Mechanisms underlying the endothelium-independent relaxation induced by angiotensin II in rat aorta

It has been suggested that low concentrations of angiotensin It cause vasoconstriction, whereas high concentrations evoke vasodilation. Thus, this work aimed to characterize functionally the mechanisms underlying angiotensin If-induced relaxation, at high concentration, in isolated rat aortic rings. Vascular reactivity experiments, using standard muscle bath procedures, showed that angiotensin II (1-30 muM) concentration-dependently induces relaxation of phenylephrine-precontracted rings with intact or denuded endothelium. The relaxation was not altered in the presence of ethylenediamine tetraacetic acid (EDTA), a nonselective inhibitor of metalloprotease. The selective antagonist of AT(2) receptors, PD123319, inhibited angiotensin II-induced relaxation. Conversely, losartan or A-779, selective AT(1) and Ang(1-7) receptor antagonists, respectively, did not alter the relaxation induced by angiotensin II. HOE-140, a selective antagonist of the bradykinin 132 receptor, and amiloride, a Na+/H+ exchanger inhibitor, abolished angiotensin II-induced relaxation. Administration of exogenous bradykinin on precontracted tissues produced concentration-dependent relaxation, which was also inhibited by HOE-140. Preincubation of denuded-rings with N-G-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), indomethacin, or tetraethylammonium (TEA) reduced angiotensin II-induced relaxation. The combination of L-NAME, indomethacin, and TEA completely abolished the relaxation induced by angiotensin II. 4-Aminopyridine (4-AP) as well as charybdotoxin reduced angiotensin II-induced relaxation. On the other hand, neither apamin nor glibenclamide altered the relaxation induced by angiotensin II. The major new finding of this work is that it demonstrated functionally the existence of AT(2) receptors located on smooth muscle of rat aortic rings that mediated vasorelaxation via stimulation of B-2 receptors by bradykinin, which in turns results in the activation of the NO-cGMP pathway, vasodilator cyclooxygenase product(s), and voltage-dependent and Ca2+-activated large-conductance K+ channels.