Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100 240, on endocrine and renal functions in healthy volunteers

Objective To investigate the endocrine and renal effects of the dual inhibi tor of angiotensin converting enzyme and neutral endopeptidase, MDL 100 240 . Design A randomized, placebo-controlled, crossover study was performed in 1 2 healthy volunteers. Methods MDL 100 240 was administered intravenously over 20 min at single do ses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pre ssure, plasma angiotensin converting enzyme activity, angiotensin II, atria l natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP ex cretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. Results Supine systolic blood pressure was consistently decreased by MDL 10 0 240, particularly after the high dose and during the low-salt intake. Dia stolic blood pressure and heart rate did not change. Plasma angiotensin con verting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic pepti de levels remained unchanged. In contrast, urinary atrial natriuretic pepti de excretion increased dose-dependently under both diets, as did urinary cy clic GMP excretion. Effective renal plasma flow and the glomerular filtrati on rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100 240 (P < 0.00 1) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and dist al fractional sodium reabsorption were not significantly altered by the tre atment. Uric acid excretion was increased. The safety and clinical toleranc e of MDL 100 240 were good. Conclusions The increased fall in blood pressure in normal volunteers toget her with the preservation of renal hemodynamics and the increased urinary v olume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100 240 as a double-enzyme inhibitor from inhibitors of the angiotensin con verting enzyme alone. The differences appear to be due, at least in part, t o increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade. J Hypertens 1999, 17:427-437 (C) Lippincott William s & Wilkins.