Rat atrial natriuretic factor stimulates renin release from renal cortical slices

We investigated the effect of synthetic rat atrial natriuretic factor (ANF) on renin release from rat renal cortical slices. Rat ANF (10(-6) M) increased renin release from the slices with a concomitant increase in the levels of cGMP contents. The increase in cGMP was also prominent in the case of incubation with 10(-4) M sodium nitroprusside but was not accompanied by an enhanced release renin. 8-Bromo-cGMP did not stimulate renin release. We propose that the stimulation of renin release from rat renal cortical slices is not related to an increase in endogenous cGMP.     

Hemodynamic effects of alpha-human atrial natriuretic peptide in healthy volunteers

The hemodynamic effects of synthetic alpha-human atrial natriuretic peptide (alpha-hANP) were evaluated in a double-blind, placebo-controlled study with echocardiography and systolic time intervals in 11 healthy volunteers. During an infusion of alpha-hANP for 30 min, when plasma ANP concentration increased to a peak level of approximately 300 pg/ml, an increase occurred in diuresis (+174%, p less than 0.01 vs. placebo) and natriuresis (+148%, p less than 0.05). Heart rate increased (+10%, p less than 0.05), but the mean arterial pressure remained unchanged. The left ventricular end-diastolic diameter was reduced (-3%, p less than 0.01), as was the left ventricular end-systolic diameter (-11%, p less than 0.001). Total peripheral resistance (-12%, p less than 0.05) and midsystolic circumferential wall stress (-16%, p less than 0.05) decreased, while cardiac output increased (+15%, p less than 0.05), as did fractional shortening (+15%, p less than 0.001). Within 30 min postinfusion, all differences between the ANP and placebo treatments had disappeared. No significant difference between the treatments was observed in preejection period or preejection period/left ventricular ejection time ratio. In conclusion, when administered as a short infusion, alpha-hANP causes peripheral arterial vasodilation and thus, by reducing left ventricular afterload, improves the pump function of the heart. Venous vasodilating effect of alpha-hANP may contribute to the decrease in left ventricular preload, but a diuresis-induced reduction in circulating intravascular volume may also be influenced.     

Plasma immunoreactive atrial natriuretic peptide levels after subcutaneous alpha-hANP injection in normal humans

The plasma hormone and urine effects of 100 micrograms of alpha-human atrial natriuretic peptide (alpha-hANP) given by subcutaneous (s.c.) injection, were studied in eight healthy male volunteers. A control s.c. injection was administered on a separate day, and the study was single-blind. The peak immunoreactive atrial natriuretic peptide (IR-ANP) level of 29.4 +/- 4.4 pmol/L reached at 5 min was threefold higher than on the control day. Area under the IR-ANP response curve was approximately 1/32 of that after the same dose of alpha-hANP given by intravenous (i.v.) injection. alpha-hANP s.c. injection was not associated with significant effects on plasma renin activity (PRA), plasma aldosterone, or urine electrolyte excretion. It was concluded that only a small percentage of intact alpha-hANP is absorbed into the circulation after s.c. injection. With the dose of peptide and the injection vehicle chosen, alpha-hANP had little or no biological effect.     

A RENIN-SECRETING TUMOUR SENSITIVE TO CHANGES IN CENTRAL BLOOD VOLUME (PRESUMABLY VIA SYMPATHETICS) BUT NOT TO CIRCULATING ANGIOTENSIN II

1. A 17 year old female presented with severe hypertension, hypokalaemia and elevated levels of plasma renin activity due to a renin-secreting tumour. 2. Renin was responsive to posture, low sodium diet, saline infusion and frusemide, but relatively unresponsive to raising or lowering circulating levels of angiotensin II. 3. Renal venous renin levels lateralized to the side of the tumour with good contralateral suppression when measured with control of posture and avoidance of prior stimulation, with and without angiotensin converting enzyme inhibition. 4. Levels of atrial natriuretic peptide were elevated and responsive to posture, saline infusion and angiotensin infusion. 5. The tumour was evident on computerized tomography, but not on intravenous pyelography or renal angiography. 6. Responsiveness of renin secretion to normal stimuli in reninoma may make diagnosis difficult, and renal vein sampling under controlled conditions is necessary.     

EFFECTS OF ATRIAL NATRIURETIC PEPTIDE ON PHENYLEPHRINE-INDUCED RENIN RELEASE IN DOGS

1. The effect of atrial natriuretic peptide (ANP) on alpha-adrenoceptor agonist-induced renin release was examined in the de-ennervated kidney of the anaesthetized dog pretreated with propranolol (1 mg/kg, intravenous). 2. Phenylephrine (50 ng/kg per min) infused into the renal artery increased the renal secretion rate of renin (RSR) without affecting systemic blood pressure or renal blood flow. 3. Although basal RSR was unaffected, the phenylephrine-induced increase in RSR was abolished during intrarenal arterial infusion of ANP (10 ng/kg per min). 4. The results suggests that exogenously administered ANP could suppress alpha-adrenoceptor-mediated renin release in the dog.     

Effect of brain natriuretic peptide on cyclic GMP accumulation in a kidney epithelial cell line (LLC-PK1)

The effect of porcine brain natriuretic peptide (pBNP) on cyclic GMP accumulation was studied in the kidney epithelial cell line, LLC-PK1. The addition of pBNP to the LLC-PK1 cells produced a time- and concentration-dependent increase in cyclic GMP accumulation and this effect was equipotent to that of alpha-human atrial natriuretic peptide (alpha-hANP). The simultaneous addition of pBNP and alpha-hANP at the maximal effective concentration of 10(-6) M did not have an additive effect on the cyclic GMP contents. The findings suggest that pBNP and alpha-hANP may share the same receptor in the LLC-PK1 cells.     

Effect of alpha-human atrial natriuretic peptide on the synthesis of dopamine in the rat kidney.

1. The present study has examined the influence of alpha-human atrial natriuretic peptide (alpha-hANP) on the synthesis of dopamine and its deamination into 3,4-dihydroxyphenylacetic acid (DOPAC) in rat kidney slices loaded with exogenous L-dihydroxyphenylalanine (L-DOPA). 2. alpha-hANP (3.3 and 330 nM) was found to produce a marked reduction (63-78% reduction) in the time-dependent accumulation of newly-formed dopamine and of its deaminated metabolite DOPAC in kidney slices loaded with 10 microM L-DOPA. alpha-hANP (330 nM) was also found to decrease the accumulation of newly-formed dopamine (45-66% reduction) and DOPAC (38-61% reduction) in experiments in which increasing concentrations (1-100 microM) of L-DOPA were used. This inhibitory effect was found to be potentiated by zaprinast (M&B 22,948; 10 microM), a guanosine cyclic 3',5'-monophosphate (cyclic GMP) phosphodiesterase inhibitor. Alone, zaprinast also decreased the accumulation of both dopamine (54-71% reduction) and DOPAC (73-92% reduction). 3. In kidney homogenates, alpha-hANP (330 nM) was found to affect neither the formation of dopamine nor its deamination to DOPAC. 4. Both alpha-hANP (330 nM) and zaprinast (10 microM) were found not to affect the formation of dopamine and DOPAC in kidney slices obtained from rats on a high salt diet during the previous 6 weeks. A similar situation was also found to occur when kidney slices obtained from 24-months old rats were used.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECTS OF AROTINOLOL, AN α- AND β-ADRENOCEPTOR ANTAGONIST, ON RENIN RELEASE FROM RAT KIDNEY CORTICAL SLICES

The effects of arotinolol on changes in renin release in rat kidney cortical slices in response to isoproterenol (IP) or norepinephrine (NE), were studied in comparison with those of AC-623, a main metabolite of arotinolol, and other typical adrenoceptor antagonists. Arotinolol, at concentrations of 10(-8) to 10(-4) mol/l, inhibited the increasing effect of 10(-6) mol/l IP on renin release, in a concentration-dependent manner. Similar results were observed with AC-623, propranolol or labetalol, although the inhibitory potencies of these agents were considerably lower than that of arotinolol. The blocking effect of arotinolol on the 10(-5) mol/l NE-induced decrease in renin release was much less potent than seen with other alpha-adrenoceptor blocking agents such as prazosin, phenoxybenzamine and labetalol. These data suggest that the potent blocking effects of arotinolol and its metabolite on the increased renin release in response to beta-adrenoceptor stimulation may contribute to the antihypertensive effect of this agent.     

VASOCONSTRICTOR RESPONSES TO COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM IN CYCLOSPORIN-INDUCED HYPERTENSION IN THE RAT

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 ± 3 mmHg vs control 125 ± 1 mmHg, P<0.0001). 3. Mesenteric resistance arteries (200–300 μm) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10-¹¹-10^?6 mol/L), angiotensin I (10-^l1-10^?6 mol/L) and angiotensin II (10-¹²-10^?6 mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.     

Effects of a synthetic atrial natriuretic polypeptide on intrarenal hemodynamics in dogs

The effects of a synthetic human atrial natriuretic polypeptide (alpha-hANP) on the intrarenal distribution of blood flow were examined in anesthetized dogs. Intrarenal infusion of alpha-hANP at a rate of 0.05 microgram/kg per min resulted in a significant increase in renal blood flow, urine flow and urinary excretion of sodium with no change in renal perfusion pressure. Measurement of the intrarenal blood flow by the microsphere method indicated a greater increase in flow rate in the juxtamedullary than in the superficial area. A significant correlation was observed during alpha-hANP infusion between changes in both urine flow and sodium excretion and inner cortical blood flow; changes in inner cortical blood flow may reflect changes in medullary blood flow. However, a smaller dose of alpha-hANP (0.01 microgram/kg per min) increased urine flow and electrolyte excretion but had no effect on the distribution of renal blood flow. Thus, neither the increased inner cortical blood flow nor the redistribution of blood flow is the sole cause of the natriuresis during infusion of alpha-hANP. Changes in intrarenal hemodynamics could contribute to the natriuresis induced by alpha-hANP, via washout of medullary solutes.     

STIMULATION OF PHOSPHATIDYLINOSITOL METABOLISM IN THE HEART

Receptor-stimulated hydrolysis of inositol phospholipids was studied in atrial and ventricular myocytes isolated from guinea-pigs. Acetylcholine and carbachol stimulated inositol phosphate accumulation with a maximum of more than 12 times the unstimulated values in atrial myocytes and 7 times in ventricular myocytes. The vasoactive peptides angiotensin II and vasopressin also stimulated inositol phosphate accumulation, but the maximum effect was lower than that mediated through muscarinic receptors. However, the adenosine analogues, L-N6-phenylisopropyladenosine and 5'N-ethylcarboxamidoadenosine which, like muscarinic agonists depress cardiac contractility, did not affect inositol phosphate accumulation at concentrations up to 10(-4) mol/l. Stimulation of phosphatidylinositol turnover in heart bears no obvious relationship to either contractility or release of atrial natriuretic factor.     

Enhancement of coronary conductance by alpha-human atrial natriuretic polypeptide without effects on myocardial contractility

The effect of synthetic human atrial 28-amino acid peptide (alpha-human atrial natriuretic polypeptide, alpha-hANP) on coronary circulation and cardiac functions was examined in open-chest dogs. Intravenous injection of alpha-hANP increased coronary and systemic conductance, and coronary and aortic blood flow with a significant fall in blood pressure. Continuous infusion of alpha-hANP into the left anterior descending coronary artery (LAD) increased LAD blood flow in a dose-dependent manner. The linear regression analysis revealed the relationship of logit (changes in mean coronary conductance (delta MCC] = 1.45 x log (coronary plasma concentration of alpha-hANP) + 7.51 (r = 0.87, n = 29). REC50 of alpha-hANP was 5.1 microM, where REC50 was the concentration to increase MCC to a half maximum MCC during reactive hyperemia after a 30-s coronary occlusion. alpha-hANP increased coronary conductance with no changes of myocardial oxygen consumption (MVO2) when blood pressure remained constant. Indices of myocardial contractility measured with a strain gauge arch, myocardial force (F), max dF/dt and LV max dp/dt, were not altered by either bolus intravenous injection or continuous intracoronary infusion of alpha-hANP. These results indicated a direct increase by alpha-hANP of coronary and systemic vascular conductance.     

Neurotensin potentiates the potassium-induced release of endogenous dopamine from rat striatal slices

The relationship between the renin-angiotensin system (RAS) and prostacyclin (PGI2) biosynthesis was studied in experimental diabetic rats. The group with diabetes induced by streptozotocin (STZ, 3.3 mmol/kg i.v.) showed prolonged hypertension, and plasma renin activity decreased markedly from 8.4 +/- 0.7 to 2.4 +/- 0.3 and 1.2 +/- 0.3 ng angiotensin I/ml per h at 2 and 8 weeks after STZ treatment. Plasma PGI2, determined as 6-keto-PGF1 alpha, decreased significantly at 8 weeks, with the values for the STZ-treated and control groups being 1490 +/- 99 and 2210 +/- 90 pg/ml, respectively. Significant suppression of renin release from renal cortical slices was observed at 8 weeks in the diabetic group, although no significant change was found in the renal renin content when compared with that of the controls. The release of PGI2 from the renal medullary slices of the diabetic group was suppressed at 2 and 8 weeks, with the suppression in aorta and renal cortical slices being apparent only at 8 weeks. These results indicate that suppression of the RAS may be related to PGI2 biosynthesis in diabetes mellitus.     

The renal, cardiovascular and hormonal actions of human atrial natriuretic peptide in man; effects of indomethacin.

The renal, cardiovascular and hormonal effects of intravenous infusion of alpha-human atrial natriuretic polypeptides (alpha-hANP) at the concentrations of 0.0125, 0.025, 0.05, 0.1 microgram kg-1 min-1 for 20 min was studied in six male volunteers before and after indomethacin administration (150 mg day-1, three times daily for 3 days). Dose-dependent diuresis and natriuresis were observed in all subjects between the concentrations of 0.025 and 0.1 microgram kg-1 min-1, which were not influenced by indomethacin. Diastolic blood pressure decreased significantly (P less than 0.05) at the higher dose (0.05 microgram kg-1 min-1) of alpha-hANP, which was attenuated by indomethacin pretreatment. The plasma concentration of the immunoreactive alpha-hANP was 73.7 +/- 25 pg ml-1 on the control in subjects taking 200 mEq day-1 of sodium, and significant diuresis occurred when plasma concentration reached approximately 330.5 +/- 74.4 pg ml-1. alpha-hANP infusion caused a dose-dependent increase in cyclic GMP, no significant changes in plasma aldosterone and 18-hydroxycorticosterone, which were not influenced by indomethacin pretreatment. Plasma renin did not change in response to alpha-hANP infusion, which was significantly decreased (P less than 0.05) after indomethacin pretreatment. These results support that the renal effects of alpha-hANP may be exerted by prostaglandin-independent mechanisms. The renal effects occur at lower doses, and cardiovascular changes occur at higher doses of alpha-hANP.     

Renal effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) in anesthetized dogs

The effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) on renal hemodynamics and urine formation were investigated in anesthetized dogs. Intrarenal arterial infusion of the peptide (1.0 microgram/min) increased renal blood flow, glomerular filtration rate and urine flow with no change in systemic blood pressure. A lower dose of alpha-hANP (0.2 micrograms/min) produced a significant diuresis and natriuresis, while renal hemodynamics remained unchanged. The urinary excretion of Na, Cl and Ca was increased in proportion to the urine flow. We propose that alpha-hANP inhibits tubular reabsorption of electrolytes, and in higher dose produces renal vasodilation.     

ATRIAL NATRIURETIC PEPTIDE INHIBITS THE ALDOSTERONE RESPONSE TO METOCLOPRAMIDE IN PATIENTS WITH GLOMERULAR DISEASE AND ESSENTIAL HYPERTENSION

1. We examined the effects of metoclopramide (MCP: 10 mg i.v.) on plasma atrial natriuretic peptide (ANP) and aldosterone concentrations (PAC) and the effect of ANP on MCP-induced PAC in four patients with primary glomerular diseases and seven patients with essential hypertension. 2. MCP injection caused no significant changes in plasma ANP. MCP produced a marked increase in PAC without a significant change in plasma renin activity. 3. The increase in PAC induced by MCP injection was markedly attenuated when preceded by the infusion of ANP (25 ng/kg per min). 4. These results suggest that the dopaminergic D₂ mechanism is not involved in the regulation of ANP secretion and that ANP modulates the dopaminergic regulation of aldosterone secretion.     

Effects of atrial natriuretic peptide on adrenergically induced norepinephrine release and vasoconstriction in the dog kidney.

The effects of atrial natriuretic peptide (ANP) on the neural control of renal blood flow were examined in anesthetized dogs. Intrarenal arterial infusion of ANP (alpha-hANP, 10 and 50 ng/kg per min) suppressed the decrease in renal blood flow but not the increase in renal venous plasma norepinephrine concentration induced by renal nerve stimulation (1 and 2 Hz, for 1 min). ANP also attenuated the blood flow response to intrarenal arterial injection of methoxamine (5-20 micrograms). These results suggest that ANP acts at a postsynaptic site to suppress adrenergically induced vasoconstriction in the dog kidney.     

Stimulation of renin secretion by 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8)

The intracellular calcium antagonist 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) prevents the release of Ca2+ from cell storage sites. The effect of this compound on renin secretion from rat renal cortical slices in vitro was investigated. TMB-8 was a potent stimulant of renin secretion within the concentration range 10(-5)M to 5 X 10(-4)M with an optimum concentration of 2 X 10(-4)M. TMB-8 overcame the inhibition of renin secretion by angiotensin II, ouabain, 60 mM KCl and A23187. The results add to the existing evidence that Ca2+ is a common inhibitory messenger for a number of compounds which affect renin release and suggest a role for intracellular calcium stores in the regulation of juxtaglomerular cell Ca2+ levels.     

Natriuretic effect of acute nifedipine administration is not mediated by the renal kallikrein-kinin system

Despite their vasodilating action, calcium antagonists increase renal sodium excretion. To ascertain whether renal kallikrein plays a role in the renal effects of calcium antagonists, nifedipine (N) (10 mg orally) or placebo (P) was given to 17 male patients with mild to moderate essential hypertension during a 6-h infusion of either saline (S) or aprotinin (A) (2 X 10(6) KIU in 200 ml of saline). Blood pressure (BP) and heart rate (HR) were measured every 10 min, and blood samples were taken at -10, 0, 30, 60, 120, 240, 360 min for plasma renin activity (PRA), creatinine, and osmolarity determinations. Urinary kallikrein, aldosterone, creatinine, and electrolytes were measured in 6-h urine collections. The acute administration of N induced a significant systolic BP (SBP) and diastolic (DBP) fall and a transient PRA increase that peaked at 30 min and were not modified by A infusion. Urinary volume (+47%), Na+ (+54%) and Cl- (+58%) excretion were significantly enhanced by N. There were less pronounced and statistically not significant increases in urinary excretion of Ca2+ (+38%) and K+ (+29%). Infusion of A did not interfere with the natriuretic effect of N. Our data do not support the hypothesis that the kallikrein-kinin system plays an important role in mediating the renal effects of nifedipine in humans.     

The differential role of exogenous and endogenous prostacyclin in the control of renin release from dog renal cortical slices

Using a continuous superfusion system of dog renal cortical slices, we studied the role of prostacyclin in the control of renin release. Superfusate renin activity and prostacyclin as 6-keto-prostaglandin F1alpha, a stable metabolite of prostacyclin, concentrations were measured by radioimmunoassay. Exogenous prostacyclin (0.1, 1, 10 microM) produced a concentration dependent and significant increase in renin release. The calcium ionophore A23187 (10 microM) produced a significant increase in 6-keto-prostaglandin F1alpha release and a significant decrease in renin release. A23187 (10 microM) hardly produced changes of 6-keto-prostaglandin F1alpha release and renin release in the absence of Ca2+. Pretreatment with indomethacin (10 microM) completely abolished the stimulatory effect of A23187 (10 microM) on 6-keto-prostaglandin F1alpha release. On the other hand, the inhibitory effect of A23187 on renin release in the pretreatment with indomethacin was almost equal to that in the "untreatment" with indomethacin. Moreover, we found that there was no association of 6-keto-prostaglandin F1alpha liberation and renin activity. These results indicate that exogenous prostacyclin promotes renin release, and suggest that renin release is not to be modulated by A23187-induced prostacyclin synthesis in dog renal cortical slices.