CHRONIC INHIBITION OF ENDOPEPTIDASE 24.11 IN ESSENTIAL-HYPERTENSION -EVIDENCE FOR ENHANCED ATRIAL-NATRIURETIC-PEPTIDE AND ANGIOTENSIN-II

Aim: To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in e ssential hypertension. Methods:Two groups of 12 white male patients wi th essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double -blind, placebo-controlled, crossover studies. Results: Candoxatril en hanced natriuresis over the initial 48 h of treatment. Twenty-four-hou r diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut incr eases in plasma and urinary cyclic GMP. Plasma angiotensin 11 and aldo sterone concentrations were also significantly increased. Plasma catec holamine concentrations were significantly increased by the higher dos e of candoxatril. Blood pressure (day 4, 24-h intra-arterial recording s) fell significantly with both doses. The infusions of exogenous ANF and angiotensin 11 on day 5 showed that candoxatril impaired the metab olic clearance of both ANF and angiotensin II with consequent enhancem ent of the biological effects of both effector peptides. Conclusions: Candoxatril augments the effects of ANF and lowers blood pressure in p atients with hypertension. However, the antihypertensive effects may b e offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibiti on in hypertensive patients may depend on the relative effects on humo ral vasodilator (including ANF) and vasoconstrictor (including the ang iotensin-aldosterone and sympathetic) systems.