ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries
ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries
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DOI：
10.1515/hsz-2012-0348
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发表时间：
2013-09-01
影响因子：
3.7
通讯作者：
Campbell, William B.
中科院分区：
文献类型：
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作者：
Gauthier, Kathryn M.;Cepura, Cody J.;Campbell, William B.
缓激肽通过释放内皮松弛因子，包括前列环素、一氧化氮（NO）和环氧二碳三烯酸（EETs），引起血管松弛。缓激肽通过血管紧张素转换酶（ACE）代谢，ACE抑制可增强缓激肽的松弛。我们的目的是表征缓激素受体和内皮因子在ACE抑制剂增强的牛冠状动脉舒张中的作用。在U46619预收缩动脉中，缓激素(10（-11)-10(-8)m）引起浓度依赖性松弛（最大松弛>= 100%,log EC50=-9.8 +/- 0.1）。在NO合成酶抑制剂n -硝基- l -精氨酸（L-NA, 30 μ m）和环氧合酶抑制剂吲哚美辛（10 μ m）存在的情况下，EET合成抑制剂咪康唑（10 μ m）的弛缓作用减弱（最大弛缓=55 +/- 10%）。缓激素2 （B2）受体拮抗剂d - arg0 - hyp3 - thi5,8 - d - phe7 -缓激素（1 μ m）可抑制缓激素的松弛（log EC50=-8.5 +/- 0.1），但B1受体拮抗剂des-Arg9[Leu8]缓激素（1 μ m）未改变缓激素的松弛。质谱分析显示，牛冠状动脉缓激素代谢产物呈时间依赖性增加（1-5）和（1-7），表明缓激素是由ACE代谢的。卡托普利（50 μ m）抑制ACE可增强缓激素弛豫（log EC50=-10.3 +/- 0.1）。L-NA或B1受体拮抗剂可消除增强的松弛，但B2受体拮抗剂不能消除。我们的研究结果表明，ACE抑制剂增强的牛冠状动脉缓激素松弛是通过内皮细胞B1受体激活和NO发生的。
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(-8) m) 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 mu m) and the cyclooxygenase inhibitor, indomethacin (10 mu m), relaxations were reduced by an inhibitor of EET synthesis, miconazole (10 mu m) (maximal relaxation=55 +/- 10%). Bradykinin relaxations were inhibited by the bradykinin 2 (B2) receptor antagonist, D-Arg0-Hyp3-Thi5,8-D-Phe7-bradykinin (1 mu m) (log EC50=-8.5 +/- 0.1) but not altered by the B1 receptor antagonist, des-Arg9[Leu8]bradykinin (1 mu m). 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 mu m) 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.