Cardioprotective effect of angiotensin-converting enzyme inhibition against hypoxia/reoxygenation injury in cultured rat cardiac myocytes
Cardioprotective effect of angiotensin-converting enzyme inhibition against hypoxia/reoxygenation injury in cultured rat cardiac myocytes
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DOI：
10.1161/01.cir.99.6.817
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发表时间：
1999-02-16
期刊：
影响因子：
37.8
通讯作者：
Nakagawa, M
中科院分区：
文献类型：
--
作者：
Matoba, S;Tatsumi, T;Nakagawa, M
背景-虽然ACE抑制剂可以保护心肌免受缺血/再灌注损伤，但这种作用的机制尚未在细胞水平上得到表征。本研究的目的是检查是否ACE抑制剂，cilazaprilat，直接保护心肌细胞缺氧/复氧（WR）injuriation.Methods和Results-Neonatal大鼠心肌细胞在原代培养暴露于缺氧5.5小时，随后复氧1小时。以肌酸激酶（CK）的释放量测定心肌细胞损伤程度。无论是西拉普利拉和缓激肽显着抑制CK释放后H/R在剂量依赖性的方式和保护心肌细胞ATP含量在WR，而CV-11974，血管紧张素II受体拮抗剂，血管紧张素II没有。Hoe 140（缓激肽B-2受体拮抗剂）、N-G-单甲基-L-精氨酸单乙酸酯（L-NMMA）和亚甲蓝（可溶性鸟苷酸环化酶抑制剂）可显著抑制西拉普利拉的保护作用，但星形孢菌素（蛋白激酶C抑制剂）、氨基胍和吲哚美辛（环氧合酶抑制剂）不抑制西拉普利拉的保护作用。Cilazaprilat显着提高缓激肽生产的培养基中的心肌细胞缺氧5.5小时后，但不是在nonmyocytes。此外，cilazaprilat显著增加缺氧时心肌细胞cGMP含量，这种增加可被L-NMMA和亚甲蓝所减弱，但不被氨基胍所减弱。主要是由于缓激肽的积累和伴随的NO的产生，NO的产生是由缺氧心肌细胞中的组成型NO合酶以自分泌/分泌的方式诱导的。旁分泌方式NO调节心肌细胞鸟苷酸环化酶和cGMP的合成，可能有助于维持心肌细胞的能量代谢，保护心肌免受H/R损伤。
Background-Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (WR) injury.Methods and Results-Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during WR, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B-2 receptor antagonist), N-G-monomethyl-L-arginine monoacetate (L-NMMA) tan NO synthase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) but not by staurosporine (a protein kinase C inhibitor), aminoguanidine tan inhibitor of inducible NO synthase), or indomethacin (a cyclooxygenase inhibitor). Cilazaprilat significantly enhanced bradykinin production in the culture media of myocytes after 5.5 hours of hypoxia but not in that of nonmyocytes. In addition, cilazaprilat markedly enhanced the cGMP content in myocytes during hypoxia, and this augmentation in cGMP could be blunted by L-NMMA and methylene blue but not by aminoguanidine.Conclusions-The present study demonstrates that cilazaprilat can directly protect myocytes against WR injury, primarily as a result of an accumulation of bradykinin and the attendant production of NO induced by constitutive NO synthase in hypoxic myocytes in an autocrine/paracrine fashion. NO modulates guanylate cyclase and cGMP synthesis in myocytes, which may contribute to the preservation of energy metabolism and cardioprotection against H/R injury.