CAPTOPRIL PRODUCES ENDOTHELIUM-DEPENDENT RELAXATION OF DOG ISOLATED RENAL-ARTERIES - POTENTIAL ROLE OF BRADYKININ

The effects of the angiotensin-converting enzyme inhibitors, captopril , lisinopril and enalapril-maleate (the latter being a prodrug thas ha s to be converted into enalaprilat), and bradykinin were investigated in the presence or absence of indomethacin and bradykinin receptor ant agonists in dog renal arterial rings precontracted with either prostag landin F-2 alpha or phenylephrine. At a high precontraction level (10 mu M of prostaglandin F-2 alpha), captopril did not relax the arteries . However, when the tension was low (0.5 mu M), both captopril and lis inopril produced endothelium-dependent relaxations. The maximum relaxa tions for captopril and lisinopril were 57 +/- 6% and 64 +/- 15%, resp ectively. Enalapril-maleate failed to relax the renal arteries even wh en the vascular tone was low. In endothelium-intact arteries precontra cted with phenylephrine (0.2 mu M), captopril and lisinopril produced a maximum relaxation and 29 +/- 5%, respectively, in arteries with int act whilst responses to enalapril-maleate were inconsistent. Renal art ery rings with rubbed endothelium failed to relax in response to brady kinin or captopril. We observed significant variations in both captopr il- and lisinopril-induced endothelium-dependent relaxations in one te nth of the preparations. The relaxations to bradykinin and captopril w ere not affected by indomethacin (3 mu M), whereas they were markedly attenuated by N-G-nitro-L-arginine (0.1 mM). The bradykinin-antagonist , N alpha-adamantane-acetyl-D-Arg-(Hyp(3), Thi(5,8), D-Phe(7))BK, or t he specific bradykinin(2) receptor antagonist, HOE140, completely abol ished the relaxation responses to captopril and reduced the potency of bradykinin, but failed to affect the acetylcholine-induced responses. The results suggest that the relaxant effect of captopril is mediated by endogenous bradykinin or by activation of bradykinin receptors. Th e proposed mechanisms by which captopril relaxes the renal arteries ar e: (1) inhibition of tissue kininase II. which leads to accumulation o f endogenous bradykinin; (2) shift in angiotensin I metabolism towards (a) relaxant angiotensin derivative(s); and (3) interaction with brad ykinin receptors.