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Pharmacological study on the derangements of myocardial cells induced by oxygen radicals, and protection from the derangements

氧自由基引起的心肌细胞紊乱及其防护的药理研究

基本信息

批准号：
05454145
负责人：
ABIKO Yasushi
金额：
$ 4.67万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

We found that H_2O_2 produces ischemia/reperfusion-like changes on the isolated rat heart in both mechanical and metabolic functions and lipid peroxidation, and that lidocain decreases the H_2O_2-induced damage. These results support our hypothesis that oxygen radicals produce ischemia/reperfusion damage, and that the anti-ischemic drug protects the myocardial damage induced by oxygen radicals. We also found that H_2O_2 produces cell damage in the presence of Fe^<2+> in the isolated cardiac cells. The H_2O_2-induced damage to the myocyte was protected by d-propranolol and K-7259, a novel derivative of dilazep. Next, we found that LPC produced ischemia/reperfusion-like damage to the isolated heart, and that d-propranolol and K-7259 attenuated the LPC-induced damage to the isolated haert. In the next experiments, we measured intraceullar Ca^<2+> concentration ([Ca^<2+>]_i) in the cardiac myocyte. LPC increased ([Ca^<2+>]_i) markedly and dilazep and d-propranolol attenuated the LPC-induced increase in ([Ca^<2+>]_i). Next, we examined the effect of beta-adrenoceptor antagonists on the LPC-induced increase in ([Ca^<2+>]_i), and found that l- and d-propranolol, and l- and dpenbutolol were effective in attenuating the LPC-induced increased in ([Ca^<2+>]_i). Lastly, we examined the effect of LPC on the ion channel in the cardiac myocyte, and found that LPC increases the non-selective cation channel current through which Ca^<2+> can pass.These results suggst that oxygen radicals like hydrogen peroxide produces peroxidation of the phospholipids of the cardiac cell membrane, releasing LPC.LPC then increases ([Ca^<2+>]_i) through non-selective cation channel. d-Propranolol and K-7259, a derivative of dilazep, attenuated both H_2O_2-induced and LPC-induced damage to the cardiac myocyte.

我们发现H_2O_2对离体大鼠心脏的机械功能、代谢功能和脂质过氧化均产生缺血/再灌注样改变，利多卡因可减轻H_2O_2引起的损伤。这些结果支持了氧自由基引起缺血再灌注损伤的假说，而抗缺血药物对氧自由基引起的心肌损伤具有保护作用。我们还发现，在Fe^<2+>存在的情况下，H_2O_2对离体心肌细胞产生损伤。d-心得安和K-7259对h_2o_2诱导的心肌细胞损伤具有保护作用。接下来，我们发现LPC对离体心脏产生缺血/再灌注样损伤，d-心得安和K-7259可减轻LPC对离体心脏的损伤。在接下来的实验中，我们测量了心肌细胞内Ca^<2+>浓度（[Ca^<2+>]_i）。LPC明显升高（[Ca^<2+>]_i），地拉安定和d-心得安可减弱LPC诱导的（[Ca^<2+>]_i）升高。接下来，我们研究了β -肾上腺素能受体拮抗剂对lpc诱导的（[Ca^<2+>]_i）升高的影响，发现l-和d-心得安，l-和丁布洛尔可有效减弱lpc诱导的（[Ca^<2+>]_i）升高。最后，我们检测了LPC对心肌细胞离子通道的影响，发现LPC增加了Ca^<2+>可以通过的非选择性阳离子通道电流。这些结果表明，氧自由基如过氧化氢使心肌细胞膜磷脂发生过氧化，释放LPC。LPC通过非选择性阳离子通道增加（[Ca^<2+>]_i）。d-心得安和K-7259（地拉唑的衍生物）均能减轻h_2o_2诱导和lpc诱导的心肌细胞损伤。