EFFECTS OF MDL-100,240, A DUAL INHIBITOR OF ANGIOTENSIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE ON THE VASOPRESSOR RESPONSE TO EXOGENOUS ANGIOTENSIN-I AND ANGIOTENSIN-II CHALLENGES IN HEALTHY-VOLUNTEERS

MDL 100,240, a dual inhibitor of angiotensin-converting enzyme (ACE) a nd neutral endopeptidase (NEP), was administered intravenously to two panels of four healthy males in a four-period, dose-increasing (0, 1.5 6, 6.25, and 25 mg, and 0, 3.13, 12.5, and 50 mg, respectively) double -blind, placebo-controlled study. Plasma ACE activity and blood-pressu re response to exogenous angiotensin I and angiotensin II i.v. challen ges and safety and tolerance were assessed over a 24-h period. MDL 100 ,240 induced a rapid, dose-related, and sustained inhibition of ACE (> 70% over 24 h at doses greater than or equal to 12.5 mg). The time int egral of ACE inhibition was related to the dose but with near-maximal values already attained at doses greater than or equal to 12.5 mg. Sys tolic and diastolic blood-pressure responses to exogenous angiotensin I challenges were inhibited in a dose-dependent fashion, whereas the e ffects of angiotensin II remained unaffected. Mean supine blood pressu re decreased transiently (3 h) at doses greater than or equal to 3.125 mg and less than or equal to 24 h with the 25- and 50-mg doses, but n ot significantly. MDL 100,240 was well tolerated. In healthy subjects, MDL 100,240 exerts a dose-dependent and long-lasting ACE-blocking act ivity, also expressed by the inhibition of the presser responses to ex ogenous angiotensin I challenges. The baroreceptor reflex, assessed by the response to exogenous angiotensin II challenge, remains unaltered .