Bradykinin Potentiation by Angiotensin-(1-7) and ACE Inhibitors Correlates With ACE C- and N-Domain Blockade

Abstract

Abstract-ACE inhibitors block B 2 receptor desensitization, thereby potentiating bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also acts as an ACE inhibitor and, in addition, may stimulate bradykinin release via angiotensin II type 2 receptors. In this study we compared the bradykinin-potentiating effects of Ang-(1-7), quinaprilat, and captopril. Porcine coronary arteries, obtained from 32 pigs, were mounted in organ baths, preconstricted with prostaglandin F 2␣ , and exposed to quinaprilat, captopril, Ang-(1-7), and/or bradykinin. Bradykinin induced complete relaxation (pEC 50 ϭ8.11Ϯ0.07, meanϮSEM), whereas quinaprilat, captopril, and Ang-(1-7) alone were without effect. Quinaprilat shifted the bradykinin curve to the left in a biphasic manner: a 5-fold shift at concentrations that specifically block the C-domain (0.1 to 1 nmol/L) and a 10-fold shift at concentrations that block both domains. Captopril and Ang-(1-7) monophasically shifted the bradykinin curve to the left, by a factor of 10 and 5, respectively. A 5-fold shift was also observed when Ang-(1-7) was combined with 0.1 nmol/L quinaprilat. Repeated exposure of porcine coronary arteries to 0.1 mol/L bradykinin induced B 2 receptor desensitization. The addition of 10 mol/L quinaprilat or Ang-(1-7) to the bath, at a time when bradykinin alone was no longer able to induce relaxation, fully restored the relaxant effects of bradykinin. Angiotensin II type 1 or 2 receptor blockade did not affect any of the observed effects of Ang-(1-7). In conclusion, Ang-(1-7), like quinaprilat and captopril, potentiates bradykinin by acting as an ACE inhibitor. Bradykinin potentiation is maximal when both the ACE C-and N-terminal domains are inhibited. The inhibitory effects of Ang-(1-7) are limited to the ACE C-domain, raising the possibility that Ang-(1-7) synergistically increases the blood pressure-lowering effects of N-domain-specific ACE inhibitors. is a heptapeptide that is formed endogenously from both Ang I and Ang II. 1 In rats and dogs, Ang-(1-7) exerts direct vasodilatory effects via nonangiotensin II type 1 (AT 1 ), non-angiotensin II type 2 (AT 2 ) receptors, possibly by stimulating bradykinin and NO release. 1,2 In contrast, in humans or pigs, no direct vasodilatory effects of Ang-(1-7) were observed, 3-7 although Ang-(1-7) did antagonize the pressor effects of Ang II, suggesting that it may cause vasodilation indirectly, by acting as an AT 1 receptor antagonist. 5,6 In addition, Ang-(1-7) potentiates bradykinin, either via an AT 2 receptor-dependent mechanism or through inhibition of ACE. 3,5,8 The latter effect is not necessarily based on blockade of bradykinin hydrolysis, because recent studies have shown that ACE inhibitors, including Ang-(1-7), potentiate bradykinin by inhibiting desensitization of its receptor. 9 -11 Somatic ACE has 2 homologous domains, each containing an active center. According to their position (N-or C-terminal), these domains are designated as the N-or C-domain, respectively. Interestingly, Ang-(1-7) inhibits t...

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