CARBOXYL-TERMINAL TRIPEPTIDYL HYDROLYSIS OF SUBSTANCE-P BY PURIFIED RABBIT LUNG ANGIOTENSIN-CONVERTING ENZYME AND THE POTENTIATION OF SUBSTANCE-P ACTIVITY INVIVO BY CAPTOPRIL AND MK-422

Abstract

The hydrolysis of substance P is catalyzed by purified rabbit lung angiotensin-converting enzyme (peptidyldipeptide hydrolase, EC 3.4.15.1). The kcat/Km for the reaction at 37.degree. is 3.3 .+-. 0.3 .times. 103 M-1 s-1, which is 60 times less than that which has been reported for the hydrolysis of angiotensin I. The initial site of hydrolysis is the antipenultimate peptide bond, which generates the tripeptide amide (Gly-Leu-Met-NH2). This hydrolysis is inhibited by the angiotensin-converting enzyme inhibitors captopril, MK-422 and EDTA, and is dependent on the concentration of Cl-. Both captopril and MK-422 potentiate the substance P-induced stimulation of salivation in rats. Thus, angiotensin-converting enzyme may be one of the enzymes that degrade substance P in vivo.