CARDIOVASCULAR EFFECTS OF THE NOVEL DUAL INHIBITOR OF NEUTRAL ENDOPEPTIDASE AND ANGIOTENSIN-CONVERTING ENZYME BMS-182657 IN EXPERIMENTAL-HYPERTENSION AND HEART-FAILURE

Combined neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition produces greater acute hemodynamic effects than eith er treatment alone. We investigated whether EMS-182657 (EMS), which be ars inhibitory activities against both NEP and ACE, elicited similar e nhanced effects. EMS inhibited NEP and ACE, in vitro (IC50 = 6 and 12 nM, respectively) and the presser response to Ang I in rats. In deoxyc orticosterone acetate (DOCA)-salt hypertensive rats sensitive to NEP i nhibition but not to ACE inhibition, EMS at 100 mu mol/kg i.v. lowered mean arterial pressure (MAP) from 180 +/- 6 to 151 +/- 5 mm Hg. In so dium-depleted, spontaneously hypertensive rats (SHR) sensitive to ACE inhibition but not to NEP inhibition, BMS at 100 mu mol/kg p.o. lowere d MAP from 151 +/- 4 to 123 +/- 5 mm Hg. Cardiomyopathic hamsters with heart failure were administered vehicle or one of the following (30 m u mol/kg i.v.): the ACE inhibitor enalaprilat; the NEP inhibitor SQ-28 603; or EMS. Enalaprilat and SQ-28603 had minimal hemodynamic effects. EMS decreased left ventricular end-diastolic pressure by 12 +/- 2 and 10 +/- 1 mm Hg and left ventricular systolic pressure by 27 +/- 2 and 23 +/- 3 mm Hg at 30 and 60 min, respectively (P < .05 vs. each other group). These changes were associated with a 40% increase in cardiac output, a 47% decrease in peripheral vascular resistance and a lowerin g of MAP by 21 +/- 3 mm Hg at 60 min (P < .05 vs. each other group). T here were no significant differences in the changes in heart rate or l eft ventricular stroke work index among the four groups. Hence, EMS-18 2657 is a dual inhibitor of NEP and ACE, is antihypertensive irrespect ive of the activity of the renin-angiotensin system and has acute hemo dynamic effects in hamsters with heart failure greater than those prod uced by selective inhibition of NEP or ACE. The NEP and ACE inhibitory activities of EMS-182657 act synergistically and mimic the interactio n resulting from combining selective inhibitors of these enzymes.