Effect of physiological levels of atrial natriuretic peptide on hormone secretion: inhibition of angiotensin-induced aldosterone secretion and renin release in normal man

Large doses of atrial natriuretic peptide (ANP) inhibit renin and aldosterone secretion in normal man, but the effect of physiological levels is unknown. We, therefore, studied the effect of a low infusion rate of alpha-human ANP (alpha hANP; 0.5 microgram/min for 180 min) on the plasma corticosteroid response to graded physiological doses of angiotensin II (0.5, 1.0, 2.0, and 4.0 ng/kg X min, each for 30 min) and ACTH (6.25, 12.5, 25, and 50 mIU, each for 30 min) in six normal men eating a low salt diet (10 mmol sodium and 100 mmol potassium daily). The angiotensin II and ACTH infusions were given from 0900-1100 h on separate days, during which randomized infusions of placebo or alpha hANP were given from 0800-1100 h according to a single blind protocol. Plasma immunoreactive ANP levels were less than 10 pmol/L on the placebo day compared to 30-50 pmol/L during the alpha hANP infusions, and were not altered by either ACTH or angiotensin II. Compared with the control observations, there was no significant change in arterial pressure or heart rate during either the alpha hANP or angiotensin II infusions. ACTH infusions evoked an incremental response in plasma aldosterone and cortisol, and the dose-response relationship was unaltered by alpha hANP. In contrast, while an incremental and significant increase in plasma aldosterone in response to angiotensin II occurred with the placebo infusion, no significant increase occurred in response to angiotensin during the alpha hANP infusion. The slope of the angiotensin II/aldosterone regression line was significantly less during all alpha hANP infusions compared to that during the placebo infusion (P less than 0.02). In addition, on the ACTH infusion day significant suppression of both PRA (P less than 0.05) and plasma angiotensin II (P less than 0.008) occurred during the alpha hANP infusion compared to that during the placebo infusion, whereas PRA was equally suppressed by angiotensin II in the presence or absence of alpha hANP. alpha hANP also increased urine volume [176 +/- 31 (+/- SEM) vs. 113 +/- 19 mL/mmol creatinine with placebo; P less than 0.03] and sodium excretion (2.14 +/- 0.48 vs. 0.58 +/- 0.22 mmol/mmol creatinine with placebo; P less than 0.004) on the ACTH infusion days. With angiotensin II, urine volume was also significantly increased by alpha hANP (150 +/- 27 vs. 81 +/- 15 mL/mmol creatinine with placebo; P less than 0.03), and urine sodium excretion doubled.(ABSTRACT TRUNCATED AT 400 WORDS)     

Renal effects of atrial natriuretic peptide during dopamine infusion

To study whether the renal effects of atrial natriuretic peptide (ANP) are different from those of dopamine, we compared the effects of dopamine and dopamine plus ANP on renal circulation. Dopamine was infused at 1 microgram/kg/min for 120 min into 7 patients with essential hypertension (EH) and 5 normotensive subjects (NT). After 40 min of dopamine infusion, ANP infusion at 25 ng/kg/min was added to dopamine for 40 min. Before, during and after the infusion, renal function and nephrogenous cGMP were determined. Dopamine did not influence blood pressure, but increased urinary Na excretion (UNaV) by 100% in EH and NT. Addition of ANP further increased UNaV by 90%, but increases in UNaV were greater in EH than in NT. Renal blood flow was increased only by dopamine, while glomerular filtration rate (GFR) was increased by both dopamine (+8%) and dopamine plus ANP (+7%) as a whole, resulting in a significant increase in filtration fraction by the addition of ANP. Plasma and urinary cGMP and nephrogenous cGMP were elevated only during ANP infusion. These results suggest that the effects of ANP and dopamine on both GFR and UNaV were additive. However, in contrast with dopamine, ANP increased efferent resistance and nephrogenous cGMP, suggesting that the renal effects of ANP are different from those of dopamine.     

Renal and adrenal resistance against atrial natriuretic peptide in congestive heart failure: effect of angiotensin I-converting-enzyme inhibition

We compared the natriuretic and diuretic effect of an intravenous infusion of 1-28 human atrial natriuretic peptide (hANP) (0.1 micrograms/kg/min over 30 min) in 10 patients with congestive heart failure (CHF) and in 10 control subjects of similar age and sex. In the controls, urine volume rose from 36.8 +/- 8.55 to 115.6 +/- 34.2 ml/30 min and urinary sodium excretion from 4.55 +/- 0.8 to 11.2 +/- 2.24 mEq/30 min before and during the infusion of ANP, respectively. In patients, baseline urine volume and sodium output were similar, however, rise in urine volume and urinary sodium was greatly reduced during the infusion of hANP. In patients with CHF, baseline plasma ANP levels (604.1 +/- 135.3 vs. 39.4 +/- 5.85 pg/ml; p less than 0.005) and urinary excretion of cyclic GMP (cGMP) (41.8 +/- 5.22 vs. 15.2 +/- 4.19 nmol/30 min; p less than 0.05) were significantly elevated compared to controls. The absolute and relative rise in cGMP excretion, however, was blunted in patients with CHF. In the controls, angiotensin I-converting-enzyme (ACE) inhibition by enalapril significantly reduced the urinary output of sodium and water after ANP infusion. Plasma ANP levels and urinary cGMP remained unaltered by ACE inhibition. Furthermore, treatment with enalapril resulted in a rise in renin and a drop in aldosterone levels. The reduction of plasma renin and serum aldosterone by ANP was maintained after ACE inhibition. In the patient group, administration of enalapril (3 X 2.5 mg every 6 h) reduced ACE activity in the serum from 84.7 +/- 16.9 to 2.13 +/- 0.88 U/l. Arterial blood pressure was lowered from 114.7 +/- 6.69 to 106.1 +/- 7.25 mm Hg systolic and from 76.9 +/- 3 to 69.2 +/- 3.7 mm Hg diastolic. However, natriuresis and diuresis and creatinine clearance following infusion of ANP remained unaltered.     

Low dose infusions of 26- and 28-amino acid human atrial natriuretic peptides in normal man

To investigate the effects of a small rise in the plasma atrial natriuretic peptide (ANP) concentration, 6 normal subjects received 2-h low dose (2 pmol/kg.min) infusions of both 28 [human alpha hANP-(99-126)]- and 26 [human ANP-(101-126)]-amino acid peptides in a placebo-controlled study. Both peptides induced more than 2-fold increases in urinary sodium, calcium, and magnesium excretion. Effective renal plasma flow was slightly reduced, glomerular filtration rate did not change, and renal filtration fraction increased during the ANP infusions. Plasma renin, angiotensin II, and aldosterone concentrations fell by about 50%. Arterial blood pressure and plasma catecholamines did not change. Hematocrit and serum albumin concentrations rose significantly. ANP effects on urinary electrolytes and the renin-angiotensin-aldosterone system were sustained for over an hour after completion of the ANP infusions. The two peptides did not differ in their effects. These results are consistent with a physiological role for plasma ANP in the regulation of extracellular fluid volume and demonstrate that minor N-terminal truncation of alpha hANP has little effect on its biological activity.     

The significance of cGMP and dopamine receptor on the natriuretic and hypotensive activities of synthetic atrial natriuretic polypeptide in essential hypertension

This study was undertaken to clarify the role of dopamine receptor (DA2) on the effects of atrial natriuretic polypeptide(ANP) on blood pressure, plasma and urinary cyclic GMP, and urinary sodium excretion, alpha-human ANP (alpha-hANP) was intravenously administrated to 7 normal subjects and 14 patients with essential hypertension as follows: first a dose of 0.01 micrograms/kg/min for 30 minutes, and then 0.03 micrograms/kg/min with or without metoclopramide(MC) for 30 minutes. After the infusion of the 0.03 micrograms/kg/min dose of alpha-hANP, systolic blood pressure fell from 115 +/- 17 mmHg to 109 +/- 15 mmHg in normal subjects, and fell significantly from 163 +/- 33 mmHg to 145 +/- 26 mmHg in patients with essential hypertension. Diastolic blood pressure fell from 101 +/- 14 mmHg to 92 +/- 7 mmHg in patients with essential hypertension but did not change in normal subjects. A dose of 0.03 micrograms/kg/min of alpha-hANP led to a threefold rise in urine volume and twofold rise in urinary sodium excretion in normal subjects, and a fivefold rise in urine volume and fourfold rise in urinary sodium excretion in patients with essential hypertension. However, there was no relationship between the hypotensive and natriuretic effects of alpha-hANP in either normal subjects or patients with essential hypertensions. The infusion of a 0.03 micrograms/kg/min dose of alpha-hANP increased plasma cyclic GMP concentration from 4.1 +/- 2.1 pmol/ml to 34.3 +/- 25.Opmol/ml in normal subjects and from 4.5 +/- 2.6 pmol/ml to 20.3 +/- 7.4 pmol/ml in patients with essential hypertension. The rise in plasma cyclic GMP by alpha-hANP was suppressed by MC both in normal subjects and patients with essential hypertension. Urinary cyclic GMP excretion also increased during the infusion of alpha-hANP, but this effect was not suppressed by MC. Furthermore, plasma aldosterone concentration (PAC), which was depressed by alpha-hANP in normal subjects and patients with essential hypertension, was increased by MC. These results suggest that the hypotensive effect of alpha-hANP may depend not only on the natriuretic effect, but also on vasodilatation, the inhibition of aldosterone production or the suppression of the sympathoadrenomedullary system. Cyclic GMP may be produced through the DA2 receptor in vascular tissue but not in the kidney.     

Renal, hemodynamic, and hormonal responses to atrial natriuretic peptide infusions in normal man, and effect of sodium intake

The effect of 60-min constant iv infusions of alpha-human atrial natriuretic peptide (alpha hANP; 200 micrograms), sufficient to increase the steady state venous plasma alpha hANP concentration to levels found in patients with some circulatory disorders, was studied in six normal men equilibrated on a high sodium diet (200 mmol daily) and again when equilibrated on a low sodium intake (10 mmol daily). In each instance, the responses to alpha hANP were compared to those to control infusions given on the preceding day. The mean steady state plasma immunoreactive ANP concentration during the infusions was 320 pmol/liter and was the same during both diets. Thus, the MCR of alpha hANP was unaffected by major changes in sodium intake. Compared to control day observations, infusions of alpha hANP induced a more than 3-fold increase in sodium excretion and at least a 2-fold increase in urine volume and calcium and magnesium excretion in subjects ingesting 200 mmol sodium daily. During the low sodium diet, alpha hANP was still diuretic and induced comparable magnesium excretion, but the natriuresis was only 11% of that during the high salt diet. No significant changes in blood pressure or heart rate occurred during alpha hANP infusions during either diet, although during both diets there was a significant rise in plasma norepinephrine (P less than 0.02), which persisted well beyond the disappearance of immunoreactive ANP from plasma. Despite this sympathetic activation, renin and aldosterone production was reduced by alpha hANP. During low salt intake, alpha hANP significantly decreased PRA (mean pretreatment, 1.79; posttreatment, 1.25 nmol/liter/h; P less than 0.03), angiotensin II (mean pretreatment, 49; posttreatment, 28 pmol/liter; P less than 0.008), and plasma aldosterone (mean pretreatment, 554; posttreatment 307 pmol/liter; P less than 0.007), whereas values during control infusions did not change. Similar percent decreases in PRA and aldosterone also occurred during the high salt diet. Plasma cortisol and arginine vasopressin did not change during the alpha hANP infusions on either diet. We conclude that steady state levels of alpha hANP in plasma, similar to those in patients with some circulatory disorders, significantly increase sodium excretion and inhibit all elements of the renin-angiotensin-aldosterone system. The natriuretic, but not the hormonal or chronotropic, effects of alpha hANP are reduced by sodium depletion in normal man.     

Plasma levels and cardiovascular, endocrine, and excretory effects of atrial natriuretic peptide during different sodium intakes in man

Endogenous plasma concentrations of human atrial natriuretic peptide (alpha hANP) as well as effects of synthetic alpha hANP on some cardiovascular, endocrine, and renal excretory parameters were investigated in 10 normal subjects during sodium (Na+) intakes of 17, 140, and 310 mmol/day, respectively. Plasma hANP was slightly but not significantly higher after 5 days of normal or high sodium intake than after 5 days of low sodium intake [54 +/- 13, 46 +/- 8, and 37 +/- 5 (mean +/- SEM) pg/ml, respectively]. alpha hANP infused at 0.1 microgram/kg X min during all Na+ intakes produced a similar fall in diastolic blood pressure (P less than 0.001) and rise in heart rate (P less than 0.001), a comparable percent increase in plasma norepinephrine (P less than 0.001), and a reduction in plasma cortisol and aldosterone (P less than 0.01-0.001) despite raised renin activity (P less than 0.05-0.001) and unchanged plasma electrolytes. alpha hANP-induced plasma volume contraction, diuresis, and natriuresis were greater during high than low Na+ intake (P less than 0.01-0.001). Therefore, in normal man different Na+ intakes are accompanied by marked modifications in renal excretory responsiveness to alpha hANP. Regardless of sodium intake, alpha hANP can promote BP reduction and hemoconcentration, elicit reflex (?) sympathetic activation, and depress basal circulating aldosterone and cortisol levels in the face of an activated renin system.     

Clinical evaluation of the captopril screening test for primary aldosteronism

In order to investigate the validity of angiotensin converting enzyme inhibition with captopril as a screening test for primary aldosteronism (PA), 50 mg of captopril were administered orally to 7 patients with PA, 17 with essential hypertension (EH), 5 with renovascular hypertension (RVH), 2 with renoparenchymal hypertension (RH) and 8 normal volunteers. The plasma aldosterone concentration (PAC) was suppressed to less than 15 ng/dl in all of the EH, RVH and RH patients and normal subjects 90 min after administration of captopril, but not suppressed in 6 of 7 patients with PA. In addition, the plasma renin activity (PRA) was increased to greater than 1 ng/ml/h in 10 of 17 patients with EH and in all with RVH, RH and the normal controls, but to less than that in 6 of 7 PA and the remaining EH patients. The PAC to PRA ratio after captopril was greater than 20 in all patients with PA, while it remained below 20 in EH, RVH and RH patients and normal controls. From these results, we conclude that the PAC to PRA ratio in the captopril administration test is a simple and useful tool to detect PA in hypertensive patients. In addition, the test has a great advantage in that it can be safely applied to outpatients with relatively severe hypertension.     

Brain natriuretic peptide and neutral endopeptidase inhibition in left ventricular impairment

Brain natriuretic peptide (BNP) is increased in left ventricular impairment and neutral endopeptidase (NEP) is involved in its metabolism. In random order, eight patients with left ventricular impairment received placebo, a 4-h infusion of human BNP (3.0 pmol/kg min), a single oral dose of NEP inhibitor (SCH 42495, 300 mg), and combined BNP and SCH 42495. Plasma BNP, cGMP, and cortisol were significantly increased by all three treatments (P < 0.05-P < 0.001). Combined treatment had a synergistic effect on plasma cGMP. The metabolic clearance rate of exogenous BNP was reduced (25%) by NEP inhibition. Endogenous plasma ANP was augmented more than BNP by NEP inhibition. Plasma aldosterone, unchanged during infusions, rose markedly after BNP and after the combined treatment (P < 0.05 for both). Urine sodium excretion, increased by NEP inhibition (P < 0.05) and by BNP (P = 0.05), was unchanged during combined treatment. Urine cGMP excretion was increased, whereas blood pressure was reduced by all active treatments (P < 0.05-0.01 for all). Heart rate increased only with combined treatment (P = 0.007). Plasma renin activity, norepinephrine, and cardiac output were unaffected. BNP infusion and NEP inhibition both induced significant hemodynamic and renal responses. The augmented hypotensive effect of combined treatments, and consequent fall in renal perfusion pressure, may underly the observed blunting of the natriuretic response that occurred despite greater than additive increments in plasma BNP, ANP, and cGMP.     

Atrial natriuretic peptide in liver cirrhosis with mild ascites

To clarify the involvement of atrial natriuretic peptide (ANP) in the pathogenesis of liver cirrhosis, we measured plasma ANP in patients with various stages of cirrhosis and in age-matched normal subjects. Urinary cyclic guanosine monophosphate (cGMP) was also measured as a marker of active biological ANP. In addition, effects of exogenous synthetic human ANP (0.5 micrograms/kg) on renal functions were examined in normal subjects and in cirrhotics without ascites or with mild ascites. Plasma ANP levels were not significantly different among these 3 groups. Urinary cGMP concentrations were significantly higher in both cirrhotics without ascites and cirrhotics with mild ascites, (340 pmol/ml, P less than 0.05 and 496 pmol/ml, P less than 0.01 respectively) than normal subjects (95 pmol/ml). In normal subjects, marked increases in urinary volume (UV), sodium excretion (UNaV), fraction excretion of sodium (FENa) and free water clearance (CH2O) were induced after ANP infusion, and significant recoveries were subsequently observed in these parameters. However, in cirrhotics, the responses to ANP infusion of UV, FENa and CH2O were far less dramatic. The response of UV, UNaV and FENa in cirrhotics with mild ascites was delayed compared to cirrhotics without ascites. These results suggest that the blunted natriuretic responsiveness to ANP is contributory to the pathogenesis of initial sodium retention in cirrhotics.     

Antihypertensive and hypotensive effects of atrial natriuretic factor in men

Synthetic atrial natriuretic factor (ANF) was administered in ascending doses (0.03, 0.20, 0.45 microgram/kg/min) to eight mildly essential hypertensive men on high (200 mEq/day) or low (10 mEq/day) sodium diets. Responses of blood pressure, heart rate, urinary volume and electrolyte excretion, renin, and aldosterone were measured. For the entire group, ANF lowered blood pressure and increased heart rate during the 0.20 and 0.45 microgram/kg/min infusions, and the antihypertensive effect of the peptide persisted for at least 2 hours after the infusions ended. Four patients (2 at 0.20 microgram/kg/min and 2 at 0.45 microgram/kg/min) experienced sudden bradycardia and hypotension at the end of or shortly after completion of ANF infusion. Renal excretion of water, sodium, chloride, calcium, and phosphorus increased in a dose-dependent fashion in response to infused ANF. Patients on the 200 mEq/day sodium diet had greater increases in urinary volume (11.1 +/- 2.8 vs 3.0 +/- 2.0 ml/min; p less than 0.05), sodium (870 +/- 134 vs 303 +/- 27 microEq/min; p less than 0.05), and chloride (801 +/- 135 vs 176 +/- 75 microEq/min; p less than 0.02) compared with patients on the low sodium diet. The apparent direct suppressive effect of a 0.03 microgram/kg/min infusion of ANF on renin and aldosterone levels was overcome at higher doses by counterregulation provoked by the depressor action. Renin was slightly (-12%) suppressed during the 0.03 microgram/kg/min infusion of ANF but increased at the 0.20 (+50%) and 0.45 microgram/kg/min (+90%; p less than 0.03) rates. Aldosterone declined significantly during the 0.03 microgram/kg/min infusion (-45%; p less than 0.01) of ANF but not during the two higher dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of plasma alpha-human atrial natriuretic polypeptide on natriuretic and diuretic effects in patients with nephrotic syndrome

The physiological mechanism regulating secretion of alpha-human atrial natriuretic polypeptide (alpha hANP) was studied by measuring plasma alpha hANP (P alpha hANP) with radioimmunoassay during water immersion (WI). Twelve healthy volunteers and sixteen patients with nephrotic syndrome were immersed in water for 4 hours. During WI, alpha hANP level and urinary cGMP excretion (UcGV) increased significantly both in volunteers and patients, the urinary volume (UV) and urinary Na excretion (UNaV) also increased significantly. The mean peak values of alpha hANP and UcGV in volunteers were significantly lower than those in the patients, whereas the mean values of UV and UNaV in the former were significantly higher than those in the latter. The increase in alpha hANP level in volunteers correlated positively with the increase of UNaV, UV and UcGV during WI. The close correlations between the increased alpha hANP level and the increased UNaV, UV and UcGV was shown in the patients. These results suggest that alpha hANP is released into the circulation by acute central hypervolemia and plays a physiologically important role in maintaining water and electrolytes homeostasis in normal subjects and that the increased alpha hANP level in nephrotic syndrome makes compensatory regulation in water and electrolytes disorders.     

Blunted vascular and renal effects of exogenous atrial natriuretic peptide in patients with cushing's disease

The role of atrial natriuretic peptide (ANP) in glucocorticoid hypertension is still controversial, as glucocorticoids enhance the secretion of ANP in vivo, but reduce its biological activity in vitro. In isolated cells, for example, the cGMP response to ANP is suppressed by dexamethasone. We tested the in vivo relevance of this observation by comparing the cGMP, endocrine, and renal responses to exogenous ANP in patients with Cushing's disease (CD; n = 10) and in a matched group of essential hypertensives (EH; n = 8) and normotensive controls (N; n = 4). alpha-human-ANP was infused at 0.01 microg/kg/min for 120 min with a 30-min recovery period; hormonal and arterial pressure measurements were performed at 30-min intervals, and renal parameters were measured at baseline and after infusion. There was a 4-fold increase in plasma ANP in all groups, but the increments in plasma cGMP were about 50% lower in CD than in N and EH; urinary cGMP was similarly lower in CD (247 +/- 61 vs. 529 +/- 146 and 384 +/- 54 nmol/150 min, respectively). This was associated with a reduced peak increase in hematocrit in CD (+2.6 +/- 0.9%) compared with N (+6.6 +/- 0.9%) and EH (+7.1 +/- 0.7%; P < 0.05 CD vs. both); the diuretic and natriuretic effects of ANP were also lower in CD than in EH with very similar systemic pressure levels (382 +/- 63 vs. 848 +/- 130 mL/150 min, and 61 +/- 14 vs. 113 +/- 14 mmol/150 min, respectively; P < 0.05 for both). The increments in plasma and urinary cGMP in response to physiological doses of ANP are thus blunted in CD patients compared with those in N and EH. This biochemical defect is associated with reduced capillary permeability and a lesser diuretic and natriuretic effect. These data are compatible with an impairment of the biological activity of ANP in glucocorticoid hypertension in humans.     

Renal and hemodynamic effects of atrial natriuretic peptide in patients with cirrhosis

The effects of anaritide, a 25-amino-acid synthetic analogue of ANP, were evaluated in 28 patients with cirrhosis complicated by ascites and/or edema. Each patient received two doses of the agent, as well as an infusion of placebo. Six different doses were tested ranging from 0.015-0.300 microgram/kg/min. The infusions lasted for 2 hours and were flanked by both baseline and recovery periods. There was a significant effect of placebo on urinary sodium and chloride excretion rates but no effect on urine flow rate. In response to anaritide, the urine flow rate increased at 0.03, 0.06, 0.075, and 0.100 microgram/kg/min. The sodium and chloride excretion rates increased at all doses except the highest dose. There was no definite effect of anaritide on urinary potassium, calcium, and phosphate excretion rates. There was also no significant effect on creatinine clearance. The mean arterial pressure decreased in response to the 0.060, 0.075, and 0.100 microgram/kg/min doses. In addition, five of the patients receiving the highest dose (0.300 microgram/kg/min) had decreases in their systolic pressures to 90 mm Hg or less. In conclusion, anaritide is natriuretic and diuretic in patients with cirrhosis complicated by ascites and/or edema. Its effect, however, on arterial pressure may limit its therapeutic potential in this patient population.     

Atrial natriuretic peptide in liver cirrhosis with mild ascites

To clarify the involvement of atrial natriuretic peptide (ANP) in the pathogenesis of liver cirrhosis, we measured plasma ANP in patients with various stages of cirrhosis and in age-matched normal subjects. Urinary cyclic guanosine monophosphate (cGMP) was also measured as a marker of active biological ANP. In addition, effects of exogenous synthetic human ANP (0.5 Μg/kg) on renal functions were examined in normal subjects and in cirrhotics without ascites or with mild ascites. Plasma ANP levels were not significantly different among these 3 groups. Urinary cGMP concentrations were significantly higher in both cirrhotics without ascites and cirrhotics with mild ascites, (340 pmol/ml, P<0.05 and 496 pmol/ml, P<0.01 respectively) than normal subjects (95 pmol/ml). In normal subjects, marked increases in urinary volume (UV), sodium excretion (UNaV), fraction excretion of sodium (FENa) and free water clearance (CH₂O) were induced after ANP infusion, and significant recoveries were subsequently observed in these parameters. However, in cirrhotics, the responses to ANP infusion of UV, FENa and CH₂O were far less dramatic. The response of UV, UNaV and FENa in cirrhotics with mild ascites was delayed compared to cirrhotics without ascites. These results suggest that the blunted natriuretic responsiveness to ANP is contributory to the pathogenesis of initial sodium retention in cirrhotics. This study was presented in part in the 25th annual meeting of the Japanese Association for the Study of the Liver, June, 1, 1989 Kanazawa, Japan.     

Changes in the levels of plasma atrial natriuretic peptide, hemodynamic measurements, and the levels of vasoactive hormones during the clinical course of congestive heart failure

To investigate the mechanism for the release of human atrial natriuretic peptide (hANP) and the pathophysiological role of hANP in patients with congestive heart failure (CHF), plasma hANP levels in patients with dilated cardiomyopathy (DCM) or acute myocardial infarction (AMI) were determined serially, and the relationship between plasma ANP levels and hemodynamic measurements or various vasoactive hormones was analyzed during the clinical course of congestive heart failure. In 63 patients with either AMI or DCM, plasma hANP, plasma renin activity, aldosterone concentration, and catecholamines were measured over 4 weeks, during the course of CHF. Cardiac catheterization with a Swan-Ganz catheter was also performed. Plasma hANP in patients with DCM was elevated continuously during the clinical course. Plasma hANP levels in patients with AMI of Groups II and IV of Forrester's class decreased on days 7 and 14 and those in patients with AMI of Group I changed within normal limits. Plasma hANP levels were correlated positively with pulmonary artery pressure and pulmonary capillary wedge pressure in patients with AMI or DCM. Plasma renin activity, noradrenaline, and adrenaline levels were elevated in the acute phase of myocardial infarction and had a tendency to decrease upon improvement in clinical status. Plasma renin activity and noradrenaline level correlated positively with plasma hANP levels. These data indicate that plasma hANP levels are regulated by atrial distension and severity of cardiac impairment, and that plasma hANP and plasma renin activity or catecholamines correlated closely during the clinical course of CHF, indicating that these hormones may be involved in the volume and electrolytes status in CHF.     

Cardiovascular, renal and endocrine effects of alpha-human atrial natriuretic peptide in patients with Cushing's syndrome and primary aldosteronism

The pharmacological effects of synthetic alpha-human atrial natriuretic peptide (alpha-hANP) in patients with Cushing's syndrome and primary aldosteronism were compared with those in normal volunteers. An infusion of synthetic alpha-hANP at 0.1 microgram/kg per min for 20 min produced a maximal plasma hANP level of 800-1200 pg/ml in patients with Cushing's syndrome and primary aldosteronism, and in normal subjects. There were significant decreases in the mean blood pressure (-10 to -15 mmHg) in patients with Cushing's syndrome and primary aldosteronism, similar to those in normal subjects. The plasma cyclic 3'5'-guanosine monophosphate (cGMP) concentrations of both groups of patients were increased fivefold over the baseline level following the infusion. Infusion of synthetic alpha-hANP caused a greater increase in the rate of sodium excretion in patients with Cushing's syndrome and primary aldosteronism compared with normal volunteers. The plasma cortisol and aldosterone concentrations did not, however, significantly change during alpha-hANP infusion in either the patients with Cushing's syndrome or those with primary aldosteronism. As synthetic alpha-hANP has a potent hypotensive effect in hypertensive patients with Cushing's syndrome and primary aldosteronism, a significant reduction in blood pressure and natriuresis seems to occur without affecting adrenocortical steroidogenesis.     

Modulation of the natriuretic response to atrial natriuretic peptide by alterations in peritubular Starling forces in the rat

The mechanisms underlying the natriuretic response to infusions of atrial natriuretic peptide (ANP) remain incompletely defined. By acting as renal vasodilators, atrial peptides may serve to alter peritubular capillary physical forces and favor a decrease in tubule solute reabsorption. Therefore, we studied the effects of known modifiers of intrarenal Starling forces on the natriuresis induced by infusion of intravenous hANP [4-28] (0.5 microgram/kg/min) in anesthetized, euvolemic Munich-Wistar rats. In the first series of studies, infusion of ANP resulted in a significant natriuresis, diuresis, and increase in inulin clearance and in a slight fall in systemic arterial pressure, as compared to vehicle infusion. Subsequent elevation of renal perfusion pressure by superimposition of angiotensin II infusion (0.1-0.2 microgram/kg/min i.v.) on continued ANP infusion resulted in marked further enhancement of natriuresis, independent of changes in glomerular filtration rate (GFR). In the second set of experiments, in which oncotic pressure in the postglomerular capillaries was elevated by hyperoncotic exchange transfusion, administration of ANP did not result in natriuresis, even though GFR increased by the same magnitude as that seen in isooncotic animals given ANP. These observations are consistent with the view that peritubular capillary hydraulic and oncotic pressures modulate the natriuretic and diuretic effects of ANP.     

Effects of repeated atrial natriuretic peptide bolus injections in cirrhotic patients with refractory ascites

The renal and hormonal effects of repeated atrial natriuretic peptide (ANP) boli (1 microgram/kg of body weight) were studied in eight cirrhotic patients with refractory ascites. Under basal conditions the patients showed a striking activation of the renin-angiotensin-aldosterone system (plasma renin activity 19.3 +/- 3.0 ng/ml.h, plasma aldosterone concentration 3.87 +/- 0.58 ng/ml) and a tenfold elevation in plasma ANP levels compared to healthy subjects (131.7, range 47.0-288.6, vs. 9.8, range 5.0-15.0, fmol/ml, p less than 0.001). The first ANP injection was followed by a remarkable increase in plasma ANP levels and by a slight increase in urinary cyclic guanosine-monophosphate excretion (from 1050.8 +/- 454.8 to 1446.6 +/- 822.2 pmol/min). A significant reduction of mean blood pressure (MBP) occurred 5 min after the first injection (from 86.7 +/- 7.2 to 79.9 +/- 5.8 mmHg, p less than 0.05), but values gradually returned to the baseline after 30 min. Heart rate (HR) increased 10 min after the first bolus injection (from 83.75 +/- 4.7 to 88.1 +/- 4.6 beats/min) and reached baseline values after 30 min. Similar behaviour of MBP and HR was observed after the second, third and fourth bolus injections. Urinary sodium excretion, urinary flow, glomerular filtration rate, plasma renin activity, and plasma aldosterone concentration did not show any significant modification during ANP administration, nor did these parameters change in the following 12-h recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disruption of the relationship between renin and atrial natriuretic peptide early in the course of ventricular dysfunction

BACKGROUND: Plasma renin activity is normal in left ventricular dysfunction in the absence of diuretic therapy. In health there is a reciprocal relationship between renin and atrial natriuretic peptide (ANP) but a positive correlation in advanced heart failure. The relationship between renin and ANP in mild left ventricular dysfunction is unknown. METHODS AND RESULTS: Patients with left ventricular dysfunction (n = 35, 18 without diuretic therapy) were compared to 20 age-matched healthy subjects. Plasma concentrations of active renin (PARC), ANP and norepinephrine were measured after 20 min rest and 45 min after an infusion of normal saline (10 ml/kg body wt.). Basal plasma ANP was increased in patients with left ventricular dysfunction compared to healthy subjects, whether or not they were receiving diuretics. PARC was similar in healthy controls and patients untreated with diuretics but was increased in diuretic treated patients. After saline loading in healthy subjects PARC fell while ANP rose. Patients with left ventricular dysfunction had a smaller decline in PARC, that did not achieve statistical significance, but had a greater increase in plasma ANP compared to healthy subjects (P<0.05). The close reciprocal relationship between PARC and ANP observed in healthy subjects before and after saline loading (r = 0.8, P<0.001 and r = 0.6, P<0.01) was weakened in those not receiving diuretics (r = 0.4, P<0.05 and r = 0.24, ns) and lost in those receiving diuretics (r = 0.1 and r = 0.08). CONCLUSIONS: Patients with left ventricular dysfunction have a disturbance of the normal reciprocal relationship between PARC and ANP which antedates diuretic treatment. This should be taken into account when interpreting plasma neuroendocrine measurements in patients with ventricular dysfunction.