COMPARISON OF CANDOXATRIL AND ATRIAL-NATRIURETIC-FACTOR IN HEALTHY-MEN - EFFECTS ON HEMODYNAMICS, SYMPATHETIC ACTIVITY, HEART-RATE-VARIABILITY, AND ENDOTHELIN

The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, atrial natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60; and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (P<.01), central venous pressure (P<.001), forearm blood flow (P<.05), and forearm vascular compliance (P<.05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (P<.01). Candoxatril lowered central venous pressure (P<.001) and increased systolic pressure (from 116+/-6 to 120+/-7 mm Hg; P<.05), endothelin (from 4.6+/-1.1 to 6.8+/-3.2 pmol/L; P<.02), and epinephrine (P<.05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.