ACUTE RENAL EFFECTS OF NEUTRAL ENDOPEPTIDASE INHIBITION IN HUMANS

The acute renal effects of neutral endopeptidase 24.11 (E-24.11) inhib ition induced by a single oral dose of sinorphan (100 mg) were investi gated in 10 healthy normotensive subjects on normal sodium diet. Sinor phan inhibited 90% of E-24.11 activity and increased plasma atrial nat riuretic peptide (ANP) and urinary guanosine 3',5'-cyclic monophosphat e (cGMP) by 70 and 100%, respectively. Sinorphan increased urinary sod ium output by 50% (P < 0.001) and decreased fractional distal reabsorp tion by 4% (P < 0.01). Sinorphan increased glomerular filtration rate (GFR) and filtration fraction by 10% 1 h after administration and decr eased 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 dextr ans over the 34- to 52-Angstrom radius range. Applying the changes alo ng with a hydrodynamic isopore with shunt model, sinorphan significant ly 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 A NP and cGMP generation and induced natriuresis through both an increas e in filtered load and a decrease in distal tubular reabsorptibn of so dium. Sinorphan increases GFR, filtration fraction, and Delta P, proba bly through an increase in efferent over afferent arteriolar resistanc e ratio.