Pharmacodynamic effects of dual neutral endopeptidase-angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans

• Published in: Clinical pharmacology and therapeutics 1999-04, Vol.65 (4), p.448-459
• Main Authors: Massien, Christine, Azizi, Michel, Guyene, Thanh‐Tam, Vesterqvist, Ole, Mangold, Bernhard, Ménard, Joël
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aldosterone - blood; Angiotensin II - blood; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Antihypertensive agents; Antihypertensive Agents - pharmacology; Atrial Natriuretic Factor - blood; Atrial Natriuretic Factor - urine; Biological and medical sciences; Cardiovascular system; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors - pharmacology; Fosinopril - pharmacology; Humans; Male; Medical sciences; Neprilysin - antagonists & inhibitors; Pharmacology. Drug treatments; Pyridines - pharmacology; Reference Values; Renin - blood; Thiazepines - pharmacology; Time Factors
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(99)70140-2

Background There is currently no clear evidence that dual neutral endopeptidase–angiotensin‐converting enzyme inhibitors have effects on angiotensin‐converting enzyme, renin, or blood pressure that are different from specific angiotensin‐converting enzyme inhibitors in humans. Methods and results In a double‐blind, placebo‐controlled crossover study, single oral doses of the dual neutral endopeptidase–angiotensin‐converting enzyme inhibitor, 10 mg BMS‐186716 and the angiotensinconverting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0‐24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS‐186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9 ± 3 pg/mL; P < .05 versus 10 mg BMS‐186716 and placebo) compared with 10 mg BMS‐186716 (16 ± 5 pg/mL) and placebo (16 ± 5 pg/mL). BMS‐186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2 ± 1.3–fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0‐24) of plasma active renin did not differ significantly between 10 mg BMS‐186716 (3898 ± 333 pg · h · mL−1) and 20 mg fosinopril (4383 ± 302 pg · h · mL−1; difference not significant). Both drugs decreased blood pressure, but the AUC(0‐24) of the changes in mean blood pressure differed significantly from placebo (79 ± 84 mm Hg · h) only for 20 mg fosinopril (181 ± 6 mm Hg · h; P < .05) but not for 10 mg BMS‐186716 (118 ± 7 mmHg · h). Conclusions In this model, single oral doses of 10 mg BMS‐186716 and 20 mg fosinopril induced similar 24‐hour in vivo angiotensin‐converting enzyme inhibition. BMS‐186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin‐converting enzyme inhibition. BMS‐186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS‐186716 had a shorter blood pressure–lowering effect than 20 mg fosinopril. Clinical Pharmacology & Therapeutics (1999) 65, 448–459; doi: