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

Abstract

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p<0.05). Plasma A'-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p<0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 ±8 mmol on the low sodium and 98 ±34 mmol on the high sodium diet (p<0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p<0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on iV-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of JV-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril. (Hypertension 1991;18:798-804) A bnormalities in the renal handling of sodium / \ may be important in the development of A. \ . essential hypertension.1 The finding of elevated plasma levels of human atrial natriuretic factor-(99-126) ] in many patients with essential hypertension indirectly supports this concept.2 Low-dose intravenous infusion of atrial natriuretic peptide (ANP) in normal subjects causes an increase in sodium and water excretion, 3 inhibition of renin, 3 and redistribution of fluid from the intravascular to the extravascular space, 4 with an increase of plasma levels of ANP within the physiological range. Furthermore, higher infusion rates of ANP, which

Enhanced Natriuretic Response to Neutral Endopeptidase Inhibition in Heart-Transplant Recipients

“…[13][14][15][16] Interestingly, greater natriuresis is observed when ANP levels are elevated, further supporting the potential role of NEP-I in Htx. [17][18][19][20] Therefore, the aim of this study was to investigate for the first time whether NEP-I further increases circulating ANP after heart transplantation, and whether such increase is associated with enhanced diuresis and natriuresis in Htx as compared with control subjects.…”

Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo

“…10,17 However, a reduction in blood pressure has not been clearly demonstrated in normotensive subjects, 10,18,20,21 and two studies have even reported an increase in blood pressure 22,23 despite the potent vasodilator actions of the natriuretic peptides. 12,13,16 Also, several studies on hypertensive patients 19,[32][33][34][35] have not demonstrated a reduction in blood pressure. Interestingly, and perhaps relevant to our own findings, a recent study in patients with chronic heart failure showed that candoxatril increases systemic vasoconstriction and decreases cardiac index.…”

“…Although NEP inhibitors have been reported to lower blood pressure in patients with essential hypertension, 24 -31 this finding has not been universal. 19,[32][33][34][35] Thus, the therapeutic value of NEP inhibitors in hypertension remains uncertain. In patients with heart failure, these agents do not reduce afterload although they do reduce pulmonary capillary wedge pressure, presumably because of natriuresis.…”

Vasopeptidase inhibitors: will they have a role in clinical practice?

“…This explains why NEP inhibitors such as candoxatril, thiorphan and phosphoramidon increase circulating ANP concentrations in humans and induce natriuresis (Figure 2), but do not lower [42,[44][45][46][47][48][49][50] or even increase blood pressure in normotensive subjects [51]. In patients with essential hypertension, certain NEP inhibitors lower blood pressure [52][53][54]; whereas others increase it [50,55]. Chronic treatment with NEP inhibitors augments the effects of ANP and lowers blood pressure in patients with hypertension.…”