Vasorelaxation to Angiotensin I After Angiotensin Converting Enzyme Inhibition
We aimed at studying the vasoactive function of angiotensin I (Ang I) degradation products in the absence of tissue ACE (angiotensin-converting enzyme) activity. The effect of Ang I on captopril (10-5 M)-treated rat aortic rings pre-contracted with phenylephrine (Phe, 10-7 M) was studied. Mechanism of action of Ang I degradation products were analyzed using Ang-receptor antagonists [D-Ala7- Ang-(1-7), A779 - Ang-(1-7)-selective; PD123319, PD - AT2 receptor specific; Sar1-Thr8-Ang II, sarthran - nonspecific), bradykinin B2 receptor antagonist (HOE140) and inhibitors of neutral endopeptidase (thiorphan, NEPi) or prolyl endopeptidase (Z-Pro-Pro-aldehyde dimethylacetal, PEPi). Ang I induced an evident dose-dependent relaxation of the pre-contracted aortic rings treated with captopril, with a maximum relaxation at 10-7 M (10-9 M: -18.64 ± 1.63; 10-8 M: -27.6 ± 1.9; 10-7 M: -34.3 ± 2.1 % of Phe contraction). Additional treatment with A779 (10-6 or 10-5 M), HOE140 (10-6 M), high dose of PD (10-5 M) or PEPi significantly inhibited the relaxation to Ang I. Sarthran, PD (10-6 M) or NEPi did not significantly affect the relaxation to Ang I. Endothelium removal prevented the relaxation to Ang I. Our results indicate that in the absence of tissue ACE activity Ang I is metabolized, predominantly by prolyl endopeptidase present on endothelium, to Ang-(1-7) that induces vasorelaxation with the participation of putative Ang-(1-7) receptors, AT2 and B2 receptors. This may constitute an additional mechanism for the effects of ACE inhibitors.