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.     

SUPPRESSOR CALCIUM INFUSION RAISES PLASMA ATRIAL NATRIURETIC PEPTIDE CONCENTRATIONS IN HUMANS

1. Calcium was infused in normal subjects in subpressor dosage to examine the effects of raised calcium levels on atrial natriuretic peptide (ANP) concentrations. 2. Calcium infusion progressively raised serum ionized and total calcium concentrations significantly, without raising mean arterial pressure or heart rate. 3. Plasma ANP concentrations increased significantly by 5 min of infusion and increased further by 15 min (approximately 40%) to levels which were maintained to 60 min. 4. Urinary sodium excretion increased by 140% during calcium infusion. 5. Calcium may affect secretory as well as contractile functions of the atrial myocyte.     

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.     

IN VIVO AND IN VITRO EFFECTS OF ATRIAL NATRIURETIC PEPTIDE ON RENIN RELEASE

1. This study investigated the effect of atrial natriuretic peptide on renin release from the kidney. The in vitro direct effect was examined in the animal experiment using renal cortical slices of rat, and the in vivo effect was observed in the human infusion study. 2. In the in vitro experiments, alpha-human atrial natriuretic peptide (alpha-hANP) ranging 10(-9) to 10(-6) mol/L did not change the basal renin release rate from the renal cortical slices (-9% at 10(-6) mol/L, NS). Isoproterenol (10(-6) mol/L) increased renin release by 40% (P < 0.001), whereas angiotensin II (10(-6) mol/L) suppressed it by 48% (P < 0.001). However, alpha-hANP did not affect the stimulative effect of isoproterenol or the inhibitory effect of angiotensin II. 3. Also in the human study, infusion of 25 ng/kg per min alpha-hANP failed to change the plasma renin activity in normotensive subjects (-4%) or patients with essential hypertension (+5%), or even in patients with raised renin levels such as renovascular hypertension (+10%) or congestive heart failure (-13%). 4. These results put forth negative views on the direct involvement of atrial natriuretic peptide in renin release from the juxtaglomerular apparatus.     

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 COLLECTING DUCT FUNCTION EVALUATED BY STOP-FLOW IN RABBITS

1. The effect of a low dose of a synthetic atrial natriuretic peptide (ANP), rat atriopeptin II (23 amino acids), on stop-flow sodium concentrations was examined in rabbits in water diuresis. 2. Atrial natriuretic peptide (2 micrograms/kg body weight) was injected intravenously as a bolus either before or after the commencement of stop-flow. 3. Atrial natriuretic peptide induced a significant natriuresis within 2 min of injection. This natriuresis was associated with smaller increases in urine volume and potassium excretion. Atrial natriuretic peptide did not alter blood pressure. 4. Atrial natriuretic peptide did not significantly alter stop-flow sodium concentrations. 5. These findings indicate that ANP does not directly alter sodium transport across medullary collecting ducts. 6. It is proposed that ANP acts via a mediator to alter sodium movement across terminal segments of the nephron.     

ADRENALECTOMY OVERCOMES THE BLUNTED NATRIURETIC RESPONSE TO ATRIAL NATRIURETIC PEPTIDE DURING HYPOCAPNIA IN RATS

1. Hypocapnia has been shown to blunt the natriuretic effect of atrial natriuretic peptide (ANP) independently of the renal nerves. In order to examine whether the adrenal glands are a limiting factor for the natriuretic effect of ANP, we evaluated the natriuretic responses of adrenalectomized rats to ANP infusion during hypocapnia. 2. Rats subjected to total adrenalectomy (ADX) or sham-operation (sham) were divided into hypocapnic and normo-capnic groups depending on their arteria. PCO₂ levels. 3. In sham rats, ANP infusion at a rate of 12 μg/kg per h resulted in a smaller increase in the fractional excretion of sodium during hypocapnia (mean±SEM: 1.02±0.40%, n = 10) than normocapnia (3.95±0.64%, n = 9; P < 0.001). The level of fractional excretion of sodium with ANP infusion during hypocapnia was not significantly different from the level in saline-infused hypocapnic sham rats (0.93 ±0.62%, n= 10). In hypocapnic ADX rats (n= 11), ANP induced greater increases in the fractional excretion of sodium (5.59±1.35%) than did saline infusion (1.04+1.02%, n= 10; P < 0.002). In the absence of adrenal glands, the magnitude of natriuresis after ANP infusion during hypocapnia and normocapnia (3.32 ±1.07%, n = 9) were the same. 4. We conclude that the natriuretic effect of ANP is blunted during hypocapnia in the presence, but not in the absence, of adrenal glands. Our data suggest that the adrenal glands have an important role in limiting the natriuretic effect of ANP.     

INAPPROPRIATELY ELEVATED LEVELS OF ATRIAL NATRIURETIC PEPTIDE MAY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF ORTHOSTATIC HYPOTENSION

1. Overnight recumbent and upright plasma atrial natriuretic peptide (ANP) levels were markedly elevated (P less than 0.001) in patients with orthostatic hypotension (OH). 2. Overnight urinary clearance of ANP was significantly lower (P less than 0.01) in patients with OH, and was inversely correlated with plasma ANP levels (r = -0.94, P less than 0.01). The same negative correlation (r = -0.87, P less than 0.01) was seen in normal subjects. 3. Reduced urinary clearance of ANP may be associated with reduced filtered load and increased binding of ANP to the neutral endopeptidase 24.11 receptor binding sites in the proximal renal tubule. 4. ANP may be involved in the pathophysiology of orthostatic hypotension.     

ATTENUATED RENAL RESPONSE TO ATRIAL NATRIURETIC PEPTIDE INFUSION IN RATS WITH HEART FAILURE

1. The natriuretic and diuretic effects of three atrial natriuretic peptide (ANP) infusion rates were examined in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. 2. The natriuretic and diuretic effects of ANP were observed in controls and rats with infarction, but the effects were significantly attenuated in the latter. 3. Rats with chronic left heart failure were less sensitive to the renal effects of ANP compared with controls. 4. Impaired sodium and water excretion in chronic heart failure may be due partly to an attenuated renal response to ANP.     

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.     

BLUNTED NATRIURETIC RESPONSE TO ENDOGENOUS ATRIAL NATRIURETIC PEPTIDE DURING RAPID CARDIAC PACING IN ANAESTHETIZED DOGS

1. We investigated whether diuresis and natriuresis induced by endogenous atrial natriuretic peptide (ANP) were blunted during rapid cardiac pacing. 2. Changes in plasma ANP, renal function and haemody-namics during rapid cardiac pacing were studied in anaesthetized closed-chest dogs. Dogs were paced via the right ventricle at a rate of 200 b.p.m. (moderate pacing) or 250 b.p.m. (severe pacing) for 180 min. 3. The maximal increases in plasma ANP and urinary excretion of cGMP during severe pacing were four- and three-fold higher, respectively, than those during moderate pacing. Despite the higher concentration of plasma ANP, the maximal increases in urine volume, urinary excretion of sodium and fractional excretion of sodium during severe pacing were similar to those during moderate pacing. Mean arterial pressure and renal vascular resistance were decreased only by severe pacing. The increase in total peripheral resistance during severe pacing was significantly smaller than that during moderate pacing. However, the glomerular filtration rate was kept at basal levels by both moderate and severe pacing. 4. These results suggest that there are certain mechanisms that counteract renal tubular sodium reabsorption induced by endogenous ANP under conditions of severe pacing. The suppression occurs at tubular sites but not at glomerular sites. One of the possibilities for the suppression is the decrease in renal perfusion pressure accompanied by decreases in peritubular capillary hydrostatic pressure.     

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 ANGIOTENSIN AND NORADRENALINE ON ATRIAL NATRIURETIC PEPTIDE LEVELS IN MAN

1. A significant positive correlation was found between changes in circulating noradrenaline (NA) levels and changes in atrial natriuretic peptide (ANP) levels during NA infusion and clonidine administration. 2. A significant positive correlation was also found between changes in arterial blood pressure and changes in ANP level during infusion of angiotensin II and of NA. 3. Two patients with very high circulating NA levels due to phaeochromocytoma, but receiving alpha- and beta-blockade, did not have clearly elevated ANP. A third not receiving medications and aged 73 years had elevated levels. 4. Atrial natriuretic peptide response to NA and angiotensin II may be mediated by changes in blood pressure levels or increased noradrenergic and angiotensinergic receptor activity in the atria or both. Atrial natriuretic peptide may have a role in blood pressure regulation in both normotensive and hypertensive man.     

LEVELS OF ATRIAL NATRIURETIC PEPTIDE ARE NOT ALWAYS CONSISTENT WITH ATRIAL PRESSURE: IS THERE ALTERNATIVE REGULATION AS EVIDENCED IN GORDON'S AND BARTTER'S SYNDROMES?

1. In Bartter's syndrome, atrial pressures were low, consistent with volume contraction, while atrial natriuretic peptide (ANP) levels were unexpectedly elevated. Infusion of normal saline increased both right atrial pressure (RAP) and ANP levels, while administration of prostaglandin inhibitors raised RAP, probably due to volume expansion, but ANP levels fell paradoxically. 2. In Gordon's syndrome, atrial pressures were unexpectedly low or normal despite volume expansion, while ANP levels were normal. Pressor infusions of angiotensin II either raised right and left atrial pressures (LAP) without increasing ANP, or increased ANP without increasing atrial pressures. 3. In these two syndromes, atrial pressures and ANP levels were poorly correlated, leading to the proposal that other regulators of ANP may be important.     

ATRIAL NATRIURETIC PEPTIDE LEVELS IN CONGESTIVE HEART FAILURE IN MAN BEFORE AND DURING CONVERTING ENZYME INHIBITION

1. To determine the response of plasma atrial natriuretic peptide (ANP) to treatment with an angiotensin converting enzyme (ACE) inhibitor in heart failure, seven patients (NYHA Functional Class III-IV) were studied before and after the addition of ramipril to maintenance digoxin and diuretic treatment. 2. Baseline arterial ANP levels were raised, but fell during ramipril treatment in parallel with changes in both haemodynamic recordings (arterial pressure, pulmonary artery diastolic pressure, and right atrial pressure) and hormone levels (angiotensin II and aldosterone). 3. Coronary sinus ANP, measured in three patients, was greater than concomitant arterial levels, and the coronary sinus ANP secretion rate was calculated to be between 15 and 119 pmol/min. 4. These results demonstrate that improvement in haemodynamic function during ACE inhibitor treatment is associated with a decline in elevated ANP levels, and support the concept that atrial stretch or pressure regulates the secretion of atrial peptides in man.     

DECREASED RENAL RESPONSES TO ATRIAL NATRIURETIC PEPTIDE IN RENAL WRAP HYPERTENSION

1. The effects of atrial natriuretic polypeptide (ANP) on renal function were examined in renal wrap hypertensive rabbits and sham operated rabbits. 2. ANP (2 micrograms/min) induced hypotension, but did not produce significant diuresis, natriuresis or change in the glomerular filtration rate (GFR) in renal wrap hypertensive rabbits (n = 8). 3. In sham operated normotensive rabbits (n = 4), ANP induced significant diuresis (230%) and increased GFR by about 40%. 4. Thus, ANP was markedly less effective in the impaired kidneys of renal wrapped rabbits than in normal kidneys.     

EFFECTS OF LOW DOSE INFUSION OF ATRIAL NATRIURETIC FACTOR ON ACUTE INHIBITION OF ANGIOTENSIN CONVERTING ENZYME IN NORMAL MAN

1. We have studied the effects of low dose infusions of atrial natriuretic factor (human ANF (99-126), 1.95 pmol/min per kg) on angiotensin converting enzyme (ACE) inhibitor-induced haemodynamic and hormonal changes in healthy subjects. 2. ACE inhibitor (captopril 25 mg, administered orally) was given against a background infusion of physiological saline (placebo day) or ANF (experimental day). 3. Compared with the placebo observations, ANF enhanced the fall in plasma aldosterone concentrations induced by captopril (P less than 0.05). 4. The rise of plasma renin activity following administration of ACE inhibitor which was observed during placebo infusion was abolished by ANF (P less than 0.05). 5. The responses of systemic blood pressure and heart rate to the converting enzyme inhibition were not affected by the infusion of ANF. 6. These results suggest that variations in endogenous circulating ANF may influence, in part, the response of these hormonal levels during ACE inhibition.     

RENAL INTERACTION OF ATRIAL NATRIURETIC PEPTIDE WITH ANGIOTENSIN II: GLOMERULAR AND TUBULAR EFFECTS

1. The possible interactions between the renal effects of atrial natriuretic peptide (ANP) and angiotensin II (AII) were studied in normal sodium-replete human subjects. Recent investigations have suggested that ANP inhibits the pressor and volume-retaining effects of activation of the renin-angiotensin system. Thus, ANP may attenuate the effects of AII on renal haemodynamics or tubular transport. 2. ANP (0.1 micrograms/kg per min, 60 min) was intravenously infused into eight normal human subjects with and without pretreatment with enalapril (20 mg, per oral), an inhibitor of the converting enzyme, and during infusion of AII (10 mg/kg per min). 3. ANP infusion alone caused increases in the urine volume (from 96 +/- 23 to 229 +/- 44 mL/h, P less than 0.05) and urinary sodium excretion (from 11.5 +/- 1.6 to 20.9 +/- 4.2 mEq/h, P less than 0.05). These changes were accompanied by an increase in the glomerular filtration rate (from 127 +/- 9 to 158 +/- 9 mL/min, P less than 0.05). ANP infusion after enalapril administration lowered the mean blood pressure (from 76 +/- 2 to 71 +/- 3 mmHg, P less than 0.05) to a level similar to that observed during ANP infusion alone (from 84 +/- 2 to 74 +/- 2 mmHg, P less than 0.01), but did not result in a significant diuresis (from 139 +/- 23 to 174 +/- 51 mL/h) or natriuresis (from 19.7 +/- 2.5 to 14.3 +/- 3.4 mEq/h, P less than 0.05). This combined treatment with a converting enzyme inhibitor and ANP reduced both the glomerular filtration rate (160 +/- 9 to 141 +/- 10 mL/min) and the renal plasma flow (from 775 +/- 49 to 570 +/- 45 mL/min, P less than 0.01). 4. The antinatriuretic effects of exogenous AII were reversed by superimposed ANP infusion (urinary sodium excretion: from 4.8 +/- 1.0 to 24.3 +/- 5.2 mEq/h, P less than 0.01). Under these conditions, the glomerular filtration rate increased (from 114 +/- 6 to 156 +/- 7 mL/min, P less than 0.05) to levels similar to those observed with ANP infusion alone. In addition the increased tubular sodium reabsorption induced by AII was inhibited by concomitant ANP infusion (fractional proximal tubular sodium reabsorption: from 90.7 +/- 3.5 to 80.3 +/- 16.6%, P less than 0.05, fractional post-proximal tubular sodium reabsorption: from 91.5 +/- 9.8 to 87.6 +/- 8.8%, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

NATRIURETIC AND HYPOTENSIVE EFFECTS OF BRAIN NATRIURETIC PEPTIDE IN ANAESTHETIZED DOCA-SALT HYPERTENSIVE RATS

1. Both natriuretic and hypotensive effects of brain natriuretic peptide (BNP), a novel peptide identified in porcine brain, were investigated in anaesthetized DOCA-salt rats and control rats. 2. An intravenous injection of two different doses (0.5 and 5.0 nmol/kg) of BNP produced a rapid and marked natriuresis and hypotension in DOCA-salt rats. 3. In particular, significant differences of responsiveness were observed between DOCA-salt and control rats when administered the lower dose of BNP. 4. It was suggested that DOCA-salt rats might be relatively more susceptible to BNP.