ENHANCED NATRIURETIC RESPONSE TO NEUTRAL ENDOPEPTIDASE INHIBITION IN PATIENTS WITH MODERATE CHRONIC-RENAL-FAILURE

Atrial natriuretic factor (ANF) has natriuretic, renin-suppressing and chronic hypotensive actions that may be utilized by inhibition of ANF degradation by neutral endopeptidase, E.C.24.11 (NEP). Three groups o f 8 male patients [GFR 103 +/- 8 (Normal), 64 +/- 6 (Moderate CRF), an d 16 +/- 2 ml/min (Severe CRF)] received 100 mg i.v. bolus of the NEP inhibitor candoxatrilat or placebo in random order in a double-blind c rossover study. GFR ((CR)-C-51-EDTA), ERPF (I-125-hippuran), ANF (IRMA ), urinary cGMP (RIA) and albumin (RIA) and sodium excretion and flow rate were measured hourly for two hours before and for seven hours aft er candoxatrilat administration. After candoxatrilat plasma ANF rose t wo-to threefold from baseline, and remained elevated for 5(N) and 7(M, S) hours (P < 0.01(N,S), P < 0.03(M)) associated with an immediate ris e in urine cGMP excretion from 23.5(N), 25.4(M) and 10.4(S) nmol/hr (b ase) to 51.7(N), 73.8(M) and 27.5(S)(peak) lasting 7(N,M,S) hours (P < 0.01(N,M,S)). There was a marked natriuresis in all three groups, the cumulative sodium excretion at seven hours post-candoxatrilat being 1 04(N), 140(M), 102(S) mmol (P < 0.05(N,M,S)). This was greatest in tho se with moderate CRF (moderate CRF vs. normal, P = 0.036, moderate vs. severe CRF, P = 0.01, normal vs. severe CRF, P = 0.74). Following can doxatrilat there was a near doubling of the urine flow rate (P < 0.01( N,S), P < 0.02(M)). Urine albumin excretion increased in patients with renal failure (P < 0.01), but there was no change in GFR, ERPF or sys temic blood pressure. We conclude that the marked natriuretic effects of acute NEP inhibition seen in normal subjects are enhanced in the pr esence of moderate CRF and sustained even in severe renal impairment.