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.     

Effects of a synthetic human atrial natriuretic polypeptide on regional blood flow in rats

The effects of alpha-hANP on systemic hemodynamics and regional blood flow were examined in conscious WKY and SHR. An intravenous infusion of alpha-hANP (3 micrograms/kg per min) resulted in a rapid and marked fall of blood pressure and of total peripheral resistance but with no change in cardiac output in both strains. alpha-hANP decreased vascular resistance in most organs and there was a redistribution of renal blood flow. Thus, the acute hypotensive effect of alpha-hANP is probably related to a vasodilator action.     

Renal effect of atrial natriuretic polypeptide: comparison with standard saluretics

The effects of synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) on renal hemodynamics and urine production were examined and compared with those of furosemide and trichlormethiazide (TCM) in anesthetized rats. The diuretic effect of alpha-hANP was brief but more powerful. Also, alpha-hANP produced a rapid and acute decrease in blood pressure (BP) accompanied by an increase in renal blood flow (RBF), while furosemide and TCM had no effect on either BP or RBF. Both the free water reabsorption rate (TCH2O) and free water production (CH2O) increased with administration of alpha-hANP but the linear relationship between CH2O and osmolar clearance (Cosm) and that between TCH2O and Cosm were not affected. Furosemide, on the other hand, affected the relationship between TCH2O and Cosm and between CH2O and Cosm. TCM affected only the relationship between CH2O and Cosm. These results suggest that the renal site of action and the mechanism of action of alpha-hANP differ from those of furosemide and TCM.     

Renal effects of a new member of adrenomedullin family, adrenomedullin2, in rats

A new member of the adrenomedullin family, adrenomedullin2, was identified in mammals. The effects of adrenomedullin2 on renal hemodynamics and urine formation were examined in rats. Intrarenal arterial infusion of adrenomedullin2 at rates of 30, 100 and 300 pmol/kg/min decreased blood pressure and increased heart rate in a dose-dependent fashion. Adrenomedullin2 infusion at 100 pmol/kg/min significantly increased renal blood flow and urine flow. At the higher infusion rate (300 pmol/kg/min), adrenomedullin2 significantly decreased urine flow. Continuous intrarenal infusion of adrenomedullin2 at 100 pmol/kg/min significantly increased renal blood flow from 6.7+/-0.5 to 8.8+/-0.5 ml/min and decreased renal vascular resistance from 16+/-1 to 11+/-1 mm Hg min/ml. Urine flow was significantly increased from 21.5+/-4.9 to 36.2+/-8.5 microl/min and urinary excretion of sodium was increased from 2.3+/-0.9 to 4.9+/-1.4 microEq/min. Blood pressure, heart rate and glomerular filtration rate did not change. Infusion of a similar dose of adrenomedullin also increased renal blood flow (6.8+/-0.4-8.8+/-0.6 ml/min), urine flow (25.4+/-3.2-42.8+/-9.4 microl/min) and urinary excretion of sodium (2.8+/-0.6-6.5+/-1.2 microEq/min), decreased renal vascular resistance (15+/-1-11+/-1 mm Hg min/ml) and did not alter glomerular filtration rate. Thus, the renal actions induced by adrenomedullin2 were similar to those of adrenomedullin. These data suggest that adrenomedullin2 may play an important role in the regulation of renal hemodynamics and urine formation.     

Effects of KB-2796, a new diphenylpiperazine calcium antagonist, on renal hemodynamics and urine formation in anesthetized dogs.

The effects of KB-2796, a new calcium antagonist with a diphenylpiperazine moiety, on renal hemodynamics and urine formation were investigated in anesthetized dogs. Intravenous infusion of KB-2796 (10, 30, and 100 micrograms/kg/min) decreased mean blood pressure (MBP) and renal vascular resistance (RVR) in a dose-dependent manner, but did not change renal blood flow (RBF). At the highest dose, glomerular filtration rate (GFR) and urine flow (UF) tended to decrease. Nicardipine (0.1, 0.3, and 1 microgram/kg/min) also dose-dependently decreased MBP, RVR, GFR, and UF. When KB-2796 was infused into the renal artery at lower doses of 3 and 10 micrograms/kg/min, UF and urinary excretion of electrolytes increased without a significant change in RBF and GFR. Intrarenal infusion of KB-2796 at 30 micrograms/kg/min and nicardipine at 0.3 microgram/kg/min produced a significant increase in GFR, RBF, UF, urinary excretion of electrolytes, and renin secretion rate. These results suggest that KB-2796 administered intrarenally exerts a diuretic action via tubular effects and the alteration of renal hemodynamics. However, its diuretic action might be masked by diminished urine formation via a reflex activation of the sympathetic nerves and/or via a reduction of renal perfusion pressure when it is administered systemically.     

Effects of cromakalim on renal hemodynamics and function in dogs: comparison with nicardipine.

The effects of cromakalin, a potassium channel opener, on renal hemodynamics and renal function were investigated in pentobarbital-anesthetized dogs. Intrarenal infusion of cromakalim at 0.5 micrograms/kg/min resulted in significant increases in renal blood flow (RBF), glomerular filtration rate (GFR), urine flow, and renin release. The urinary excretion rate of sodium increased by the same proportion as that of calcium. Free water reabsorption rate/osmolar clearance did not significantly change throughout the experiments. These data suggest that cromakalim did not inhibit sodium transport at the medullary portion of the ascending limb of Henle's loop and may have increased the delivery of sodium to Henle's loop. Intrarenal infusion of nicardipine increased RBF, GFR, urine flow, and the urinary excretion of electrolytes (Na, K, and Ca). The renal effects of cromakalim were very similar to those of nicardipine. Cromakalim was superimposed on a nicardipine infusion of a maximal effective dose. Superimposition of cromakalim to the nicardipine infusion did not cause any additional changes in renal hemodynamics and renal function. These data suggest that cromakalim and nicardipine exert their effects on renal hemodynamics and function via the same pathway.     

Renal effects of specific antagonists of arginine vasopressin in dogs.

To investigate the effects on renal hemodynamics of specific antagonists of arginine vasopressin (AVP), CGP 29325 (d(CH2)5-D-Tyr(Et)VAVP), which has both anti-vasopressor and anti-antidiuretic activities against AVP, and CGP 25838E (d(CH2)5-Tyr(Me)AVP), which has only anti-vasopressor activity, were administered to normally hydrated anesthetized dogs, and the effects on renal function were examined. The pressor response and constriction of renal and mesenteric arteries induced by AVP were dose-dependently blocked by intravenous CGP 25838E. Following intrarenal arterial administration (i.r.a.) of CGP 29325 at 3 micrograms/min, water diuresis occurred and urine osmolality (UOsm) decreased to less than 250 mOsm/kg. Renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNaV) remained unchanged. A higher dose (10 micrograms/min, i.r.a.) of CGP 29325 further decreased UOsm to about 110 mOsm/kg. Although arterial blood pressure (BP), GFR and UNaV remained unchanged, RBF decreased from the control value 3.7 +/- 0.35 to 2.4 +/- 0.40 ml/g.min. CGP 25838E (10 micrograms/min, i.r.a.) had no effect on renal hemodynamics and urine formation. When administered into the mesenteric artery, CGP 25838E (10 micrograms/min) increased mesenteric blood flow (MBF) from 199 +/- 34 to 240 +/- 40 ml/min without any alteration in blood pressure. We tentatively conclude that CGP 29325, at a lower dose, exerted anti-antidiuretic effects through a specific inhibition of V2 receptors, while the higher dose of CGP 29325 altered RBF, through yet to be determined mechanisms. The vasoconstrictive activity of AVP may contribute to the regulation of mesenteric circulation, but not to renal hemodynamics, in anesthetized dogs.     

Effect of L-NG-nitro-arginine, inhibitor of nitric oxide synthesis, on autoregulation of renal blood flow in dogs.

The present experiments were designed to evaluate the importance of nitric oxide in the regulation of renal hemodynamics and the autoregulation of renal blood flow (RBF) in anesthetized dogs. RBF was measured by an electromagnetic flowmeter, and renal arterial pressure (RAP) was varied by an adjustable aortic clamp. The RAP-RBF relations were examined during the intrarenal infusion of saline or agents. The intrarenal infusion of L-NG-nitro-arginine (L-NNA, 40 micrograms/kg.min) at normal RAP decreased RBF and urine flow (UF), while the infusion of L-arginine.HCI (1 mg/kg.min) increased RBF and UF. Both agents did not affect the glomerular filtration rate and mean arterial pressure. The autoregulation of RBF was impaired during the L-NNA infusion. The L-arginine infusion did not affect autoregulatory efficiency. When L-NNA (40 micrograms/kg.min) and L-arginine were infused simultaneously into the renal artery, the autoregulation of RBF was maintained. However, a higher dose of L-NNA (200 micrograms/kg.min) impaired the autoregulation of RBF. These results suggest that the basal production and/or the release of nitric oxide contributes to the regulation of renal hemodynamics and urine formation. During the reduction of RAP, nitric oxide may play an important role in the autoregulation of RBF.     

Effect of glucagon on renin secretion in the dog.

The effects of glucagon alone or in combination with theophylline on renin section were studied in relation to renal hemodynamic responses in anesthetized dogs. The intrarenal infusion of glucagon (0.5 microgram/kg/min) increased heart rate, renal blood flow, glomerular filtration rate and urine flow without any effect on renin secretion, but at a higher dose (1.0 microgram/kg/min) it increased renin secretion significantly. Theophylline (0.1 mg/kg/min) did not affect renal hemodynamics but caused a slight increase in renin secretion after 30--60 min infusion. The combined infusion of glucagon (0.5 microgram/kg/min) with theophylline (0.1 mg/kg/min) increased renin secretion markedly, although it produced renal hemodynamic changes similar to those induced by glucagon alone. These effects were not suppressed by d,l-propranolol (1.0 microgram/kg/min). It is suggested that the increase in renin secretion caused by the combined infusion of glucagon and theophylline resulted mainly from an increase in cyclic AMP in the juxtaglomerular cells, and not from stimulation of beta-adrenoceptors.     

Effects of endothelin-1 on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

The effects of endothelin-1 (ET-1) on renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs, and comparisons were made with effects of Bay K 8644, a calcium channel agonist. RNS at a low frequency (0.5-2.0 Hz) produced significant decreases in urine flow and urinary excretion of sodium and increased NE secretion rates without influencing renal hemodynamics. RNS, at a high frequency of 2.5-5.0 Hz which diminishes renal hemodynamics, affected urine formation and NE secretion rate more potently than did low-frequency RNS. Intrarenal arterial infusion of ET-1 (1.0 ng/kg/min) decreased the baseline level of renal blood flow by 25% and that of urinary excretion of sodium by 54-69% but did not alter basal levels of NE secretion rate. During ET-1 infusion, low-frequency RNS-induced antidiuresis was observed to an extent similar to that seen without ET-1 infusion, whereas increase in NE secretion rate elicited by RNS was significantly inhibited by ET-1 infusion (45-65% of the values without ET-1 infusion). In addition, in the case of high-frequency RNS, ET-1 did not affect antidiuretic responses but did inhibit the increase in NE secretion rate by approximately 55%. In contrast, alterations in renal excretory responses and NE secretion rate elicited by RNS were not influenced by Bay K 8644 infusion (1.0 micrograms/kg/min), a dose that decreased renal blood flow to the same degree as did 1.0 ng/kg/min of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained dilatation of large coronary artery by alpha-human atrial natriuretic peptide in conscious dogs: a comparison with nitroglycerin

The effects of alpha-human atrial natriuretic peptide (alpha-hANP) on the coronary circulation were compared with those of nitroglycerin in 16 conscious dogs chronically instrumented with a pair of miniature sonomicrometers and an electromagnetic flow probe placed on the left circumflex coronary artery. alpha-hANP (1 and 10 micrograms) and nitroglycerin (0.1, 1 and 10 micrograms) were administered intracoronarily via a cannula implanted in the proximal left circumflex coronary artery. Both alpha-hANP and nitroglycerin dose dependently increased the coronary diameter and coronary blood flow. Although alpha-hANP (10 micrograms) and nitroglycerin (1 microgram) dilated the large coronary artery to almost the same extent (92 +/- 10 vs. 98 +/- 8 microns), the time course of the dilating action differed; the peak dilatation occurred at 5.6 +/- 0.8 and 0.9 +/- 0.07 min (P less than 0.01), and full recovery occurred at 31.5 +/- 3.8 and 5.5 +/- 1.3 min (P less than 0.01) after alpha-hANP and nitroglycerin, respectively. Topical application of alpha-hANP (50 micrograms) to the epicardial coronary artery of three anesthetized open-chest dogs did not affect the coronary diameter and coronary blood flow, while nitroglycerin (50 micrograms) increased both variables. Thus, intracoronary alpha-hANP dilates the large coronary artery more gradually and more sustainedly than nitroglycerin does.     

Effect of SA-446, an angiotensin-converting enzyme inhibitor, on renal function in anesthetized dogs: special reference to arachidonic acid metabolites

Intravenous infusion of SA-446 (1 mg/min) decreased systemic blood pressure and increased renal blood flow in anesthetized dogs. These changes were accompanied by a slight natriuretic response. During the infusion of this dose of SA-446, the pressor response to angiotensin I was abolished and the depressor response to bradykinin was markedly potentiated. Administration of indomethacin (13 mg/kg i.v.) suppressed natriuresis and, to some extent, the renal vasodilation caused by SA-446. Before and after administration of SA-446, four arachidonate metabolites, prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2, were determined in plasma and urine by radioimmunoassay. There were no remarkable changes in levels of prostaglandins and thromboxane B2 in arterial and renal venous plasma. The urinary excretion of the metabolites varied little, but thromboxane B2 excretion did significantly decrease. Thus, reduction in the biosynthesis of thromboxane B2 in the kidney may relate to the effects of SA-446 on renal hemodynamics and urine formation.     

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.     

Effects of angiotensin I-converting enzyme inhibitor (SA-446) on renal function in dogs

The effects of an orally active inhibitor of angiotensin-converting enzyme (SA-446) on systemic arterial pressure, renal function and renin release were examined in anesthetized dogs. Intrarenal infusion of the larger dose of SA-446 (0.1 mg/min) caused an increase in RBF, urine flow and renin release and caused a fall in blood pressure. The smaller dose of SA-446 (0.02 mg/min) did not affect the blood pressure, but it increased the urine flow. However, the same dose of SA-446 in combination with probenecid caused a significant fall in blood pressure. The potentiation of SA-446 with probenecid may be explained by the elevation in plasma SA-446 concentration via the inhibition of its tubular secretion by probenecid.     

Renal vascular effects of dilazep antagonized by 3-isobutyl-1-methyl-xanthine

The effects of different doses of dilazep on renal hemodynamics, urine formation, and renin release were studied in anesthetized dogs. Intrarenal arterial infusion of dilazep (1 microgram/kg/min) increased renal blood flow, with no change in systemic arterial blood pressure and renal venous plasma renin activity. Renal vasodilation induced by dilazep was completely inhibited by intrarenal arterial infusion of 3-isobutyl-1-methyl-xanthine (IBMX; 11.1 micrograms/kg/min), a potent adenosine receptor antagonist, but not by indomethacin (13 mg/kg i.v.). These results suggest that dilazep has a vasodilatory action in the kidney--one that is independent of the renal renin-angiotensin system. The inhibitory action of IBMX on the dilazep-induced renal vasodilation indicates that the renal vascular effects of dilazep may be exerted by augmentation of endogenous adenosine and mediated through adenosine receptors.     

The role of endogenous angiotensin II in antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

We examined the possible involvement of endogenous angiotensin II (ANG II) in norepinephrine (NE) overflow and antidiuresis induced by renal nerve stimulation (RNS). RNS at a frequency of 0.5-2.0 Hz, which did not influence renal hemodynamics, produced significant reductions in urine flow and urinary excretion of sodium, and elevations in NE secretion rate (NESR) and renin secretion rate (RSR). Intrarenal arterial (i.r.a.) infusion of phentolamine (10 micrograms/kg/min) abolished the RNS-induced antidiuresis. In dogs receiving captopril (15 micrograms/kg/min i.v.), RNS-induced antidiuresis and increase in NESR were significantly attenuated. The i.r.a. administration of propranolol at 5 micrograms/kg/min, a dose that inhibited completely the RNS-induced increase in RSR, did not influence the alterations in NESR and urine formation in response to RNS. During ANG II infusion (1 ng/kg/min i.r.a.), RNS produced a reduction in urine formation and an increase in NESR, at a magnitude similar to that seen without ANG II infusion. These results suggest that RNS at a low frequency increased the NESR and RSR without affecting renal hemodynamics and that the antidiuretic effect was probably produced via the activation of postsynaptic alpha-adrenoceptors, but not via the ANG II receptor, located on the renal tubules. The release of NE appears to be modulated by ANG II through the activation of a facilitatory prejunctional mechanism, which is maximally stimulated by endogenously and locally generated basal levels of ANG II.     

Beta blockers induce different intrarenal effects in humans: demonstration by selective infusion of tertatolol and propranolol

The effects of tertatolol and propranolol on renal circulation were studied in patients with normal renal function to test the hypothesis that various beta blockers may have different vasomotor effects within the renal vascular bed. Left renal blood flow was measured by the continuous thermodilution method before (t0), and 5 (t1), 10 (t2), 20 (t3), and 30 (t4) minutes after a selective infusion of tertatolol (0.25 mg, N = 4) or propranolol (2.5 mg, N = 4) into the left renal artery. Heart rate, cardiac output, aortic and right atrial pressures, and systemic vascular resistances did not significantly vary after either drug throughout the study. Plasma renin activity and plasma aldosterone in arterial and renal venous blood started to decrease at t1 after each drug. After propranolol, renal blood flow, renal vascular resistance and the renal arteriovenous oxygen difference were unchanged. Conversely, after tertatolol at t3, renal blood flow was increased (from 426 +/- 18 mL/min/1.73 m2 to 509 +/- 56 mL/min/1.73 m2, P = .03), renal vascular resistance and renal arteriovenous oxygen difference were decreased (P less than .001), and the renal blood flow/cardiac output ratio was increased (P = .03). The filtration fraction did not vary after either drug, as attested by the unchanged polyfructosan extraction coefficient. This clinical study shows that selective infusion of a single low dose of tertatolol into the renal artery results in a delayed intrarenal vasodilator effect, while at the dose tested propranolol does not modify renal hemodynamics.     

Inhibitory effect of nisoldipine on angiotensin-II-induced renal actions in anesthetized dogs

Renal effects of nisoldipine, a potent calcium channel blocker, were examined in anesthetized dogs. Intrarenal arterial infusion of nisoldipine (2, 10, and 50 ng/kg per min) had no effect on mean systemic blood pressure and heart rate and there was no significant change in renal hemodynamics during infusion of various doses of the drug. Urine flow and urinary excretions of sodium, chloride, and potassium were increased by nisoldipine in a dose-related manner. Fractional excretions of sodium and chloride were markedly elevated with the highest dose given thereby indicating that tubular reabsorptions of sodium and chloride were inhibited by nisoldipine. Nisoldipine (50 ng/kg per min) abolished the decreasing effects of angiotensin-II on glomerular filtration rate, urine flow, and urinary excretion of electrolytes but not the decrease in renal blood flow by the peptide. Angiotensin-II-induced reduction of fractional excretion of electrolytes was completely blocked by nisoldipine. Renal responses to norepinephrine were unaffected by nisoldipine. Thus, nisoldipine administered intrarenally to anesthetized dogs exerts a diuretic action by way of tubular effects, as is the case with other dihydropyridine calcium channel blockers. Nisoldipine seems to effectively antagonize the renal response to angiotensin-II. Thus, the preferential inhibition of angiotensin-II-induced antidiuresis may mean that nisoldipine interferes with stimulatory effects of angiotensin-II on the renal tubular reabsorption of electrolytes and water.     

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.     

Influence of asimadoline, a new kappa-opioid receptor agonist, on tubular water absorption and vasopressin secretion in man

AIMS: The purpose of the study was to investigate the effects of asimadoline, a new kappa-opioid agonist, on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects. METHODS: In a placebo-controlled, randomised, double-blind crossover design we studied the effects of single oral doses of 1, 5, and 10 mg of asimadoline, in 24 healthy volunteers. Two hour control urine collections were followed by 2 h postdose urine collections and subsequently 2.5% saline was given i.v. at a rate of 0.3 ml min(-1) kg(-1) during another 2 h urine collection. Blood was obtained hourly. Arginine-vasopressin (AVP), atrial natriuretic peptide (alpha-hANP), endothelin (ET-1) and cAMP were determined by r.i.a. or ELISA. RESULTS: GC-MS measurements revealed Cmax values of asimadoline in plasma ranging from 18 ng ml(-1) at the 1 mg dose, 91 ng ml(-1) at the 5 mg dose, to 214 ng ml(-1) at the 10 mg dose after an average of 1.1-1.4 h. Without effects on blood pressure, heart rate, GFR or urine electrolyte excretion, urine volume increased after 1-2 h after administration of 5 and 10 mg asimadoline from 3.3+/-1.3 to 5.6+/-1.4 (P<0.05) and from 3.2 +/-1.6 to 5.5+/-2.2 ml min(-1) (P<0.01), respectively. CH2O rose from 0.2+/-1.5 to 2.0+/-1.6 (P<0.05) and from 0.6+/-1.6 to 3.0+/-1.6 ml min(-1) (P<0.01). Urinary excretion of AVP was suppressed only with the 10 mg dose from 46+/-23 to 25+/-15 fmol min(-1) (P<0.05) without and from 410+/-206 to 181+/-125 fmol min(-1) (P<0.05) with stimulation by 2.5% saline. Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5% saline infusion. Changes in the alpha-hANP or ET-1 systems were not affected by asimadoline. CONCLUSIONS: Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level. Suppression of AVP secretion was observed only at the highest dose level of 10 mg of asimadoline.