Acute renal effects of neutral endopeptidase inhibition in humans

Abstract

The acute renal effects of neutral endopeptidase 24.11 (E-24.11) inhibition induced by a single oral dose of sinorphan (100 mg) were investigated in 10 healthy normotensive subjects on normal sodium diet. Sinorphan inhibited 90% of E-24.11 activity and increased plasma atrial natriuretic peptide (ANP) and urinary guanosine 3',5'-cyclic monophosphate (cGMP) by 70 and 100%, respectively. Sinorphan increased urinary sodium output by 50% (P < 0.001) and decreased fractional distal reabsorption by 4% (P < 0.01). Sinorphan increased glomerular filtration rate (GFR) and filtration fraction by 10% 1 h after administration and decreased renal plasma flow by 10%. Mean arterial pressure, renal vascular resistance, plasma aldosterone concentration, and renin activity were unmodified. Sinorphan decreased fractional clearance of neutral dextrans over the 34- to 52-A radius range. Applying the changes along with a hydrodynamic isopore with shunt model, sinorphan significantly increased capillary pressure gradient (delta P; 39 +/- 1 vs. 34 +/- 1 mmHg; P < 0.01), whereas ultrafiltration coefficient was unchanged. In conclusion, endopeptidase inhibition increased endogenous plasma ANP and cGMP generation and induced natriuresis through both an increase in filtered load and a decrease in distal tubular reabsorption of sodium. Sinorphan increases GFR, filtration fraction, and delta P, probably through an increase in efferent over afferent arteriolar resistance ratio.