hyperalbuminaemia. However, other mechanisms may explain the hyperalbuminaemia-induced

Transcription

1 J. Physaol. (1980), 299, pp With 3 text-figurew Printed in Great Britain INFLUENCE OF RAISING ALBUMIN CONCENTRATION ON RENIN RELEASE IN ISOLATED PERFUSED RAT KIDNEYS BY JOHN C. S. FRAY AND ANTHONY S. KARUZA From the Department of Physiology, School of Medicine, University of California, San Francisco, California 94143, U.S.A. (Received 15 February 1979) SUMMARY 1. Experiments were conducted in isolated perfused rat kidneys to determine the effect of raising perfusate albumin concentration on renin release. 2. Raising albumin concentration in the perfusion fluid from 20 g/l. to 60 g/l. (high albumin concentration) increased renin release and renal perfusate flow rate. The effect was reversible. 3. Ureteral occlusion did not prevent the rise in renin release and renal perfusate flow induced by high albumin concentration. 4. Propranolol (0.28 mm) did not block the renin release stimulated by high albumin concentration, but it inhibited the release stimulated by isoprenaline (2.43 FM). 5. Clonidine (10 /LM) and oxymetazoline (10 lzm) constricted the renal vasculature and stimulated renin release during high perfusate albumin concentration providing perfusion pressure was kept constant. 6. Low renal perfusion pressure (50 mmhg) and isoprenaline (2.43 /sm) stimulated renin release in perfusion experiments with both 20 and 60 g/l., but the rate of renin release was substantially greater with 60 g/l. 7. On the other hand, perfusion fluid deprived of calcium induced a greater increase in renin release in kidneys perfused with 20 g/l. than in those with 60 g/l. 8. We conclude that high albumin concentration stimulates renin release in isolated perfused rat kidneys by a mechanism which does not involve the renal nerve, direct renal vasodilation or sodium excretion. High albumin concentration may increase the sensitivity of the kidney to acute stimulation by a mechanism involving calcium. INTRODUCTION Raising albumin concentration in plasma increases renin release in dogs, but the mechanism has not been determined. Hall & Guyton (1976) have suggested that the increased renin release is mediated by a macula densa mechanism sensitive to tubular sodium. Their conclusion is based on the lowered sodium excretion observed during hyperalbuminaemia. However, other mechanisms may explain the hyperalbuminaemia-induced renin release, and these have not been excluded with certainty. For example, renal afferent arteriolar dilation is associated with dextran, and presumably Mail reprint request to: Dr John C. S. Fray, Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts, /80/ $07.50 A) 1980 The Physiological Society

2 46 J. C. S. FRA Y AND A. S. KARUSA albumin, infusion (Navar, Baer, Wallace & McDaniel, 1971), and afferent arteriolar dilation has been suggested to stimulate renin release (Eide, Loyning & KMil, 1973; Eide, Loyning, Langard & Kiil, 1977; Kiil, 1975). Catecholamine secretion from the renal nerves may be responsible since hyperalbuminaemia alters catecholamine secretion (Faucheux, Buu & Kuchel, 1977), an important stimulus for renin release (Davis & Freeman, 1976). Furthermore, raising albumin concentration increases the sensitivity of the renal vascular smooth muscles to vasoconstrictor drugs (Bullivant, 1978 b); thus raising plasma albumin concentration might also increase the sensitivity of the juxtaglomerular apparatus to acute stimulation. This last possibility is especially interesting since it has been shown that the juxtaglomerular apparatus regulates its secretary activity by altering the sensitivity of the release mechanism to acute stimulation (Fray, 1978a; Lopez, Reid, Rose & Ganong, 1978). These studies were designed to test these possibilities. First, if vasodilation is the haemodynamic stimulus for renin release in general, and for the hyperalbuminaemiainduced renin release in particular, then pharmacologically induced vasoconstriction should inhibit the renin release induced by high albumin. Secondly, catecholamines stimulate renin release by a,-adrenergic mechanism (Ganong, 1972; Davis & Freeman, 1976); thus if hyperalbuminaemia-induced renin release is mediated by catecholamines secreted from the nerve terminals at the juxtaglomerdilar apparatus, then propranolol should block its effect. Thirdly, the juxtaglomerular apparatus can alter the sensitivity of its release mechanism (Fray, 1978a; Fray & Mayer, 1977; Lopez et al. 1978); if the sensitivity is increased, then low renal perfusion pressure and isoprenaline infusion should stimulate a greater rate of renin release during high albumin concentration. Finally, since calcium plays a key role in the mechanism of renin release (Vandongen & Peart, 1974; Peart, 1977; Logan, Tenyi, Peart, Breathnach & Martin, 1977; Fray & Park, 1979; Fray, 1977; Park & Malvin, 1978; Lester & Rubin, 1977; Harada & Rubin, 1978), we tested to see whether removing calcium from the perfusion fluid altered the renin release induced by high albumin concentration. METHODS Male Wistar rats ( g) were maintained on a low sodium chloride intake as described previously (Fray, 1978a). The rats were kept two per cage and fed for days before the right kidneys were prepared for perfusion. Kidneys removed from sodium-deprived rats are generally more responsive to stimuli affecting renin release (Fray, 1977, 1978a; Lopez et al. 1978). The kidneys were perfused by a procedure described previously (Fray, 1976). Briefly, each rat was anaesthetized with sodium pentobarbitone (40 mg per kg, intraperitoneally) and the right kidney was exposed through a mid-line abdominal incision and a lateral extension. The ureter was cannulated (with PE 50 tubing, heated and drawn to reduce the tip diameter) in urine collection experiments only. In the ureteral occlusion experiments, the ureter was ligated before the kidney was removed. All blood vessels on and around the right renal artery were identified, tied, and cut between sutures. The abdominal aorta was cannulated, permitting perfusion fluid to flow only to the right kidney. The kidney was then transferred to a tray in a temperaturecontrolled box (37 0C) and perfused at a known pulsatile pressure and flow. The perfusion fluid consisted of bovine serum albumin (Fraction V, Powder, Miles Laboratories, Inc.) mixed with Krebs-Henseleit bicarbonate solution. Albumin concentration was either 20, 40, 60 or 80 g/l. of medium; glucose was 10 mm; the Krebs-Henseleit solution contained Na mm, K+ 4-2 mm, Ca mm, Mg mm and HCO mm. In the experiments for calciumfree perfusions, calcium was removed from the fluid without adding other ions. The perfusion fluid was stored at -40 C, and before an experiment it was thawed and poured into the perfusion

3 HIGH ALBUMIN CONCENTRATION AND RENIN RELEASE 47 apparatus; the fluid was gassed (95 % 02 and 5 % CO,) and recirculated. Pharmacological agents (isoprenaline, propranolol, clonidine, and oxymetazoline) were added directly to the perfusion system. Kidneys were perfused for at least two 10 min periods, except where indicated otherwise in Results. Mean perfusion pressure was held constant at 100 mmhg except in experiments in which it was lowered to 50 mmhg or raised to 150 mmhg. Any additional procedures are mentioned in the context of the results. At the end of each 10 min period a 1 ml. sample of perfusate was taken from the perfusion system and pipetted into a 5 ml. plastic test tube (containing ED' 'A) for determination of perfusate renin concentration. The sample was frozen until renin concentration was determined using renin-free nephrectomized dog plasma for substrate as described previously (Fray, 1976). Since the volume of the perfusion medium was kept constant and recirculated, perfusate renin concentration represented cumulative renin released from the perfused kidney each period. Renin release has been expressed as nanograms of angiotensin I per min of perfusion per g kidney tissue (ng/min per g). Note, however, that angiotensin I implies angiotensin I generated per hr of incubation at ph 7-4. Urinary sodium concentration was determined by flame photometry. Results for each set of experiments were reported as mean + s.e. Student's t test was used to assess the statistical significance of differences between any two sets of experiments during either the first or the second period (Hinchen, 1969). RESULTS Effect of raising perfusate albumin concentration Table 1 illustrates that raising albumin concentration in the perfusion fluid from 20 to 80 g/1. increased both renin release and renal perfusate flow. Both variables were stable over the two 10 min periods. However, there was no consistent correlation between renin release and perfusate flow. For example, when albumin concentration was raised from 20 to 40 g/l. renin release remained constant whereas flow increased 79 % (P < 0.05). Furthermore, when albumin concentration was raised from 40 to 60 g/l. renin release increased 53 % (P < 0.05) whereas perfusate flow remained constant (P> 0-5). Inspection of the data indicates that both renin release and renal TABLTE 1. Effect of raising perfusate albumin concentration on renin release and perfusate flow in isolated rat kidneys Period 1 Period 2 A A Albumin Renin Perfusate Renin Perfusate concentration release flow release flow g/l. ng/min per g ml./min per g ng/min per g ml./min per g 20 (n= 11) (n= 11) * (n= 11) (n= 11) Each period represents perfusion for 10 min. Values in period 2 were not significantly different from corresponding values in period 1. Values represent mean + S.E. of mean. perfusate flow were increased when albumin was raised from 20 to 60 g/l. Consequently, subsequent experiments were designed to use only 20 and 60 g/l. in an attempt to determine the mechanism of renin release during perfusion with the higher concentration of albumin (60 g/l). Table 2 indicates that, in addition to affecting renin release and renal flow, high albumin concentration significantly reduced sodium excretion. Renin release,

4 J. C. S. FRAY AND A. S. KARUZA 48 perfusate flow and sodium excretion were reversible. To test whether the rise in renin release was related to the fall in sodium excretion, additional kidneys were perfused after the ureter had been occluded. Again, raising albumin concentration stimulated renin release and increased perfusate flow (Table 2). During ureteral occlusion renal perfusate flow was lower in both 20 and 60 g/l. perfusions. TABLr 2. Effect of raising perfusate albumin concentration on renin release, perfusate flow, and sodium excretion in isolated perfused rat kidneys with the ureter cannulated or occluded Perfusion Renin Perfusate Sodium medium release flow excretion (g albumin/l.) ng/min per g ml./min per g,uequiv/min per g Ureter cannulated (n = 5) Period Period P P<0-05 P<0*001 P<O005 Period *2+ 1* n.s. n.s. n.s. Ureter occluded (n= 5) Period Period P P<0*05 P<0*01 Each period represents perfusion for 10 min. Values represent mean+ s.e. of mean. N.s. represents not significant when compared to corresponding values in period 1. Mean perfusion pressure was kept constant at 100 mmhg in all experiments. Effect of perfusion pressure, isoprenaline and propranolol Fig. 1 shows that low perfusion pressure induced a greater rate of renin release and renal perfusion flow in kidneys perfused with 60 g/l. (P < 0 05). In addition, when kidneys were prefused with 60 g/l. at 150 mmhg renin release was significantly suppressed (61P (n = 5) ng/min per g compared to control (100 mmhg) (n= 5) ng/min per g, P < 0.05). Fig. 2 indicates that, as with low perfusion pressure, isoprenaline (2.43,UM) produced a greater rate of renin release in kidneys perfused with 60 g/l. Perfusion flow during periods of control and of isoprenaline infusion was not significantly different (P > 0.05). Basal (control) renin release during 60 g/l. perfusion was not blocked by propranolol (0-28 mm) ( ng/min per g n= 6; compared to control of 94* ng/min per g n = 48); although propranolol inhibited the renin release induced by isoprenaline ( ng/min per g n= 6; compared to ng/min per g with isoprenaline alone) (see Fig. 2). These experiments indicated that, in addition to increasing basal renin release, high albumin increases the sensitivity of the kidney to acute stimulation with low perfusion pressure and isoprenaline. Effect of vasoconstriction with clonidine and oxymetazoline Renal vasodilation has been suggested as a major stimulus for renin release (Eide et al. 1973; Eide et al. 1977). Since renal perfusate flow was higher in kidneys perfused with 60 g/l., we argued that by pharmacologically lowering this flow we should also

5 HIGH ALBUMIN CONCENTRATION AND RENIN RELEASE 49 lower renin release. Fig. 3 shows that this was not the case; clonidine (10 /m) and oxymetazoline (10 /LM) produced renal vasoconstriction and stimulated, not inhibited, renin release provided renal perfusion pressure (mean) was kept constant at 100 mmhg. Perfusate flow (ml./min per g) a)w 0. C.E cn - a, (A C Uc a)- I Control Low pressure (50 mmhg) Fig. 1. Effect of low and high albumin concentration on renin release induced by low perfusion pressure (50 mmhg). Kidneys were perfused at 100 mmhg for 10 min (control) with medium containing 20 (n = 3) or 60 (n = 3) g albumin/l. and theniat:50 mmhg for an additional 10 min (low pressure). Values represent mean + S.E. of mean. Effect of removing calcium from the perfusion fluid Some of the most powerful inhibitors of renin release (angiotensin II, high perfusion pressure, and high extracellular concentrations of potassium) are only effective when calcium is present in the extracellular fluid (Vandongen & Peart, 1974; Park & Malvin, 1978; Fray & Park, 1979). In fact, when calcium is removed from the extracellular fluid, high perfusion pressure and high concentrations of potassium no longer inhibit but stimulate renin release. To test whether removing calcium from the perfusion fluid altered the renin release pattern in kidneys perfused with 20 g/l. additional kidneys were perfused. Surprisingly, in general renin release was greater in kidneys perfused with 20 g/l. (Table 3). DISCUSSION These experiments demonstrate that increasing perfusate albumin concentration stimulates renin release from isolated perfused rat kidneys. Since similar findings have been reported in anaesthetized dogs (Hall & Guyton, 1976; Humphreys, Reid,

6 50 J. C. S. FRAY AND A. S. KARUZA Perfusate flow (mi./min per g) c400.e CL ' 20g/l. 060 gl. C._ G c n=12 n6 0 No isoprenaline + Propranolol Isoprenaline + Propranolol Fig. 2. Effect of low and high albumin concentration on renin release induced by isoprenaline (2-43 /M). Kidneys were perfused for 10 min (control) with control medium containing 20 or 60 g albumin/l. and then with isoprenaline added to the medium for an additional 10 min. Values represent mean + s.e. of mean. TABLE 3. The effect of calcium removal on the sensitivity of the kidney during high albumin concentration Renin release (ng/min per g) A-o Perfusion medium 100 mmhg 50 mmhg Isoprenaline 20 g albumin/i. + OCa (n = 4) 60 g albumin/i. + OCa (n= 3) 797* Each kidney was perfused for 4-10 min periods. Period 1 served as control with either 20 or 60 g albumin/i. with 2*5 mm-ca in the medium. Renin release during this period was and ng/min per g for 20 and 60 g/l., respectively. In periods 2, 3 and 4, kidneys were perfused at 100 mmhg, 50 mmhg, or with isoprenaline (2-43 #M) at 100 mmhg. Perfusion medium during these three periods consisted of either 20 g albumin/i. without Ca or 60 g/l. without Ca. Values represent mean + S.E. of mean. Ufferman, Lieberman & Early, 1975), this establishes that the site of action and the mechanisms involved are localized within the kidney. These results also show a decreased sodium excretion associated with the increased renin release, and thus they are consistent with one of the macula densa hypotheses of renin release (Vander,

7 HIGH ALBUMIN CONCENTRATION AND BENIN RELEASE 51 Perfusate flow (ml./min per g) ± '. 4n a * 300 cm -C CD a,1 200._ C a) 100 n =48 [. -8 n Control Clonidine Oxymetazoline Fig. 3. Effect of clonidine (10 /M) and oxymetazoline (10 Hm) on renin release. Kidneys were perfused at 100 mmhg with 60 g albumin/l. medium containing clonidine or oxymetazoline. Values represent mean + S.E. of mean. 1967) which holds that hyperalbuminaemia decreases sodium concentration at the macula densa and stimulates renin release (Hall & Guyton, 1976; Humphreys et al. 1975). Since actual tubular sodium concentrations were not measured in these studies, we cannot make a conclusive statement regarding sodium concentration at the macula densa. Interestingly, however, a consistent relationship between sodium concentration at the macula densa and renin release cannot be demonstrated in isolated perfused kidneys subjected to a wide variety of stimuli (Fray, 1976, 1978b). We believe the ureteral occlusion experiments in the present studies should throw some light on the role of a macula densa mechanism. The change in rate of renin release when kidneys were switched from 20 to 60 g/l. was at least twofold whether or not the ureter was occluded (see Table 2). This suggests that the mechanism by which high concentrations of albumin stimulates renin release in the isolated perfused kidney does not involve the macula densa as a primary receptor, though the possibility that the macula densa plays a role must be considered. Recently it was observed that raising albumin concentrations alters cell membrane permeability and changes the sensitivity of the cells to vasoactive agents (Bullivant, 1978a, b; Wurzel, Bacon, Kalt & Zwiefach, 1964). Consequently, we have sought an alternative explanation for the effect of hyperalbuminaemia on the juxtaglomerular apparatus in the contexts of the other mechanisms controlling renin release. In search of such an explanation at least four possibilities deserve emphasis. The first possibility is that renal afferent arteriolar dilation has been postulated as the stimulus sensed by the intra-renal stretch receptor to trigger renin release (Eide

8 52 J. C. S. FRAY AND A. S. KARUZA et al. 1973; Eide et al. 1977; Kiil, 1975). There are four reasons why afferent arteriolar dilation may not be the stimulus effecting renin release in general and in these studies in particular. First, agents such as papaverine, acetylcholine, bradykinin, eledoisin, and prostaglandins directly dilate afferent arterioles, but only prostaglandin E2 stimulates renin release (Baer & Navar, 1969; Davis & Freeman, 1976; Osborn, Noordewier, Hook & Baile, 1978; Tagawa & Vander, 1969). Secondly, in the physiological or pathophysiological instances where the greatest increases in renin release have been observed, increased release is associated with renal vasoconstriction, not vasodilation (Davis & Freeman, 1976; Witty, Davis, Shade, Johnson & Prewitt, 1972). In fact, in such instances, vasodilation inhibits renin release (Davis & Freeman, 1976). Thirdly, the vasodilation hypothesis holds that renin release peaks when the afferent arterioles are maximally dilated (Kiil, 1975; Eide etal. 1973; Eide et al. 1977) and that the afferent arterioles dilate maximally when the ureter is totally occluded (Eide et al. 1977). Inspection of Table 1 indicates that basal renin release peaked at 60 g/l., but renal perfusion flow increased another 59 % when albumin concentration was raised further to 80 g/l. Furthermore, the 79 % increase in perfusion flow rate from 20 to 40 g/l. perfusions was not associated with an increased renin release. The fourth reason why vasodilation may not account for the increased renin release during high albumin is that vasoconstriction potentiates the response. Similar results with these vasoconstrictors have been reported by others provided the renal perfusion pressure is prevented from rising (Nolan & Reid, 1978). Taken together, these data do not support the hypothesis that vasodilation itself is the haemodynamic signal for the stretch receptor in general or the stimulus for renin release during high perfusate concentrations of albumin. The second possibility is that the renin release induced by high albumin might involve a,6-adrenergic mechanism since high perfusate albumin alters catecholamines output at nerve terminals (Faucheaux et al. 1977). Propranolol, a potent,6-adrenergic blocking drug which partially inhibited the renin release induced by isoprenaline, a,8-adrenergic agonist, had no effect on that induced by high albumin. This suggests that a f,-adrenergic mechanism was not involved. The third possibility is that high perfusate albumin concentration increases the sensitivity of the juxtaglomerular cell to acute stimulation. The sensitivity of the juxtaglomerular cell can be increased by sodium deprivation (Bunag, Page & McCubbin, 1966; Fray, 1978a; Lopez et al. 1978) and renal perfusion pressure reduction (Eide, Loyning & Kiil, 1974). In our studies, rate of renin release stimulated by low perfusion pressure and isoprenaline infusion was much greater during high albumin perfusion. This suggests that high albumin increases the sensitivity of the juxtaglomerular cell to acute haemodynamic and adrenergic stimulation. The final possibility is that extracellular calcium plays a role in the mechanism whereby high albumin stimulates renin release. Because extracellular calcium plays a key role in the mechanism of renin release and because albumin binds calcium avidly, we measured the ionized calcium concentration in the 20 and 60 g/l. perfusion fluids prepared identically. Ionized calcium concentration in the 20 and 60 g/l. fluids was 0 55 and 0-41 mm, respectively. Thus the increased renin release during perfusion with the higher albumin concentration may be explained by the lower concentration of extracellular ionized calcium. Looked at in a slightly different way, these studies

9 HIGH ALBUMIN CONCENTRATION AND RENIN RELEASE 53 might also provide important clues regarding the lower renin release observed with 20 g/l. When calcium was present in the perfusion fluid 20 g/l. inhibited renin release, whereas when calcium was absent it did not. Similar observations have been reported for the other power inhibitors of renin release, angiotensin II (Vandongen & Peart, 1974), high renal perfusion pressure (Fray & Park, 1979) and high extracellular concentrations of potassium (Fray, 1978b; Park & Malvin, 1978; Fray & Park, 1979). Since these inhibitors of renin release have been postulated to act by raising the intracellular concentration of calcium at the juxtaglomerular cell (Vandongen & Peart, 1974; Fray & Park, 1979), low perfusate albumin concentration may also act by a similar mechanism. The converse would be expected for high perfusate albumin, that is, it stimulates renin release by lowering the intracellular concentration of calcium. In summary, although high perfusate albumin concentration may stimulate renin release by a mechanism involving the macula densa, other mechanisms might be involved. These other mechanisms do not involve direct dilation of the afferent arterioles or catecholamine released from the renal nerves, but they might involve increased sensitivity of the juxtaglomerular cells. Extracellular calcium plays a role in the mechanism of renin release by high albumin concentrations. We thank Ms Anita J. Fullard and Ms Helen Hughes for their technical assistance and Ms Patti Durant for her secretarial assistance. These studies were supported at the University of California by grants from the California Heart Association and U.S. Public Health Service AM 06704, and at the University of Massachusetts Medical School by NIH grant HL REFERENCES BAER, P. G. & NAvAR, L. G. (1973). Renal vasodilation and uncoupling of blood flow and filtration rate autoregulation. Kidney Int. 4, BuILIvANT, M. (1978a). Volume changes in cells of the outer medulla during perfusion of the rat kidney. J. Phyeiol. 280, BuLLIvANT, M. (1978b). Autoregulation of plasma flow in the isolated perfused rat kidney. J. Phy8iol. 280, BUNAG, R. D., Page, I. H. & McCUBBIN, J. W. (1966). Influence of dietary sodium on stimuli causing renin release. Am. J. Phy8iol. 211, DAVIS, J. 0. & FREEMAN, R. H. (1976). Mechanisms regulating renin release. Physiol. Rev. 56, EIDE, I., LoYNING, E. & KIIL, F. (1973). Evidence of hemodynamic autoregulation of renin release. Circulation Re. 32, EIDE, I., LoYNING, E. & KIIL, F. (1974). Potentiation of renin release by combininng renal arterial constriction and f-adrenergic stimulation. Scand. J. clin. Lab. Inve8t. 34, EIDE, I., LOYNING, E., LANGARD, 0. KIIL, F. (1977). Mechanism of renin release during acute ureteral constriction in dogs. Circulation Re8. 40, FAUCHEUX, B., Buu, N. T. & KucHEL, 0. (1977). Effects of saline and albumin on plasma and urinary catecholamines in dogs. Am. J. PhySiol. 232, F FRAY, J. C. S. (1976). Stretch receptor model for renin release with evidence from perfused rat kidney. Am. J. Physiol. 231, FRAY, J. C. S. (1977). Stimulation of renin release in perfused kidney by low calcium and high magnesium. Am. J. Physiol. 232, F FRAY, J. C. S. (1978a). Mechanism of increased renin release during sodium deprivation. Am. J. Physiol. 234, F FRAY, J. C. S. (1978b). Stretch receptor control of renin release in perfused rat kidney; effect of high perfusate potassium. J. Physiol. 282, FRAY, J. C. S. & MAYER, P. V. H. (1977). Decreased plasma renin activity and renin release in rats with pheochromocytoma. Clin. Sci. 53,

10 54 J. C. S. FRAY AND A. S. KARUZA FRAY, J. C. S. & PARK, C. S. (1979). Influence of potassium, sodium, perfusion pressure, and isoprenaline on renin release induced by acute Ca deprivation. J. Phy&iol. 292, GANONG, W. F. (1972). Sympathetic effects on renin secretion: mechanism and physiological role. Adv. exp. Med. Biol. 17, HALL, J. E. & GUYTON, A. C. (1976). Changes in renal hemodynamics and renin release caused by increased plasma oncotic pressure. Am. J. Physiol. 231, HARADA, E. & Rubin, R. P. (1978). Stimulation of renin secretion and calcium efflux from the isolated perfused cat kidney by norepinephrine after prolonged calcium deprivation. J. Physiol. 274, HINCHEN, J. D. (1969). Practical Statistic8 for Chemical Re8earch. London: Methuen. HUMPHREYS, M. H., REID, I. A., UFFERMAN, R. C., LIEBERMAN, R. A. & EARLY, L. E. (1975). The relationship between sodium excretion and renin secretion by the perfused kidney. Proc. Soc. exp. Biol. Med. 150, KIIL, F. (1975). Influence of autoregulation on renin release and sodium excretion. Kidney Int. 8, S208-S218. KNOX, F. G., WILLIS, L. R., STANDHOY, J. W., SCHNEIDER, E. G., NAVAR, L. G. & OTr, C. E. (1972). Role of peritubular Starling forces in proximal reabsorption following albumin infusion. Am. J. Physiol. 223, LESTER, G. E. & RUBIN, R. P. ( 1977). The role of calcium in renin secretion from isolated perfused cat kidney. J. Physiol. 269, LOGAN, A. G., TENYI, I., PEART, W. S., BREATHNACH, A. S. & MARTIN, B. G. H. (1977). The effect of lanthanum on renin secretion and renal vasoconstriction. Proc. R. Soc. B 195, LOPEZ, G. A., REID, I. A., ROSE, J. C. & GANONG, W. F. (1978). Effect of norepinephrine on renin release and the cyclic AMP content of rat kidney slices: modification by sodium deficiency and a-adrenergic blockage. Neuroendocrinology 27, NAVAR, L. G., BAER, P. G., WALLACE, S. L. & MCDANIEL, J. K. (1971). Reduced intrarenal resistance and autoregulatory capacity after oncotic dextran. Am. J. Physiol. 221, NOLAN, P. L. & REID, I. A. (1978). Mechanism of suppression of renin secretion by clonidine in the dog. Circulation Res. 42, OSBORN, J., NOORDEWIER, B., HOOK, J. B. & BAILE, M. D. (1978). Mechanism of prostaglandin E2 stimulation of renin secretion. Proc. Soc. exp. Biol. Med. 159, PARK, C. S. & MELVIN, R. L. (1978). The role of calcium in the control of renin release. Am. J. Physiol. 234, F PEART, W. S. (1977). The kidney as an endocrine organ. Lancet il, TAGAWA, H. & VANDER, A. J. (1969). Effect of acetylcholine on renin secretion in salt-depleted dogs. Proc. Soc. exp. Biol. Med. 132, VANDER, A. J. (1967). Control of renin release. Physiol. Rev. 47, VANDONGEN, R. & PEART, W. S. (1974). Calcium dependence of the inhibitory effect of angiotensin on renin secretion in the isolated perfused kidney of the rat. Br. J. Pharmacy. 50, WITTY, R. T., DAVIS, J. O., SHADE, R. E., JOHNSON, J. A. & PREWITT, R. L. (1972). Mechanisms regulating renin release in dogs with thoracic caval constriction. Circulation Re". 31, WURZEL, M., BACON, R. C., KALT, R. B. & ZWIEFACH, B. W. (1964). Vasoactive properties of plasma protein fractions. Am. J. Physiol. 206,