), 227, 816-826. 46. Zusman, R. M. and Reiser, H. R., J. C l i n . Invest. (1977), 60, 215-223. 47. Zinner, S. H., Margolius, H. S., Rosner, B . , Reiser, H. R. and Kass, Ε. H., Am. J. Epidem. (1976), 104, 124-132. 48. Galvez, O. G . , Bay, W. H., Roberts, B. W. and F e r r i s , R. F., Circ. Res. (1977), 40, (Suppl 9), 11-16. 49. Rocha, A. S. and Rokko, J. P . , J. C l i n . Invest. (1973), 52, 612-623. 50. Croxatto, H. R., Roblero, J. S., Garcia, R. L., Corthorn, J. H. and San Martin, M . , Acta Physiol. Latino Am. (1973), 22-23, 556-558. 51. Lee, J. B . , Proc. 6th Int. Congr. Nephrol. (1975), 1, 348-354. 52. Cragoe, E . J., Jr., Schultz, Ε. Μ., Schneeberg, J. D . , Stokker, G. E., Woltersdorf, O. W., Jr., F a n e l l i , G. Μ., Jr., and Watson, L . S., J. Med. Chem. (1975), 18, 225-228. RECEIVED

August 21, 1978.


Diuretic Agents - ACS Publications - American Chemical Society

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