ATRIAL NATRIURETIC PEPTIDE FRAGMENTS IN DOGS WITH EXPERIMENTAL HEART FAILURE

1. This study in the canine arteriovenous (AV) fistula model of high-output heart failure (HOHF) evaluated the chronic temporal changes in plasma ANF and pro ANF 31–67 and their relationship to body-fluid balance and the renin-aldosterone axis. In addition, the haemodynamic, hormonal and renal excretory effects of synthetic pro ANF 31–67 infusions were examined in normal and AV fistula dogs with compensated HOHF. 2. Following the construction of the AV fistula, the dogs exhibited chronic parallel elevations in right atrial pressure and the plasma concentrations of ANF and pro ANF 31–67. The gradual increases in the two peptides were associated with a gradual decrease in plasma renin activity and the re-establishment of sodium balance. 3. In normal and compensated AV fistula dogs, synthetic pro ANF 31–67 produced similar significant reductions in arterial blood pressure, right atrial pressure and elevations in urinary sodium excretion. These effects were not associated with increases in plasma or urinary cyclic GMP (cGMP). 4. These results suggest that the elevation in the endogenous circulating levels of pro ANF 31–67 in the AV fistula dogs may represent one chronic adaptive mechanism to achieve body fluid homeostasis. Furthermore, via potentially different mechanisms of action, ANF and pro ANF 31–67 may coordinate and contribute to the regulation of haemodynamic and renal function during physiological and pathophysiological situations.     

STIMULATION OF SODIUM AND WATER SECRETION WITHOUT INHIBITION OF GLUCOSE ABSORPTION IN THE RAT JEJUNUM BY VASOACTIVE INTESTINAL PEPTIDE (VIP)

1. Infusion of vasoactive intestinal peptide (VIP) into the arterial blood supply of the small intestine in anaesthetized rats did not alter either the perfusion pressure in the superior mesenteric artery or the active absorption of glucose from the jejunum, but did produce a large net secretion of Na⁺ and water into the lumen of the jejunum. 2. The results are compared to the effects of prostaglandin E₁ which stimulates Na⁺ and water secretion and inhibits glucose active absorption in the rat jejunum.     

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.     

INTESTINAL ABSORPTION OF CAPTOPRIL AND TWO THIOESTER ANALOGS IN RATS AND DOGS

The objectives of this study were (i) to determine whether the reduced absorption of captopril from the colon of humans also occurs in rats and (ii), after confirmation of the relevance of a new rat model, to evaluate the intestinal absorption of captopril and several of its analogs. A model was developed and validated in which specific sites within the GI tract of rats were surgically implanted with a cannula such that animals could be dosed while conscious and unrestrained. The absorption of captopril after administration into the lower GI tract of rats was significantly reduced relative to the upper GI tract, which was consistent with results reported previously in humans. In rats, the absorption of the S-benzoyl thioester prodrug of captopril (SQ-25868) from the lower GI tract was substantially greater than that of captopril. However, the absorption of the S-benzoyl thioester prodrug of 4-phenyl thio-captopril (SQ-26991) from the lower GI tract was only marginally better than that of captopril. In additional studies in dogs, a 12 h controlled-release formulation of SQ-25868 provided sustained blood levels of captopril while maintaining acceptable bioavailability (>80%). Two approaches were tried, without success, to stabilize captopril in vivo: (i) complexation with zinc (SQ-26284) and (ii) use of ascorbic-acid-buffered (pH 3·5) vehicle. The zinc complex might have failed because it has very low solubility, whereas the pH-3·5-buffered vehicle was quickly neutralized within the colonic lumen in rats, and did not stabilize captopril against oxidation. Rapid neutralization might explain why the colonic bioavailability of captopril was not substantially increased when this pH-3·5-buffered vehicle was tried in humans. © 1997 by John Wiley & Sons, Ltd.     

SODIUM LOADS ENHANCE THE NATRIURETIC RESPONSES TO ATRIAL NATRIURETIC PEPTIDE AND NEUTRAL ENDOPEPTIDASE INHIBITORS IN CONSCIOUS CYNOMOLGUS MONKEYS

1. The effects of sodium supplements on the renal responses to human atrial natriuretic peptide (hANP 99–126) and to the selective inhibitors of neutral endopeptidase 3.4.24.11 (NEP) SQ 28 603 and candoxatrilat were determined in conscious monkeys. 2. When the monkeys’ diet was changed from 0.55% sodium to 1.1% sodium, the natriuretic response to 100 μmol/kg intravenous of SQ 28603 increased from 665 ± 64 to 1015 ± 224 μEq/3h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 pmol/kg, P.o., of SQ 28603 from 700 ± 332 μEq/3h in normal monkeys to 2437 ± 841 μEq/3h. Therefore, the non-human primate model was appropriate for investigating the effects of sodium loads on the urinary ANP and cGMP responses to exogenous ANP in the presence and absence of NEP inhibitors. 3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99–126 in monkeys treated with vehicle or 10 μmol/kg intravenous of candoxatrilat. The sodium and ANP excretions stimulated by hANP 99–126 were positively correlated with each other and with the calculated intravenous sodium load in the presence or absence of candoxatrilat. 4. SQ 28 603 and candoxatrilat (0.3 to 10 μmol/kg intravenous) each produced significant, dose-related potentiation of the natriuretic, cGMP and ANP responses to 0.3 nmol/kg intravenous of hANP 99–126 in monkeys receiving 5 mL/kg + 0.2 mL/min saline. In addition, the highest dose of SQ 28 603 produced significant depressor activity. 5. In conclusion, the increased natriuretic activity of hANP 99–126 in sodium loaded monkeys was mediated, in part, by increased ANP delivery to the guanylate cyclase linked ANP receptors in the distal renal tubules.     

重组人脑钠肽对慢性心衰犬血流动力学和肾功能的影响

目的研究国产重组人脑钠肽(rhBNP)对慢性心衰犬血流动力学及肾功能的影响。方法用右心室快速起搏(RVP)或狭窄下腔静脉(TIVCC)形成犬的心衰模型。结果RVP心衰犬iv rhBNP后,平均动脉压(MAP)、左室内压(LVSP)、LVdp/dt、肺动脉压(PAP)、左室舒张末期压(LVEDP)、总外周阻力(TPR)及肾血管阻力(RVR)呈剂量依赖性下降,LVdp/dt/P、左室做功(LVW)、心输出量(CO)和心率(HR)无明显改变;TIVCC心衰犬在iv同剂量rhBNP后,MAP,LVEDP和CO下降,其他心功能指标无明显改变。两种心衰犬给药后尿量和尿钠排出量均增加。结论rhBNP有舒张血管和利尿作用,能明显降低心衰犬的心脏前后负荷,不影响心脏收缩功能。     

EFFECTS OF SODIUM DEPLETION ON TISSUE CONCENTRATIONS OF THE NATRIURETIC HORMONE VASOACTIVE INTESTINAL PEPTIDE

1. Variations in dietary sodium intake have been shown to affect the plasma concentration, the metabolic clearance rate and secretion rate of vasoactive intestinal peptide (VIP). In this study we sought to determine the effect of sodium depletion on the concentration of VIP in plasma and in three tissues, namely heart, lung and kidney. 2. Male Sprague-Dawley rats were placed on low or normal sodium diets and drinking water ad libitum. A third group was placed on a low salt diet and in addition were given frusemide, 1 mg/kg per day in the drinking water. After 7 days the rats were killed, a blood sample collected and tissues harvested. VIP concentrations were determined by radio-immunoassay on unextracted plasma and in tissue after extraction. 3. There were significant differences between the three groups in the Concentration of VIP in the lung (P< 0.0005), kidney (P< 0.005) and plasma (P< 0.025) but not the heart. In the group that received frusemide and the low sodium diet, VIP in the lung was significantly lower than the low sodium (P< 0.005) and normal sodium (P< 0.0001) groups. Similar differences were noted in the kidney (frusemide vs low sodium, P< 0.001; frusemide vs normal, P< 0.01) and plasma (frusemide vs low sodium P< 0.001, frusemide vs normal P< 0.05). 4. We conclude that sodium depletion decreases the concentration of VIP in plasma and in its metabolizing tissues.     

EFFECT OF cGMP INHIBITORS ON THE ACTIONS OF NITRODILATORS IN RAT AORTA

1. The involvement of cGMP in vasodilatation produced by a range of nitrodilators was investigated using two different protein kinase G inhibitors, r_(p) 8-bromoguanosine-3′5′-cyclic monophosphothioate (RBrcGMPS) and KT5823. 2. The nitric oxide donors sodium nitroprusside (SNP), glyceryltrinitrate (GTN) and s-nitroso-acetylpenicillamine (SNAP), the endothelium-dependent vasodilator acetylcholine (ACh) as well as the cGMP analogues 8-(4-chlorophenylthio)-cGMP (CPTcGMP) and β-phenyl-1-N²-etheno-8-bromo-cGMP (PETcGMP) all relaxed rat aortic rings preconstricted with phenylephrine (0.1 μmol/L). 3. The protein kinase G inhibitor KT 5823 (10 μmol/L) produced a very small inhibition of the vasodilatation produced by GTN, but had no effect against vasodilatation produced by SNP, CPTcGMP or PETcGMP, which suggests that KT 5823 is not a useful tool in this system. 4. In contrast, RBrcGMPS (0.5 mmol/L) produced a rightward shift of the concentration-response curves to SNP, CPTcGMP and PETcGMP. RBrcGMPS (0.5 mmol/L) also completely abolished vasodilatation to ACh and GTN but, surprisingly, had no effect on vasodilatation produced by SNAP. 5. The guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 and 10 μmol/L) completely inhibited the relaxation produced by GTN, whereas SNAP still had an appreciable relaxant effect after ODQ (1 μmol/L). 6. The differential effect of RBrcGMPS and ODQ on the nitrodilators suggests that there are differences in the mechanism of dilatation between the nitrodilators.     

RENAL DENERVATION POTENTIATES THE NATRIURETIC AND DIURETIC EFFECTS OF ATRIAL NATRIURETIC PEPTIDE IN ANAESTHETIZED RABBITS

1. The role of the renal nerves in modulating the action of atrial natriuretic peptide (ANP) in the kidney was studied by comparing the responses to ANP in innervated and surgically denervated kidneys in anaesthetized rabbits. 2. A low dose of ANP (0.05 μg/kg per min, i.v.) was used to minimize the confounding effects of systemic hypotension. 3. The natriuretic and diuretic responses to ANP were significantly greater in denervated kidneys than in kidneys with intact innervation. Sodium excretion from denervated kidneys rose by 7.49 ± 3.11 μmol/min in response to ANP (-55%, P<0.05) compared to 0.84 ± 0.59 μmol/min (-28%, NS) in innervated kidneys. Urine flow increased markedly in denervated kidneys by 73.2 ± 29.9 μmol/min (-60%, P<0.05) but not in innervated kidneys. 4. Fractional sodium excretion increased significantly in denervated kidneys in response to ANP (median 2.3% to median 3.0%, P<0.05). 5. Renal blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure were unchanged in response to ANP in either denervated or innervated kidneys. Pre-glomerular vascular resistance fell in denervated kidneys during ANP infusion. 6. The natriuresis and diuresis observed in the denervated kidneys, due to an increased fractional excretion of sodium without increases in GFR or glomerular capillary pressure, is consistent with effects of ANP on tubular reabsorption of sodium. 7. Thus, ANP produced a natriuresis and diuresis at a low dose in denervated but not in innervated kidneys. This indicates that reflex activation of renal nerves may antagonize the renal effects of ANP.     

THE EFFECT OF ATRIAL NATRIURETIC PEPTIDE INFUSION ON RENAL HAEMODYNAMICS AND PLASMA LIPOPROTEINS IN PUROMYCIN AMINONUCLEOSIDE NEPHROSIS IN RATS

1. The effect of continuous intravenous administration of 1 UmUg/h atrial natriuretic peptide (ANP) for 4 days was studied in normal male Sprague-Dawley rats and rats made nephrotic with puromycin aminonucleoside (PA). 2. ANP infusion significantly increased urinary sodium and potassium excretion by 3 days of infusion in control rats but not in PA-treated rats. ANP infusion significantly increased glomerular filtration rate in PA-treated rats, while effective renal plasma flow was similarly decreased compared with non-infused nephrotic rats. 3. Plasma high density lipoproteins (HDL) were significantly decreased and low density lipoproteins (LDL) were increased in PA-treated rats that received ANP; HDL were increased in normal rats infused with ANP. 4. Competitive binding studies demonstrated a lower density of specific ANP receptors in glomerular membranes from rats injected with PA, while binding affinity was unchanged. 5. Infusion with exogenous ANP did not promote natriuresis in PA nephrosis despite an enhancement of glomerular filtration rate (GFR), thus suggesting that sodium retention in this model is due to a post-glomerular defect. Plasma lipoprotein composition in both normal and nephrotic rats may be affected by ANP.     

THE SPECIFICITY OF BILE SALTS IN THE INTESTINAL ABSORPTION OF MICELLAR CHOLESTEROL IN THE RAT

1. Two aspects of cholesterol absorption; (a) the importance of solubilization and (b) the effects of different bile salts on the mucosal metabolism and lymphatic output of cholesterol, have been investigated using two different in vivo techniques. 2. Bile diverted lymph fistula rats were infused intraduodenally at a steady rate with a constant lipid mixture containing labelled cholesterol, labelled oleic acid and mono-olein. The lipids were completely solubilized in either bile salts or a non-toxic non-ionic detergent, Pluronic F68. Labelled fatty acid was efficiently absorbed from either micellar infusate but virtually no labelled cholesterol appeared in the lymph in the absence of bile salts. 3. Short-term perfusions of the intestine of anaesthetized rats with the same micellar perfusates as above showed approximately 20% of the labelled cholesterol in the mucosa after 30 min perfusion with the bile salt micellar solutions. When the non-ionic micelles were used virtually no isotopic cholesterol left the lumen. 4. Mucosal uptake of labelled cholesterol was linearly dependent on the concentration of solubilized cholesterol in the perfusate and was not dependent on the bile salt concentration. 5. After 30 min the total amount of perfused isotopic cholesterol was recovered from either the lumen or the mucosa, but some fatty acid appeared to have been transported away from the mucosa by this time. 6. The initial rate of mucosal uptake of labelled cholesterol was similar from micellar perfusates using either taurocholate, taurodeoxycholate or taurofusidate. In contrast, after 8 h of infusion, lymphatic output of labelled cholesterol was markedly greater with taurocholate. 7. The increased lymph output with taurocholate was associated with an increase in the esterified fraction of both labelled and unlabelled cholesterol. Fatty acid was absorbed and esterified equally from all three types of perfusate. 8. These results suggested that for the first step in cholesterol absorption, viz. uptake from the lumen, solubilization by a planar detergent was essential. After up take, the more rapid transfer of cholesterol to lymph in the presence of trihydroxy bile acids appeared to be related to a more efficient esterification of cholesterol, but not to a more efficient resynthesis of triglyceride, the other major component of lymph chylomicrons.     

POSSIBLE MECHANISMS INVOLVED IN THE NATRIURETIC RESPONSE TO ATRIAL NATRIURETIC FACTOR (ANF) AND PROANF 31–67 IN THE RAT

1. The present study was conducted to compare the mechanisms involved in the natriuretic response to atrial natriuretic factor (ANF) and pro ANF 31–67. The peptides were infused intravenously into anaesthetized rats at 10 pmol/min for 40 min. 2. Only ANF produced a significant decrease in arterial pressure; the maximum decrease was 11 mmHg (P<0.05). 3. Both peptides produced significant increases in sodium excretion (P<0.05) but only ANF increased the cyclic GMP (cGMP) excretion rate (P<0.01) and neither peptide had a significant effect on plasma renin activity or glomerular filtration rate (GFR). Pro ANF 31–67 did not increase the plasma levels of ANF. 4. These results demonstrate that both ANF and proANF 31–67 have natriuretic effects via a tubular mechanism and suggest that the natriuretic effects of ANF are mediated by cGMP while the effects of pro ANF 31–67 are mediated by a different mechanism, not involving changes in cGMP excretion, changes in GFR or a reduction in renin secretion.     

A COMPARISON OF THE CARDIAC ACTIONS OF DOPAMINE AND NORADRENALINE IN ANAESTHETIZED DOGS AND GUINEA-PIG ATRIA

1. The positive chronotropic and inotropic actions of dopamine and noradrena-line have been compared in anaesthetized dogs and isolated guinea-pig atria. 2. Inotropic activity was measured with a strain-gauge arch in vagotomized dogs or estimated from max (dp/dt) in dogs with denervated hearts. 3. The effects of propranolol and haloperidol on the concentration-response curves to both amines were studied in isolated atria. 4. In anaesthetized vagotomized dogs noradrenaline was more potent than dopamine but dopamine appeared to have a selective inotropic action, less apparent with noradrenaline. In denervated hearts, doses of noradrenaline and dopamine which caused similar increases in max (dp/dt) also caused similar increases in heart rate. 5. In isolated atrial preparations, concentrations of dopamine and noradrenaline which produced similar increases in force of contraction also had similar chronotropic effects. 6. Propranolol produced a shift to the right of the concentration-response curves to both dopamine and noradrenaline but the antagonism of noradrenaline was quantitatively greater. Haloperidol had no effect in concentrations below those found to cause general tissue depression. 7. It is concluded that neither dopamine nor noradrenaline show any real difference in their relative inotropic and chronotropic activities in the absence of autonomic innervation.     

EFFECTS OF VOLUME EXPANSION AND CONTRACTION ON PLASMA LEVELS OF ATRIAL NATRIURETIC PEPTIDE IN MAN

1. Effects of saline infusion and blood removal on atrial natriuretic peptide (ANP) in normal subjects were examined in order to better define the magnitude of acute central volume regulatory influences on ANP. 2. Plasma ANP levels increased progressively during volume expansion with saline infusion, increasing by 18% after 30 min and by 93% after 120 min, and did not change during recumbency alone. 3. Plasma ANP levels immediately after a standard blood donation performed semirecumbent were significantly lower than before blood donation; they fell by 18%. 4. The magnitude of the fall in ANP induced by blood donation correlated significantly with basal plasma ANP. 5. In man, ANP responds to both increases and decreases in central blood volume, consistent with a role for ANP in blood volume homeostasis.     

EFFECT OF ATRIAL NATRIURETIC PEPTIDE ON CELLULAR ELEMENT CONCENTRATIONS IN RAT PROXIMAL TUBULES: EVIDENCE FOR INHIBITION OF THE SODIUM PUMP

1. In order to further define the action of atrial natriuretic peptide (ANP) on proximal tubular (PT) transport, combined clearance and electron microprobe X-ray (EMPX) experiments were performed on five male Wistar rats infused with ANP (0.16 nmol/kg per h) and nine control animals. 2. Electron microprobe X-ray analysis of PT cell electrolytes (mmol/ kg wet weight) revealed a similar [Na]_i in both the control and ANP treated groups (16.4 ± 0.4 vs 16.5 ± 0.4; P= 0.894). [Cl]_i was lower in the ANP treated animals (14.8 ± 0.3 vs 12.0 ± 0.3; P<0. 0001) as was [K]_i (131.4 ± 1.4 vs 114 ± 1.7; P<0.0001). The PT cells in the ANP treated group had a significant reduction in dry weight (20.1 ± 0.3 g%vs 19.0 ± 0.3 g%; P<0.024), indicating significant cell swelling. Thus, despite a normal [Na]_i, there was net accumulation of Na_i following ANP treatment. 3. These results are consistent with accumulation of Nai due to inhibition of the Na pump followed by cell swelling and subsequent regulatory volume decrease with exit of K and Cl. These results are the first to show the effect of ANP on PT intracellular electrolytes.     

EFFECT OF OPIATE, GENERAL ANAESTHESIA AND SURGERY ON PLASMA ATRIAL NATRIURETIC PEPTIDE LEVELS IN MAN

1. Animal data suggest that opiates, halothane anaesthesia and activation of the sympathetic system stimulates release of atrial natriuretic peptide (ANP). To examine whether this is so in man, venous ANP levels were measured in five patients undergoing elective cholecystectomy. 2. Plasma levels of cortisol, aldosterone, norepinephrine and epinephrine increased 3-6 fold during the study. Cortisol-aldosterone relationships were close in all patients (r = 0.73-0.97), whereas plasma renin activity and aldosterone correlations were strong in only two subjects. 3. Baseline plasma ANP concentrations were within the normal range and were not altered by opiate injection, anaesthesia, or surgery. 4. Unlike experimental animals, man exhibits little or no ANP response to opiates, halothane, or surgical stimulation of the sympathetic nervous system.     

EVIDENCE AGAINST THE INVOLVEMENT OF VASOACTIVE INTESTINAL PEPTIDE IN OVINE PAROTID SECRETION AND BLOOD FLOW

1. The proposition that stimulation of the secretomotor nerve to the ovine parotid gland might involve co-release of vasoactive intestinal peptide (VIP) was tested by studying responses to infusion of VIP directly into the gland's arterial blood supply and by assay of VIP in parotid venous blood. 2. In unstimulated glands, an arterial blood concentration of 1.5 - 2.5 X 10(-9) mol/L VIP did not evoke fluid secretion but it increased K+ and phosphate secretion and glandular blood flow. The same blood concentration of VIP potentiated the stimulation of salivary flow rate caused by intraarterial infusion of bethanechol but nerve stimulation was not potentiated. VIP increased glandular blood flow in both conditions of stimulation. 3. Atropine blocked neurally stimulated salivary secretion but an increase in glandular blood flow was still detectable. There was therefore no evidence for a non-cholinergic neural mechanism for salivary secretion. 4. Furthermore, VIP concentrations in glandular venous blood were not increased by nerve stimulation. 5. The results indicate that exogenous VIP can affect the flow and composition of ovine parotid secretion but was not involved in the response to secretomotor nerve stimulation.     

INFLUENCE OF EXTRA-INTESTINAL INFLAMMATION ON THE IN VITRO ABSORPTION OF 14C-GLUCOSE AND THE EFFECTS OF ANTIINFLAMMATORY DRUGS IN THE JEJUNUM OF RATS

Inflammation was induced in the hind legs of rats by formalin injection and the in vitro jejunal absorption of ¹⁴C-glucose was studied. Treatment of rats with formalin caused a reduction in the in vitro absorption of glucose from the jejunum. Oral administration of oxyphenbutazone or a herbal anti-inflammatory drug (Withania somnifera) prior to formalin injection, resulted in no alteration in the jejunal absorption of glucose.     

EFFECTS OF ARGININE VASOPRESSIN, ANGIOTENSIN II AND ENDOTHELIN-1 ON THE RELEASE OF BRAIN NATRIURETIC PEPTIDE IN VIVO AND IN VITRO

1. The stimulatory effects of the vasoactive peptides arginine vasopressin (AVP), angiotensin II (AII) and endothelin-1 (ET-1) on the release of brain natriuretic peptide (BNP) were investigated in anaesthetized rats and in cultured rat atrial and ventricular cardiocytes. 2. A bolus injection of AVP induced a dose-dependent increase in plasma immunoreactive (ir)-BNP concentration in rats. AII induced a rapid and transient elevation in the ir-BNP level, while the increase produced by ET-1 was long-lasting. The elevation of the plasma ir-BNP concentration after stimulation by these three vasoconstrictors appeared to be paralleled by the elevation in mean blood pressure. 3. In the in vitro study, the rat atrial and ventricular cardiocytes both secreted ir-BNP into the medium in a time-dependent manner. ET-1 clearly stimulated the secretion of ir-BNP in both atrial and ventricular cardiocytes. In contrast, AVP and AII had no stimulatory effect in vitro. 4. Reverse-phase high performance liquid chromatography of the rat plasma and culture medium revealed a single major ir-BNP component that corresponded to synthetic rat BNP-45. 5. These observations indicate that AVP, AII and ET-1 stimulate the release of ir-BNP (probably rat BNP-45) through a change in blood pressure. In addition, ET-1 may also induce ir-BNP release through direct stimulation. As a cardiac hormone secreted from ventricles as well as atria, rat BNP may play a role in the regulation of blood pressure against the pressor effects of AVP, AII and ET–1.