Increased Renin Release Research Articles

Renal responses to mental stress and epinephrine in humans.

Renal blood flow, renal sympathetic nerve activity, and renin release responses to mental stress (Stroop's color-word conflict test; CWT) and intravenously infused epinephrine (Epi) were evaluated in 12 healthy volunteers. The overflows of norepinephrine (NE) and dopamine (DA) to renal venous plasma were measured as indexes of nerve activity; the fractional extraction of Epi was used to assess renal catecholamine extraction from arterial plasma. At rest, NE and DA levels were higher in renal venous plasma than in arterial plasma. Arterial Epi levels were 0.26 +/- 0.04 nmol/l, and the fractional extraction of Epi by the kidney was 46 +/- 4%. CWT increased renal vascular resistance (RVR) by 48%, renal venous NE overflow by 214% (to 708 +/- 79 pmol/min), and DA overflow by 42% (to 34 +/- 4 pmol/min). Arterial Epi increased by 197%. The vasoconstrictor response was correlated with the NE overflow response. The increased renin release (from 75 to 247 U/min, median values; P less than 0.001) was correlated to increases in mean arterial pressure and NE and DA overflows. Epi infusion increased arterial plasma Epi and renin release dose dependently to 6.43 +/- 0.27 nmol/l and by 664%, respectively. RVR and NE and DA overflows were unchanged. Renal venous DA data support the existence of a subset of renal dopaminergic nerves. Mental stress causes renal vasoconstriction, apparently due to increased renal sympathetic nerve activity. Physiological increments of circulating Epi do not affect renal blood flow but enhance renin release markedly without apparent activation of the renal nerves in humans.

Angiotensin converting enzyme inhibition and renin release from the kidney

Experiments were performed in anaesthetized cats, to determine whether renal nerves interfere with the negative feedback action of angiotensin II (Ang II) on renin release. The increase in renin release from the innervated kidney in response to captopril-induced inhibition of Ang II generation was compared with the response of the contralateral denervated kidney. Renin release was measured before (control), and 5, 15 and 30 min after the beginning of captopril infusion (1 mg/kg priming dose followed by 1 mg/kg per h for 30 min intravenously), and 60 min after the end of the infusion. During the captopril treatment renin release from both kidneys increased, but after 15 and 30 min the increase in renin release from the innervated kidneys was significantly larger than that observed in the denervated kidneys. After the captopril infusion was stopped, renin release from both kidneys returned towards control values. These results could not be explained on the basis of the changes in renal haemodynamics, excretory functions and efferent renal nerve activity observed during the captopril infusion. The data suggest that the renal nerves influence the changes in renin release caused by captopril by increasing the sensitivity of juxtaglomerular cells to the negative feedback action of Ang II.

Inhibitory Role of Ca2+ in the Control of Renin Secretion: A Study Using Supervised Dispersed Rat Renal Cortical Cells

1. The role of Ca2+ in the control of renin release was investigated using a collagenase-dispersed rat kidney cortex cell preparation. 2. Superfusion with a series of low [Ca2+] buffers in either ascending or descending order of concentration increased renin release. Exposure to 0.06 mmol/l Ca2+ increased release by 120% (P less than 0.001) when presented as the first buffer in ascending order of concentration and by 79% (P less than 0.001) when presented as the fourth and last in a series of descending order. 3. The Ca2+ entry blocking drug diltiazem in a range of concentrations increased renin release and at 10(-5) mol/l diltiazem the mean stimulation was 35% (P less than 0.01). 4. 8-(N.N-Diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) reduces the release of Ca2+ from intracellular stores and, studied over a range of concentrations, this compound increased renin release. At 10(-5) mol/l TMB-8 the mean increase was 44% (P less than 0.001). 5. None of these experimental manipulations, low [Ca2+], diltiazem or TMB-8, had any effect on the release of adenosine 3':5'-cyclic monophosphate into the cell superfusate, indicating that a decrease in intracellular [Ca2+] increases renin release by a mechanism which is independent of changes in adenosine 3':5'-cyclic monophosphate production. 6. Effects of low [Ca2+], diltiazem and TMB-8 on renin secretion were all shown to be reversible when superfusion with control buffer was resumed.

Kidney renin gene expression in spontaneously hypertensive rats

We studied the expression of kidney renin gene in hypertensive animals by measuring the kidney renin messenger (m) RNA. The kidney renin mRNA was quantified by densitometric Northern blot analysis using a 32P-labelled rat renin genomic DNA fragment as a hybridization probe. Spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) were treated with a low-sodium diet plus furosemide, captopril or propranolol for a week. Plasma renin activity (PRA) in SHR and WKY was increased similarly by sodium depletion and by treatment with captopril. PRA in both strains was not decreased significantly by treatment with propranolol. Both sodium depletion and captopril treatment caused significant increases in the kidney renin mRNA in SHR and WKY. However, the increases in the kidney renin mRNA of SHR were greater than those in the corresponding WKY (SHR, 10.0- and 22.1-fold increases; WKY, 6.2- and 7.8-fold increases, respectively). Propranolol had no effect on the kidney renin gene expression in either WKY or SHR. These results indicate that SHR show an enhanced expression of the renin gene in the kidney compared with WKY in response to stimuli that increase renin release.

The effect of theophylline and cyclic adenosine 3,5-monophosphate on renin release by afferent arterioles

The effects of theophylline and cyclic adenosine 3',5'-monophosphate (cAMP) on renin release by afferent arterioles were studied. Rabbit afferent arterioles (seven to 10), obtained by a microdissection technique, were incubated for three consecutive 20 min periods in 100 microliters of Medium 199 with 0.1% bovine serum albumin (BSA). Afferent arterioles exposed to theophylline, 1 x 10(-4) mol/l, produced a greater than 100% increase in renin release (0.18 +/- 0.04 to 0.42 +/- 0.05 ng angiotensin l/h per arteriole per h incubation). The renin release stimulated by theophylline was completely abolished by indomethacin and meclofenamate. The stimulation of renin secretion was also blocked when extracellular calcium concentration was decreased to 10(-7) mol/l and the arterioles were permeabilized with calcium ionophore. Dibutyryl cAMP (db-cAMP), 1 x 10(-4) mol/l, and forskolin, 1 mumol/l or 100 mumol/l, failed to stimulate renin release by afferent arterioles. The results of this study therefore suggest that theophylline-stimulated renin release may be mediated through a prostaglandin pathway. The stimulation of renin secretion is also dependent on the extracellular concentration of calcium.

Effect of prostanoids on renin release from rabbit afferent arterioles with and without macula densa

There is evidence that cyclooxygenase products of arachidonic acid participate in the control of renin release. In this study we tested the hypothesis that prostaglandin (PG) I2 and/or its metabolite(s), which are synthesized in the afferent arteriole (AF), stimulate renin release by acting directly on the AF while PGE2 stimulates renin release indirectly via the macula densa. AF alone and AF with macula densa attached (AF-MD) were microdissected from rabbit kidneys and incubated in vitro. The renin release rate from a single AF (or an AF-MD) was calculated and expressed as ng AI.hr-1. AF-1/hr (where AI is angiotensin I). When arachidonic acid (0.12 mM) or PGI2 (10 microM) was added to AF, renin release increased significantly (P less than 0.0001) from 1.04 +/- 0.21 to 3.12 +/- 0.86 (x +/- SEM, N = 7), and from 0.45 +/- 0.14 to 1.48 +/- 0.53 (N = 9), respectively. During the recovery period, renin release increased even further, reaching 9.53 +/- 1.76 and 4.50 +/- 1.24, respectively. A PGI2 synthetase inhibitor, 9, 11-azoprosta-5,13-dienoic acid blocked the effect of arachidonic acid. To examine whether the increases in renin release during the recovery period were due to metabolite(s) of PGI2, we tested the effect of both 6-keto-PGE1 (an active metabolite of PGI2) and carba-PGI2 (a synthetic analog that is metabolized differently from PGI2). Six-keto-PGE1 and carba-PGI2 increased renin release only during the experimental period with no further increase during the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural control of renin release.

Among the major mechanisms controlling the renal release of renin, renal nerves are known to exert a direct stimulating action on juxtaglomerular cells that is mediated by beta-adrenoceptors. Activation of the renal nerves also exerts an important permissive role in order to amplify and possibly accelerate responses to stimuli affecting the vascular and macula densa mechanisms. Reduction of renal perfusion pressure, intravenous infusion of furosemide, and captopril administration cause a greater increase in renin release from innervated kidneys than from denervated kidneys. A complex interaction between neural and non-neural mechanisms in the control of renin secretion is suggested. Efferent renal nerve activity controlling the renin secretion rate is mainly under the inhibitory influence of vagal afferent fibers originating from the cardiopulmonary region. Recent experiments have demonstrated that a similar reflex tonic inhibition of renin secretion is also exerted by renal afferent fibers.

Stimulatory effects of neuronally released norepinephrine on renin release in vitro.

Extracellular high potassium inhibits renin release in vitro by increasing calcium concentrations in the juxtaglomerular cells. We found that the decreased response of renin release from rat kidney cortical slices in high potassium solution (20-80 mM) changed to a strikingly increased one in the presence of nifedipine at doses over 10(-6) M. We then examined the stimulatory effect of extracellular high potassium in the presence of nifedipine on renin release. The enhancement of release was significantly suppressed either by propranolol or by metoprolol but not by prazosin. High potassium plus nifedipine-induced increase in renin release was markedly attenuated by renal denervation. The enhancing effect was not observed when the slices were incubated in calcium-free medium. Divalent cations such as Cd2+, Co2+, and Mn2+ (0.1-3.0 mM) blocked this enhancement in a concentration-dependent manner. High potassium elicited an increase in 3H efflux from the slices preloaded with [3H]norepinephrine. The increasing effect was not influenced by nifedipine but was abolished by the removal of extracellular calcium or by the addition of divalent cations. These observations suggest to us that the high potassium plus nifedipine-induced increase in renin release from the slices is mediated by norepinephrine derived from renal sympathetic nerves and that this neuronally released norepinephrine stimulates renin release via activation of beta-adrenoceptors.

Haemodynamic regulation of renal prostaglandin and renin release.

To examine the relationship between renal release of the prostaglandins E2 (PGE2) and I2 (PGI2) and renin during autoregulatory vasodilation, experiments were performed in anaesthetized dogs with denervated kidneys. Autoregulatory vasodilation was induced by reducing renal arterial pressure (RAP) or by raising ureteral pressure in steps. During progressive renal arterial constriction, PGE2 and PGI2 release reached maximal values (10.6 +/- 1.7 for PGE2 and 6.6 +/- 1.1 pmol min-1 for PGI2 release) at RAP of 70-80 mmHg, associated with almost no increase in renin release. By further reduction of RAP, prostaglandin release was not significantly altered, whereas renin release reached maximal values (18.7 +/- 2.4 micrograms AI min-1) when autoregulatory vasodilation was complete at RAP below 55-60 mmHg. During progressive elevation of ureteral pressure, the release of PGE2, PGI2 and renin increased in concert in a curvilinear fashion, reaching maximal values at a ureteral pressure of 85 mmHg. There was no further increase during ureteral occlusion and the plateau values averaged 23.6 +/- 3.7 pmol min-1 for PGE2, 8.0 +/- 1.6 pmol min-1 for PGI2 and 16.6 +/- 3.4 micrograms AI min-1 for renin. We conclude that vascular dilation enhances both prostaglandin and renin release. During reduction of RAP, preglomerular arteries are dilated at higher RAP than are afferent arterioles. Release of prostaglandins synthetized in arteries consequently occurs at higher RAP than release of renin, which is not enhanced until afferent arterioles ultimately dilate at RAP approaching 60 mmHg. In contrast, elevation of ureteral pressure provides nearly uniform enhancement of prostaglandin and renin release, indicating a more uniform dilation of the whole preglomerular vascular tree.

Endothelin inhibits renin release from isolated rat glomeruli

The effect of endothelin on renin release from isolated rat glomeruli was examined. Endothelin inhibited basal renin release in a dose-dependent manner with an IC50 of 1.0 x 10(-9) M. Endothelin also inhibited renin release stimulated by isoproterenol (10(-5) M). Nifedipine (10(-5) M), a calcium channel blocker, induced an increase in renin release. Endothelin did not affect this nifedipine-induced renin release. These results suggest that endothelin inhibits renin release via a calcium entry mechanism and increases intracellular calcium.

Vasoactive intestinal peptide and renin secretion.

VIP has now been shown to produce an increase in renin release in a number of species, including humans. Our work suggests that VIP is capable of producing this effect by a direct action on the renin-secreting juxtaglomerular cells of the kidney. We have found no evidence to support the possibility that VIP produces this effect as a neurotransmitter in the kidney. In this regard, it should be noted that VIP has been identified as a cotransmitter primarily in cholinergic neurons. The kidney is thought to lack cholinergic innervation, and acetylcholine has no effect on renin secretion. We have explored two conditions where renin secretion is known to increase and found that circulating levels of VIP did not increase along with the increase in PRA. Thus, at least in hemorrhage and dietary sodium restriction, VIP does not appear to affect renin secretion through a humoral mechanism. There could be other untested situations where a humoral effect of VIP might come into play since we have shown that the whole animal is capable of increasing plasma VIP to levels that affect renin release. Studies employing recently developed VIP antagonists have the potential to determine in which physiological or pathological situations VIP contributes to the control of renin secretion. For example, in endotoxic shock, plasma levels of both VIP and PRA are significantly elevated. Could the increase in PRA be partly dependent on an action of circulating VIP?

Increased renin release by exogenous prostaglandin E1 in liver cirrhosis with and without ascites.

To evaluate the sensitivity of the renin-angiotensin-aldosterone system in patients with liver cirrhosis, prostaglandin E1 was intravenously administered at the rate of 50 micrograms/hour for two hours to the 11 control subjects and 11 patients with liver cirrhosis (6 compensated and 5 decompensated). Basal plasma renin activity (PRA) in decompensated patients was significantly higher than those in control and compensated cirrhotics (P less than 0.01). Basal plasma aldosterone was also higher in decompensated than in control and compensated patients, but without significance. PGE1 had no virtual effect on PRA in control, but stimulated PRA in liver cirrhotics, in which statistical significance was only observed in decompensated (basal vs. one hour after PGE1: 2.4 +/- 0.9 ng/ml/min (mean +/- SE) vs. 6.9 +/- 2.1: P less than 0.025). The rate of renin release was significantly higher in compensated than in decompensated (327 +/- 50% vs. 143 +/- 26: P less than 0.05). Though PGE1 also increased plasma aldosterone in liver cirrhotics, statistical change was not seen. Fractional excretion of urinary sodium after PGE1 increased significantly in control (P less than 0.025), but not in liver cirrhotics. These results indicate that the renin-angiotensin-aldosterone system is easily activated by PGE1 in patients with liver cirrhosis and further suggest that the sensitivity of this system in compensated is more augmented than in decompensated patients.

Properties of the macula densa mechanism for renin release in the dog.

To study the macula densa mechanism for renin release, both the macula densa and the haemodynamic mechanisms were activated in anaesthetized dogs with denervated kidneys, either by renal arterial constriction to a renal arterial pressure (RAP) of 52 +/- 2 mmHg or by ureteral occlusion to a ureteral pressure of 95-105 mmHg, 20-25 mmHg below RAP. Renal arterial constriction increased renin release from 0.3 +/- 0.2 to 16 +/- 4 micrograms AI min-1. At low RAP, renin release was subsequently reduced to 7 +/- 3 micrograms AI min-1 when sodium excretion was raised far above control values by plasma volume expansion and acetazolamide infusion. Ethacrynic acid (3 mg kg-1 body wt.) restored renin release to pre-expansion values, and a large dose (25 mg kg-1 body wt.) prevented renin release from falling even after unclamping the artery. During ureteral occlusion with stopped glomerular filtration, plasma volume expansion, acetazolamide and ethacrynic acid infusion did not alter renin release. On the other hand, beta-adrenergic stimulation by isoproterenol raised renin release equally (by 30-40 micrograms AI min-1) before and after plasma volume expansion, during both renal arterial constriction and ureteral occlusion. Indomethacin (10 mg kg-1 body wt.) abolished renin release induced by ethacrynic acid infusion and ureteral occlusion. We conclude that the macula densa mechanism for renin release is inactivated by high NaCl reabsorption during plasma volume expansion and acetazolamide infusion, reactivated by inhibition of NaCl reabsorption with ethacrynic acid and completely inhibited by indomethacin. The degree of activation does not influence the renin release induced by beta-adrenergic stimulation.

Effects of thromboxane synthase inhibitors on renal function.

In general the effects of thromboxane A2(TXA2) on renal function are opposite those produced by other prostanoids. TXA2 synthase inhibitors decrease the biosynthesis of TXA2 and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA2 synthase might alter renal function by reducing TXA2 production and/or increasing prostaglandin (PG) biosynthesis. This hypothesis was tested by comparing the changes in renal function induced by suprarenal aortic constriction in anesthetized dogs pretreated with either a TXA2 synthase inhibitor (UK38,485; n = 7 or OKY1581; n = 7) or vehicle (0.1 M Na2CO3; n = 9). Several renal function parameters were compared in control versus treated animals by analysis of variance. Neither UK38,485 (1 mg/kg, i.v.) nor OKY1581 (10 mg/kg, i.v.) significantly altered renal artery hypotension-induced changes in mean arterial blood pressure, heart rate, renal blood flow, renal vascular resistance, glomerular filtration, filtration fraction, urine flow rate, sodium excretion rate, fractional sodium excretion, potassium excretion, or fractional potassium excretion. However, both UK38,485 and OKY1581 seemed to attenuate the increase in renal renin secretion rate induced by suprarenal aortic constriction. We conclude that acute administration of TXA2 synthase inhibitors does not modify acute renal artery hypotension-induced changes in either electrolyte excretion or renal hemodynamics. However, acute administration of TXA2 inhibitors attenuates suprarenal aortic constriction-induced increases in renin release in anesthetized dogs by unknown mechanisms.

Influence of angiotensin II (AII) and angiotensin I (AI) on renal renin synthesis and release.

This study examined the effect of exogenous AI and AII on renin synthesis and release. AII or AII + AI were given using osmotic minipumps, over a 7 day period to rats receiving oral Enalapril. Enalapril caused a marked increase in renin release and synthesis. AII abolished the rise in plasma and renal renin observed with Enalapril. AI had no inhibitory or stimulatory effect on renin release or synthesis in rats receiving Enalapril and AII.

Plasma Angiotensin I Determines the Rate of Angiotensin II Generation Even during ACE Inhibition

After single or multiple administration of an angiotensin converting enzyme(ACE) inhibitor, plasma angiotensin(ANG) II recovers more rapidly than plasma ACE-activity. To investigate the dynamics of the biochemical changes induced by ACE inhibition, 6 normal volunteers received in a randomized order one dose of enalapril (E, 20mg), an ACE-inhibitor with a 35 hour terminal half-life, or benazepril (B, 20 mg), an ACE-inhibitor with a 23 hour terminal half-life. Biochemical effects of the 2 agents were compared at 0-4 hours and 14-30 hours after drug intake. ACE-inhibition was estimated in vivc by the ratio between plasma ANG II and blood ANG I (ANG II/ANG I) and in vitro by a radioenzymatic assay. At peak inhibition (4 hours after E, 2 hours after B), plasma ACE-activity was inhibited with E by 94% in vivo and by 98% in vitro, compared to 98% and 97%, respectively, with B. Twenty-four hours post drug, plasma ACE-activity was inhibited with E by 84% in vivo and by 83% in vitro, compared to 64% and 94%, respectively, with B. Plasma ACE-inhibition largely exceeded 24 hours and was independent of terminal half-lives. ANG II levels were initially suppressed by 88% with E and by 95% with B, but they returned to their initial values within 24 hours. Active renin measured by IRMA was increased to 183% and 313% 4 and 24 hours after E, and to 342% and 337% after B. Corresponding ANG I levels were 240% and 319% for E, and 329% and 295% for B; they were highly correlated to active renin (r=0.82, n=252, p<0.001). Thus, 24 hours post-drug, ANG II/ANG I was still reduced but the biologically effective product of the renin-angiotensin system(RAS), ANG II, has returned to its initial level, as a consequence of the increase in renin secretion and ANG I production. The RAS is reset at a time when ACE-inhibition is still effective. Feed-back increase in renin release seems to be an important factor contributing to the reappearance of ANG II in plasma in the presence of ACE-inhibition.

Vasodilators, antihypertensive therapy and the kidney

Both traditional and newer treatments of essential hypertension are discussed in relation to kidney function and renal perfusion. In essential hypertension, renal vascular resistance is routinely increased and renal blood flow is often decreased. Reduced sodium intake as a form of therapy will cause a decrease in both renal blood flow and glomerular filtration, most likely due to an angiotensin-induced renal vasoconstriction caused by the reactive increase in renin release. Treatment with diuretics produces the same effects, also angiotensin-mediated. The addition of a β-adrenergic blocking agent to prevent renin release may be a good choice, but individual agents within this class must be examined for direct renal vasoconstriction. The effects of “nonspecific” vasodilators on renal perfusion and renal sodium handling vary with the patient but may produce antinatriuresis, sodium retention and decrease in glomerular filtration. Studies with calcium antagonists have shown promising results. Nifedipine studies show a substantial increase in renal plasma flow, a well-maintained glomerular filtration rate and a brisk diuresis and natriuresis. However, patients with the lowest baseline renal flow do not show these benefits. Diltiazem has shown a potentiated renal vascular response in normotensive patients of hypertensive parents. Angiotensin converting enzyme inhibitors such as captopril and enalapril have produced increased renal blood flow and well-maintained glomerular filtration in patients with essential hypertension. The agents available for treating hypertension have improved dramatically in the past decade. A salutary effect on the kidney will remain high on the list of important characteristics to be considered in choosing one of these agents.

Effect of atrial natriuretic factor on renin release in isolated afferent arterioles

This study was designed to examine the effect of alpha-human atrial natriuretic polypeptide (alpha-hANP) on renin release in the absence of tubules, glomeruli and macula densa. Rabbit afferent arterioles were microdissected and incubated for two consecutive, 20 minute periods. Hourly renin release rate from a single arteriole was calculated. Basal renin release rate was 0.97 +/- 0.13 ng AI.hr-1.Af-1/hr (X +/- SEM, N = 18) and remained stable throughout the incubations. When afferent arterioles were exposed to alpha-hANP (0.01, 0.1 or 1 microM), renin release rate did not change significantly. Isoproterenol (5 microM) increased renin release rate from 0.92 +/- 0.28 to 1.50 +/- 0.46 ng AI.hr-1.Af-1/hr (N = 7, P less than 0.01). After pretreatment of afferent arterioles with alpha-hANP (1 microM), isoproterenol still increased renin release rate from 0.98 +/- 0.24 to 1.64 +/- 0.37 ng AI.hr-1.Af-1/hr (N = 7, P less than 0.01). The increases in renin release rate induced by isoproterenol were not different between the two groups. Pretreatment of rabbits with furosemide for two days before experiments resulted in greater basal renin release rates from microdissected afferent arterioles (1.70 +/- 0.35 ng AI.hr-1.Af-1/hr, N = 14). However, exposure to alpha-hANP (1 microM) did not alter this elevated renin release rate. It is concluded that atrial natriuretic factor may not have a direct action on juxtaglomerular cells.

Partial characterization of a renin-releasing factor from plasma and hypothalamus.

Previous studies have indicated that administration of the serotonin releaser p-chloroamphetamine HCl produces a dose-dependent increase in renin secretion through a blood-borne renin-releasing factor. The present studies were designed to partially characterize this renin-releasing factor using an in vitro kidney slice method for the bioassay of renin-releasing activity. Plasma from p-chloroamphetamine-treated, nephrectomized rats was used to obtain the renin-releasing factor, which was fractionated by ultrafiltration into fractions of molecular weight ranges of 1000 to 5000, 5000 to 10,000, and 10,000 to 20,000. The molecular weight ranges of the renin-releasing factor was determined to be between 5000 and 10,000. Since previous studies have shown that lesions in the hypothalamus prevent the effect of p-chloroamphetamine on renin secretion, we tested whether a hypothalamic extract can release renin from kidney slices. Addition of extracts of boiled rat hypothalamic tissue to the kidney slices caused an increase in renin release. Addition of cerebellar extracts produced a smaller increase in renin release, whereas addition of pituitary extracts had no effect. Fractionation by ultrafiltration of bovine hypothalamic extract revealed that the fraction with a molecular weight range of 5000 to 10,000 possessed the highest renin-releasing ability. The 1000 to 5000 (molecular weight) fraction possessed a sizeable renin-releasing activity, but the 10,000 to 20,000 fraction had no renin-releasing activity. Both bovine hypothalamus fractions (molecular weights between 1000-5000 and 5000-10,000) and plasma fraction lost their renin-releasing activity after digestion with pronase, suggesting that the renin-releasing factor or factors are peptides. These results suggest that a renin-releasing factor originate in the hypothalamus.

Inhibition of renin release by analogues of adenosine in rabbit renal cortical slices.

Renal cortical slices obtained from male New Zealand rabbits were used to investigate the role of adenosine in the regulation of renin release. Isoproterenol produced a significant (p less than 0.01), twofold to threefold increase in renin release, that was both dose-dependent and time-dependent. Addition of either the l-phenylisopropyl or the N6-ethylcarboxamido derivative of adenosine attenuated this stimulation at concentrations as low as 10(-9) M or 10(-8) M, respectively. Higher doses of d-phenylisopropyladenosine (10(-6) M) or adenosine (10(-5) M) were necessary to significantly reduce the beta-adrenergic response (p less than 0.01). Inhibition was absent in slices preincubated with 10(-5) M 8-phenyltheophylline, a concentration that had no effect on either basal or stimulated renin release. The site of inhibition appeared to be distal to beta-adrenergic and prostaglandin receptors since l-phenylisopropyladenosine (10(-8) M) blocked stimulation by selective beta-adrenergic receptor agonists, prenalterol (10(-6) M) or salbutamol (10(-5) M), and by prostaglandin E1. These data suggest that adenosine and its analogues inhibit renin release and that this inhibition may be mediated by a receptor-dependent action on a common point in the pathway leading to release.