Atrial natriuretic factor in hypertension: bioactivity at normal plasma levels.

Abstract

To ascertain whether small shifts in plasma atrial natriuretic factor (ANF) exerted biological effects in hypertension, we studied the renal, hemodynamic, and hormonal effects of ANF ] infused at a dose (0.75 pmol/kg/min for 3 hours) that would induce changes in plasma ANF confined to the normal, resting range, in a group of six young men with uncomplicated, mild essential hypertension. During ANF infusions, the patients excreted 11.8±2.0 mmol (mean±SEM) sodium more than during the time-matched placebo phase natriuresis (/><0.001, mean increase of 53% above placebo values). Urinary excretion of cyclic guanosine monophosphate rose to more than double (212%, p< 0.001) placebo values. Plasma renin activity (0.4±0.05 vs. 0.9±0.12 nmol/l/hr, /?<0.0001) and aldosterone concentrations (102±4 vs. 184±47 pmol/l, p<0.05) were clearly suppressed during administration of ANF. Plasma norepinephrine also fell significantly below placebo values (268±17 vs. 439±35 pg/ml, p<0.05). Urine volume, the excretion of electrolytes other than sodium, hematocrit, effective renal plasma flow, glomerular filtration rate, and filtration fraction were unaffected by ANF. Similarly, plasma concentrations of epinephrine, arginine vasopressin, adrenocorticotropic hormone, and cortisol were unchanged. Blood pressure and heart rate were unchanged. Minor perturbations in plasma ANF concentrations exert clear biological effects in patients with mild essential hypertension. These data suggest that such minor shifts in plasma ANF are of physiological relevance in mild hypertension and probably contribute to volume homeostasis in this condition. {Hypertension 1989;14:261-268) A trial natriuretic factor (ANF) continues to / \ attract intense interest as a potentially major .Z \ . regulator of body fluid volumes and arterial pressure. Studies in humans have clearly demonstrated that this peptide may induce natriuresis, suppress the renin-angiotensin-aldosterone system, and lower arterial pressure.1 -3 Recently, we demonstrated that such effects occur in normotensive subjects even with low doses of ANF, which induce perturbations in plasma peptide concentrations entirely within the resting normal range. 4 Far less is known concerning the effect of physiological doses of ANF in hypertensive patients. The response to high doses of ANF appears qualitatively similar in both normotensive and hypertensive subjects. 5 -6 However, data suggest the natriuretic effect of ANF is partially pressure dependent and thus is enhanced in hypertension.

Effect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers.

“…The current data are derived from contrived circumstances in which plasma Ang II concentrations were rapidly elevated from normal to pathophysiological levels, and it remains to be confirmed that endopeptidase 24.11 inhibition will continue to significantly delay metabolic clearance of Ang II in the medium or longer term with more gradual or subtle elevation of endogenous angiotensin II, and, if so, whether such an action would be sufficient to exert significant hemodynamic effects. However, the potential importance of the observed interaction indicates that carefully controlled trials (of a range of endopeptidase inhibitors) that incorporate monitoring of both clinical status and neurohumoral status will be required to establish the appropriate role, if any, of endopeptidase 24.11 inhibitors in the management of cardiovascular disease.…”

“…'-4 Endopeptidase 24.11 appears to play a central role in the initial degradation of atrial natriuretic factor (ANF).5-7 Endopeptidase 24.11 inhibitors have been shown to enhance plasma ANF and induce ANF-like end-organ effects in animals as well as both normal volunteers and patients with hypertension and heart failure.2-4,8 ANF exerts beneficial hemodynamic effects in hypertension and heart failure,9'10 but data have been limited because of the peptide's short half-life and the necessity for parenteral administration. Therefore, orally active endopeptidase 24.11 inhibitors may offer a method for testing the effects of chronic enhancement of ANF bioactivity in cardiovascular disease.…”

“…However, ANF is not the sole vasoactive substrate for endopeptidase 24 Baseline and intrainfusion values of plasma Ang II and aldosterone concentrations are listed in Table 1 and/or illustrated in Figure 1. Basal levels of angiotensin and aldosterone were unchanged by the lower dose (group 1) of candoxatril.…”

“…Because even small increments in plasma ANF may reduce aldoste-rone secretion in normal23 and hypertensive24 men, it is possible that enhanced plasma ANF levels before and/or during Ang II administration in candoxatriltreated subjects (Figure 3) The renin-angiotensin-aldosterone system is also activated in patients with deteriorating heart failure and animal models of heart failure.29 31 Many of the adverse manifestations of heart failure seem secondary to raised RAAS activity and are ameliorated by converting enzyme inhibition.31-33 Candoxatril has caused beneficial hemodynamic effects when given to heart failure patients in acute single-dose studies. 3 However, the more long-term effects of endopeptidase 24.11 inhibition on RAAS activity in heart failure remain undetermined. It may be necessary to coadminister converting enzyme inhibitors or Ang II antagonists to gain optimum benefit from the use of endopeptidase inhibition in heart failure and hypertension.…”

Dietary sodium and inhibition of neutral endopeptidase 24.11 in essential hypertension.

“…- 21 Of note is that the biologic response to an increase in plasma ANP levels after NEP inhibition is likely to be greater than after the same increase in plasma ANP after ANP infusion. This is because tissue levels of ANP at sites of ANP-guanylate cyclase receptor binding and NEP activity will be greater for the same plasma ANP level achieved after NEP inhibition compared with that after ANP infusion.…”