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Aliskiren reduces myocardial ischemia-reperfusion injury by a bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanism.

Hypertension (Dallas, Tex. : 1979) (2014-01-15)
Suang Suang Koid, James Ziogas, Duncan John Campbell
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-Valine, reagent grade, ≥98% (HPLC)
Sigma-Aldrich
L-Valine, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 98.5-101.0%
Supelco
Valsartan, Pharmaceutical Secondary Standard; Certified Reference Material
SAFC
L-Valine
Sigma-Aldrich
L-Valine, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
Valsartan, ≥98% (HPLC)
Supelco
L-Valine, Pharmaceutical Secondary Standard; Certified Reference Material
USP
Valsartan, United States Pharmacopeia (USP) Reference Standard
Valine, European Pharmacopoeia (EP) Reference Standard
Supelco
L-Valine, certified reference material, TraceCERT®
Valsartan, European Pharmacopoeia (EP) Reference Standard
Valsartan for system suitability, European Pharmacopoeia (EP) Reference Standard
Valsartan for peak identification, European Pharmacopoeia (EP) Reference Standard