ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries

Kathryn M. Gauthier; Cody J. Cepura; William B. Campbell

doi:10.1515/hsz-2012-0348

Article

ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries

Kathryn M. Gauthier , Cody J. Cepura and William B. Campbell

Published/Copyright: May 29, 2013

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From the journal Biological Chemistry Volume 394 Issue 9

Abstract

Bradykinin causes vascular relaxations through release of endothelial relaxing factors including prostacyclin, nitric oxide (NO) and epoxyeicosatrienoic acids (EETs). Bradykinin is metabolized by angiotensin converting enzyme (ACE) and ACE inhibition enhances bradykinin relaxations. Our goal was to characterize the role of bradykinin receptors and endothelial factors in ACE inhibitor-enhanced relaxations in bovine coronary arteries. In U46619 preconstricted arteries, bradykinin (10^-11-10^-8m) caused concentration-dependent relaxations (maximal relaxation ≥100%, log EC₅₀=-9.8±0.1). In the presence of the NO synthase inhibitor, N-nitro-L-arginine (L-NA, 30 μm) and the cyclooxygenase inhibitor, indomethacin (10 μm), relaxations were reduced by an inhibitor of EET synthesis, miconazole (10 μm) (maximal relaxation=55±10%). Bradykinin relaxations were inhibited by the bradykinin 2 (B2) receptor antagonist, D-Arg0-Hyp3-Thi5,8-D-Phe7-bradykinin (1 μm) (log EC₅₀=-8.5±0.1) but not altered by the B1 receptor antagonist, des-Arg9[Leu8]bradykinin (1 μm). Mass spectrometric analysis of bovine coronary artery bradykinin metabolites revealed a time-dependent increase in bradykinin (1–5) and (1–7) suggesting metabolism by ACE. ACE inhibition with captopril (50 μm) enhanced bradykinin relaxations (log EC₅₀=-10.3±0.1). The enhanced relaxations were eliminated by L-NA or the B1 receptor antagonist but not the B2 receptor antagonist. Our results demonstrate that ACE inhibitor-enhanced bradykinin relaxations of bovine coronary arteries occur through endothelial cell B1 receptor activation and NO.

Keywords: bradykinin receptors; captopril; endothelium; epoxyeicosatrienoic acids

Corresponding author: Kathryn M. Gauthier, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

The authors thank Ms. Gretchen Barg for secretarial assistance and Dr. Kasem Nithipatikom and Ms. Marilyn Isbell for mass spectrometric analyses. This study was supported by a grant from the National Institutes of Health (HL-83297 and HL-51055).

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Received: 2012-12-6

Accepted: 2013-5-16

Published Online: 2013-05-29

Published in Print: 2013-09-01

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https://doi.org/10.1515/hsz-2012-0348

Keywords for this article

bradykinin receptors; captopril; endothelium; epoxyeicosatrienoic acids