Modulatory effect of endopeptidase inhibitors on bradykinin-induced contraction of rat uterus.
Bradykinin (BK) affects a variety of smooth muscle types, including uterus. These effects are generally short-lived due to metabolism by a variety of enzymes including angiotensin converting enzyme (ACE), endopeptidase 24.11 (EP-24.11) and endopeptidase 24.15 (EP-24.15). The uterotonic action of BK and the limitation of that action by peptidases were examined using isolated rat uterus. BK contracted the estrus, diestrus and day 22 pregnant rat uterus. N-[1(R,S)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (10(-7) M), a specific inhibitor of EP-24.11, and N-[1(R,S)-carboxy-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 there 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 uterus. Partially purified uterine homogenates metabolized specific model substrates for EP-24.11 and EP-24.15. The enzyme activities were inhibited by N-[1(R,S)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate and N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, respectively, and increased 5- to 8-fold at term pregnancy as compared to estrus.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, West Virginia School of Osteopathic Medicine, Lewisburg.
J A
JA
Schriefer
C J
CJ
Molineaux
D000818:Animals; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D010450:Endopeptidases / Q000502:physiology*; D004971:Estrus / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D011247:Pregnancy; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000378:metabolism
D011480:Protease Inhibitors; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; D010450:Endopeptidases; D001920:Bradykinin