Angiotensin-(1–7) potentiates responses to bradykinin but does not change responses to angiotensin I

Abstract

Angiotensin-(1–7) (Ang-(1–7)), a bioactive peptide in the renin–angiotensin system, has counterregulatory actions to angiotensin II (Ang II). However, the mechanism by which Ang-(1–7) enhances vasodepressor responses to bradykinin (BK) is not well understood. In the present study, the effects of Ang-(1–7) on responses to BK, BK analogs, angiotensin I (Ang I), and Ang II were investigated in the anesthetized rat. The infusion of Ang-(1–7) (55 pmol/min i.v.) enhanced decreases in systemic arterial pressure in response to i.v. injections of BK and the BK analogs [Hyp3, Tyr(Me)8]-bradykinin (HT-BK) and [Phe8ψ (CH2-NH) Arg9]-bradykinin (PA-BK) without altering pressor responses to Ang I or II, or depressor responses to acetylcholine and sodium nitroprusside. The angiotensin-converting enzyme (ACE) inhibitor enalaprilat enhanced responses to BK and the BK analog HT-BK without altering responses to PA-BK and inhibited responses to Ang I. The potentiating effects of Ang-(1–7) and enalaprilat on responses to BK were not attenuated by the Ang-(1–7) receptor antagonist A-779. Ang-(1–7)- and ACE inhibitor-potentiated responses to BK were attenuated by the BK B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor sodium meclofenamate had no significant effect on responses to BK or Ang-(1–7)-potentiated BK responses. These results suggest that Ang-(1–7) potentiates responses to BK by a selective B2 receptor mechanism that is independent of an effect on Ang-(1–7) receptors, ACE, or cyclooxygenase product formation. These data suggest that ACE inhibitor-potentiated responses to BK are not mediated by an A-779-sensitive mechanism and are consistent with the hypothesis that enalaprilat-induced BK potentiation is due to decreased BK inactivation.