St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
Hypertension. 2014 Apr;63(4):768-73. doi: 10.1161/HYPERTENSIONAHA.113.02902. Epub 2014 Jan 13.
Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.
血管紧张素转换酶抑制剂和血管紧张素 AT1 受体阻滞剂通过缓激肽 B2 受体和血管紧张素 AT2 受体介导的机制减少心肌缺血再灌注损伤。肾素抑制剂阿利克仑增加心脏组织激肽释放酶和缓激肽水平。在本研究中，我们研究了阿利克仑对心肌缺血再灌注损伤的影响以及 B2 和 AT2 受体在这种作用中的作用。雌性 Sprague-Dawley 大鼠用阿利克仑（每天 10mg/kg）和缬沙坦（每天 30mg/kg）单独或联合治疗，并用 B2 受体拮抗剂依卡替班（每天 0.5mg/kg）或 AT2 受体拮抗剂 PD123319（每天 30mg/kg）治疗 4 周，然后进行心肌缺血再灌注损伤。阿利克仑增加了心脏缓激肽水平，并减弱了缬沙坦诱导的血管紧张素 II 水平升高。在载体处理的大鼠中，心肌梗死面积（%危险区域，平均值±SEM，n=7-13）为 43±3%。阿利克仑、缬沙坦及其联合治疗分别将其降低到相似程度，分别为 24±3%、25±3%和 22±2%。依卡替班逆转了阿利克仑和阿利克仑联合缬沙坦的心脏保护作用，但缬沙坦单独治疗则没有，表明缬沙坦诱导的心脏保护作用不是由 B2 受体介导的。PD123319 逆转了阿利克仑、缬沙坦和阿利克仑联合缬沙坦的心脏保护作用。阿利克仑通过 B2 受体和 AT2 受体介导的机制保护心脏免受心肌缺血再灌注损伤，而缬沙坦的心脏保护作用是通过 AT2 受体介导的。此外，阿利克仑减弱了缬沙坦诱导的血管紧张素 II 水平升高，从而防止缬沙坦通过 AT2 受体介导的心脏保护作用。
