MODULATORY EFFECT OF ENDOPEPTIDASE INHIBITORS ON BRADYKININ-INDUCED CONTRACTION OF RAT UTERUS

Bradykinin (BK) affects a variety of smooth muscle types, including ut erus. These effects are generally short-lived due to metabolism by a v ariety of enzymes including angiotensin converting enzyme (ACE), endop eptidase 24.11 (EP-24.11) and endopeptidase 24.15 (EP-24.15). The uter otonic action of BK and the limitation of that action by peptidases we re examined using isolated rat uterus. BK contracted the estrus, diest rus and day 22 pregnant rat uterus. 1(R,S)-carboxy-3-phenylpropyl]-Phe -p-aminobenzoate (10(-7) M), a specific inhibitor of EP-24.11, and arb oxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (10(-6) M), a specific inhibitor of EP-24.15, enhanced BK-induced contraction in the estrus and pregnant uterus. Enalaprilat (6 x 10(-8) M), an inhibitor of ACE, also enhanced BK-induced contraction. The enzyme inhibitors alone did not contract the uterus. Bradykinin B2 receptor antagonism blocked the effects of the inhibitors. ACE is present in the rat uterus, but ther e are no reports of EP-24.11 or EP-24.15. Here we report that EP-24.11 and EP-24.15 activities are present in the estrus and pregnant rat ut erus. Partially purified uterine homogenates metabolized specific mode l substrates for EP-24.11 and EP-24.15. The enzyme activities were inh ibited by 1(R,S)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate and rboxy -3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, respectively, and increa sed 5- to 8-fold at term pregnancy as compared to estrus. It is conclu ded that BK may have a physiological role in the uterus during estrus as well as in labor, and that local metabolism of BK represents a pote ntial control point for uterine contraction.