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

结果发现，H_2O_2可引起大鼠离体心机械功能、代谢功能和脂质过氧化反应的类缺血/再灌注样改变，利多卡因可减轻H_2O_2所致的损伤。这些结果支持我们的假设，即氧自由基产生缺血/再灌注损伤，抗缺血药物对氧自由基诱导的心肌损伤具有保护作用。我们还发现，在Fe~(2+)和Gt~(2+)存在时，H_2O_2对心肌细胞有损伤作用。D-心得安和地拉西普的新衍生物K-7259对H_2O_2诱导的心肌细胞损伤有保护作用。接下来，我们发现LPC对离体心产生缺血/再灌注样损伤，d-心得安和K-7259可减轻LPC对离体心的损伤。在接下来的实验中，我们测量了心肌细胞内钙离子浓度([Ca^&lt；2+&gt；]i)。LPC显著增加([Ca^&lt；2+&gt；]i)，地拉西普和d-心得安可减弱LPC引起的([Ca^&lt；2+&gt；]i)升高。接下来，我们观察了β-受体拮抗剂对LPC诱导的[[Ca^&lt；2+&gt；]_i升高的影响，发现L和d-普奈洛尔、L和丁丁洛尔均能有效地减轻LPC诱导的[Ca^&lt；2+&gt；]_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增加了非选择性阳离子通道电流，钙离子可通过该通道通过。这一结果表明，氧自由基如过氧化氢引起心肌细胞膜磷脂的过氧化，释放LPC。LPC随后通过非选择性阳离子通道增加([Ca^&lt；2+&gt；]i)。D-心得安和地拉西普的衍生物K-7259可减轻H_2O_2和LPC引起的心肌细胞损伤。

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.