Potentiation of the hypotensive effect of bradykinin by angiotensin-(1-7)-related peptides

In this study, we evaluated the bradykinin potentiating activity and ACE in hibitory activity of several Ang-(1-7)-related peptides Ang-(2-7), Ang-(3-7 ), Ang-(4-7), Ang-(1-6), Ang-(1-5) and the selective antagonist of Ang-(1-7 ): D-[Ala(7)]Ang-(1-7) (A-779). In vivo experiments were performed in freel y moving Wistar rats. ACE activity was evaluated by a fluorometric assay in rat plasma using Hip-His-Leu as a substrate. Intravenous injections of Ang -(1-7) (2.2 nmol) transformed the effect of a single dose of bradykinin (1 nmol) into the effect produced by a double dose. A similar bradykinin poten tiating activity was demonstrated for Ang-(2-7) and Ang-(3-7); On the other hand, Ang-(1-5), Ang-(1-6), Ang-(4-7) and A-779 did not change the hypoten sive effect of bradykinin in doses ranging from 8 up to 25 nmols. The hypot ensive effect of bradykinin was increased by intravenous infusion (0.3 ng/m in) of Ang-(1-7) > Ang-(2-7) > Ang-(3-7). Conversely, Ang-(1-5), Ang-(1-6), Ang-(4-7) or A-779 did not change the hypotensive effect of bradykinin. AC E inhibition with Ang-(1-7) related peptides occurred in the order: Ang-(2- 7) greater than or equal to Ang-(3-7) > Ang-(1-7) [>>] Ang-(1-5) > Ang-(4-7 ) greater than or equal to Ang-(1-6) A-779. A-779 in concentrations up to 1 0(-5) M did not change the ACE inhibitory activity of Ang-(l-7). These resu lts suggest that Ang-(1-7), Ang-(2-7) and Ang-(3-7) can modulate bradykinin actions in vivo. More important, our data pointed out that alternative mec hanisms besides interaction with ACE are required to explain the bradykinin potentiating activity of Ang-(1-7). (C) 1999 Elsevier Science Inc. All rig hts reserved.