We investigated the hemodynamic, renal and hormonal responses to neutral endopeptidase inhibition (NEP) during a 6 hour, double-blind, randomized, placebo controlled study in seven chronic, stable heart-transplant patients. Baseline characteristics were similar during both experiments and no significant changes were observed after placebo. NEP-inhibition increased circulating endothelin (from 2.01 ± 0.1 to 2.90 ± 0.2 pmol/L, P<0.01), ANP from 21.5 ± 2.7 to 29.6 ± 3.7 pmol/L, P<0.01) and its second messenger cyclic guanosine monophosphate (cGMP). Noteworthy, systemic blood pressure did not increase. Renal plasma flow and glomerular filtration rate remained unmodified after NEP-inhibition. Filtration fraction (33 ± 13 %), diuresis (196 ± 62%), and natriuresis (315 ± 105 %) increased significantly in relation with ANP and cGMP. A strong inverse relationship was observed between excreted cGMP and sodium reabsorption (r = -0.71, P<0.0001). Thus, despite significantly increasing endothelin, NEP-inhibition did not adversely influence systemic or renal hemodynamics in transplant patients. ANP, possibly through a tubular action, enhances the natriuresis observed after NEP-inhibition.