Role of ACE and NEP in bradykinin-induced relaxation and contraction response of isolated porcine basilar artery.
The aim of the present study was to clarify the role of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) in bradykinin (BK)-induced relaxation and contraction of isolated porcine basilar artery by measuring isometric tension, ACE and NEP activities and their localization. BK induced endothelium-dependent relaxation followed by contraction; however, in the presence of indomethacin BK induced relaxation but not contraction, in contrast, in the presence of L-nitro-arginine BK induced contraction but not relaxation. Captopril and thiorphan increased the p D(2) value for BK-induced relaxation from 8.11 to 9.55 and the p A(2) value for [Thi(5,8), D-Phe(7)]-BK (a B(2)-receptor antagonist) from 6.95 to 7.59. The same treatment increased the p D(2) value for BK-induced contraction from 7.93 to 8.97 and the p A(2) value for [Thi(5,8), D-Phe(7)]-BK from 6.86 to 7.50. Captopril inhibited ACE activity with an IC(50) of 38.0 nM, and thiorphan inhibited NEP and ACE activities with an IC(50) of 1.4 nM and 295.0 nM, respectively. Endothelial denudation decreased the ACE and NEP activities by 76.7% and 15.9%, respectively, and ACE mRNA level by 59.4%, but had no significant effect on NEP mRNA level. These results suggest that BK-induced relaxation and contraction in the porcine basilar artery are enhanced by captopril and thiorphan which predominantly inhibit ACE activity localized on endothelial cells.
Miyamoto
Atsushi
A
Department of Veterinary Pharmacology, Faculty of Agriculture, Kagoshima University, Kagoshima, 1-21-24 Korimoto, Kagoshima 890-0065, Japan. miyamoto@vet.agri.kagoshima-u.ac.jp
Murata
Shin
S
Nishio
Akira
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002216:Captopril / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D043782:Receptor, Bradykinin B2; D013552:Swine; D015244:Thiorphan / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D011480:Protease Inhibitors; D043782:Receptor, Bradykinin B2; D002216:Captopril; D015244:Thiorphan; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D001920:Bradykinin