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1. Following the observation that brain natriuretic peptide enhances the urinary excretion rate of endothelin-1, the relationship between natriuretic peptides and urinary endothelin-1 was further investigated. Six healthy volunteers received, on three different occasions, increasing doses of atrial or C-type natriuretic peptide (0, 2 and 4 pmol.min-1.kg-1 for 1 h each), or placebo.2. Atrial natriuretic peptide caused significant increases in the urinary excretion of cGMP, sodium and endothelin-1, without affecting plasma endothelin-1, renal plasma flow, glomerular filtration rate and urine flow rate. C-type natriuretic peptide did not modify any of these parameters. During atrial natriuretic peptide infusion, urinary endothelin-1 directly correlated with plasma atrial natriuretic peptide, urinary cGMP and sodium excretion.3. These results indicate that enhancement of the urinary excretion of endothelin-1 by natriuretic peptides is dose-dependent and somewhat related to their ability to bind to natriuretic peptide receptors A, activate guanylate cyclase and induce a natriuretic response.

We evaluated cardiac function and the plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides during bicycle (B) and hand-grip (HG) exercises in eight healthy males. Each test was preceded by a control protocol in resting conditions. Left ventricular (LV) function (echocardiography) was evaluated during both exercises. Atrial function was assessed only during HG. Plasma ANP significantly increased during B (+236%) and HG (+77%), while there was a significant trend towards higher plasma BNP levels during B (+41%) and HG (+30%) than during the corresponding control tests. Plasma ANP correlated with heart rate in both tests, with left atrial volume, pulmonary vein flow systolic fraction and mitral flow E/A ratio in HG; BNP in both test correlated with LV dimensions and function. These data suggest that during exercise the cardiac release of ANP and BNP is differently regulated and related to changes in left atrial and LV function, respectively.

Objectives: Patients with cirrhosis and ascites have high plasma levels of atrial natriuretic peptide (ANP). Pharmacological doses of this hormone usually worsen systemic hemodynamics of cirrhotic patients. We assessed whether ANP influences cardiovascular homeostasis and renal function in patients with compensated cirrhosis at plasma levels comparable to those observed in patients with cirrhosis and ascites., Methods: Radionuclide angiocardiography was performed in eight compensated cirrhotic patients during placebo (three periods of 15 min each) and ANP infusion (2, 4, and 6 pmol/kg.min for 15 min each), together with appropriate blood and urine sampling, to evaluate left ventricular diastolic, systolic, and stroke volume, heart rate, cardiac output, arterial pressure, peripheral vascular resistance, creatinine clearance, urinary sodium excretion, plasma renin activity, plasma aldosterone, norepinephrine and hematocrit., Results: The infusion increased plasma ANP up to levels (52.03 +/- 2.29 pmol/L) comparable with those observed in 35 patients with ascites (46.42 +/- 1.57 pmol/ L). This increment was associated with significant reductions in left ventricular end diastolic volume, stroke volume, cardiac index (from 3.7 +/- 0.7 to 3.1 +/- 0.5 L/min.m2, p < 0.05) and mean arterial pressure (from 96.7 +/- 6.5 to 88.5 +/- 9.5 mmHg, p < 0.05), while heart rate and hematocrit significantly increased. Peripheral vascular resistance did not change. These hemodynamic effects occurred despite significant increases in plasma renin activity and norepinephrine. ANP also induced increases in creatinine clearance, urinary sodium excretion, and fractional sodium excretion., Conclusions: Low-dose ANP affected cardiovascular homeostasis and renal sodium handling in compensated cirrhosis, suggesting that this hormone may be involved in the pathophysiology of systemic hemodynamic and renal functional abnormalities of cirrhosis.

The mechanism(s) responsible for the release of brain natriuretic peptide (BNP), a cardiac hormone of ventricular origin, are still not completely understood. We measured plasma atrial natriuretic peptide (ANP) and BNP in 15 subjects (10 men, mean age 67 +/- 3 years) with a dual chamber pacemaker and unimpaired heart function during ventricular pacing, which is known to induce an increase in atrial pressure and plasma ANP concentration. Under ECG monitoring, all subjects received sequential atrioventricular pacing for 30 minutes and ventricular pacing for 30 minutes, at the same rate of 80 beats/min. Arterial pressure and plasma BNP and ANP levels were measured every 10 minutes throughout the study. Ventricular pacing led to atrioventricular dissociation in eight subjects and to retrograde ventriculo-atrial conduction in seven. Arterial pressure remained unchanged in all subjects. In the group with atrioventricular dissociation, plasma ANP increased from 10.14 +/- 0.58 to 16.72 +/- 0.92 fmol/mL at the 60th minute (P < 0.0001), whereas plasma BNP did not change at all (from 1.26 +/- 0.07 to 1.16 +/- 0.09 fmol/mL). In the group with retrograde conduction, plasma ANP concentration doubled (from 10.95 +/- 1.66 to 21.40 +/- 1.51 fmol/mL, P < 0.0001), BNP increased 1.5-fold (from 1.16 +/- 0.06 to 1.64 +/- 0.14 fmol/mL, P < 0.001), and the ANP:BNP ratio augmented from 10:1 to 13.4:1. These results indicate that the release of ANP and BNP is regulated by different mechanisms, supporting the view that there is a dual natriuretic peptide system, comprising ANP from the atria and BNP from the ventricles.

To assess whether intrarenal dopamine synthesis could contribute to the renal response to ANP in essential hypertension, the effects of alpha-human ANP infusion (50 ng.min-1.kg-1 b.w. for 30 min) on the urinary excretion of dopamine and sodium, urine flow rate and arterial pressure were evaluated in 7 patients with mild-moderate essential hypertension before (control period) and during DOPA-decarboxylase inhibition with carbidopa (carbidopa period). In the control period, urinary dopamine excretion was 400 pg.min-1 in baseline conditions and 340 pg.min-1 during ANP infusion. Carbidopa significantly decreased urinary dopamine excretion both before (210 pg.min-1) and during ANP (99 pg.min-1). In contrast, carbidopa did not affect sodium excretion (control from 184 to 460 mu Eq.min-1; carbidopa period from 140 to 390 mu Eq.min-1) or urine flow rate (control from 5.35 to 11.21 ml.min-1; carbidopa period from 4.29 to 11.54 ml.min-1). Arterial pressure fell significantly during ANP infusion in both periods, and no significant difference was observed between the two study days, i.e. in the absence of and during carbidopa administration. We conclude that DOPA-decarboxylase inhibition does not influence the diuretic and natriuretic response to alpha-human ANP infusion in patients with essential hypertension.

We investigated the effect of a continuous infusion (50 micrograms as an initial bolus followed by a maintenance infusion at a rate of 0.1 micrograms/min.kg body wt for 45 min) of synthetic human atrial natriuretic factor (hANF) on renal hemodynamics and the renin-angiotensin-aldosterone system in 15 cirrhotic patients with ascites. Basal hANF levels were higher in cirrhotic patients when compared with normal values. Human atrial natriuretic factor infusion induced a significant decrease in mean blood pressure (from 77.8 +/- 1.1 to 68.6 +/- 1.5 mmHg, p less than 0.001) and a significant increase in heart rate (from 76.4 +/- 2.7 to 89.8 +/- 2.4 beats/min, p less than 0.001) in the patients studied. A remarkable increase in natriuresis (i.e., greater than or equal to 200 muEq/min) was observed in 5 patients (responders), whereas the infusion did not modify sodium excretion (i.e., less than or equal to 20 muEq/min) in 6 patients (nonresponders) and induced an intermediate response in 4 patients. Human atrial natriuretic factor-induced natriuresis was related to changes in renal hemodynamics that occurred during hANF infusion. In responders, the extent of the natriuretic response paralleled the increase of effective renal plasma flow and glomerular filtration rate; in non-responders the absent natriuretic response was associated with an evident reduction of these parameters. The reduction of blood pressure was similar in responders and nonresponders, but in the latter group it was followed by a marked increase of plasma renin activity and heart rate. It is likely that in nonresponders the natriuretic effect of hANF was blunted by the hemodynamic and hormonal changes triggered by the concomitant hANF-induced hypotension. This probably occurs in the presence of a greater reduction of effective arterial blood volume, as suggested by the higher baseline levels of plasma renin activity and the inability to increase free water excretion after a water load observed in nonresponders.

The natriuretic effect of pharmacological doses of atrial natriuretic peptide (ANP) is markedly reduced in cirrhosis with ascites. The current study, which includes two protocols, was carried out to investigate whether this phenomenon is related to the altered systemic hemodynamics present in cirrhosis. In protocol A, the administration of ANP (2.5 micrograms.kg-1 as a bolus followed by a constant infusion of 0.1 microgram.kg-1.min-1) to 10 rats with carbon tetrachloride-induced cirrhosis and ascites produced a significantly lower increase in diuresis (13.4 +/- 1.3 microliters/min) and natriuresis (2.3 +/- 0.3 mu Equiv/min) than in 10 control rats (56.3 +/- 1.4 microliters/min and 8.7 +/- 0.5 mu Equiv/min, respectively), indicating a renal resistance to the effect of ANP in this experimental model of cirrhosis. The reduction of arterial pressure induced by ANP was similar in both groups. However, since baseline mean arterial pressure was significantly lower in cirrhotic rats, the degree of hypotension during ANP infusion was also greater in this group of animals (82 +/- 3 vs. 109 +/- 2 mmHg). The aim of protocol B was to assess whether normalization of arterial pressure in cirrhotic rats increases the renal response to ANP. This protocol includes two groups of 10 rats with cirrhosis and ascites infused with a glucose solution containing norepinephrine (CT-NE rats) or angiotensin II (CT-AII rats) at doses to normalize arterial pressure and an additional control group of 10 cirrhotic rats with ascites receiving only glucose solution (CT rats). Angiotensin II, but not norepinephrine or glucose solution administration, was associated with a significant increase in urine volume and sodium excretion. During ANP infusion, CT rats showed a blunted diuretic and natriuretic response. In contrast, the ANP-induced increase in urine volume and sodium excretion observed in CT-NE (53.6 +/- 10.4 microliters/min and 9.3 +/- 2.2 mu Equiv/min) and CT-AII rats (98.3 +/- 11.6 microliters/min and 15.5 +/- 2.9 mu Equiv/m), was similar or even greater than that showed by the healthy rats of protocol A. The degree of hypotension during ANP administration was also similar (CT-NE, 104 +/- 2; CT-AII, 108 +/- 5 mmHg). These results suggest that the blunted response to pharmacological doses of ANP in cirrhosis with ascites is related to altered systemic hemodynamics of cirrhosis, which further deteriorates during the infusion of the peptide.

We investigated whether the renal kallikrein-kinin system is involved in the renal effects of atrial natriuretic peptide (ANP) by measuring the glomerular filtration rate (GFR), urine volume (UV) and urinary excretion of sodium (UNaV) and kallikrein (UkkV) in 4 groups of 10 anesthetized rats before and during (two 10 min periods) the i.v. infusion of Ringer solution (control group) or different doses of ANP (0.25, 0.5 and 1 microgram, respectively). The administration of ANP was associated with a marked and significant increase in UV, UNaV, UkkV and GFR. The diuretic and natriuretic responses to ANP were dose-related, while the changes in GFR and UkkV were short-lived and not related to the dose of ANP. There was no relationship between UV or UNaV and UkkV after ANP administration. In contrast, UkkV correlated closely with GFR (r = 0.675, P less than 0.001). These data do not support the hypothesis that the kallikrein-kinin system contributes to the diuretic and natriuretic effects of ANP, but it might be involved in the renal hemodynamic action of this peptide.