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首页> 外文期刊>Biochemical Pharmacology >Anti-ischemic properties of a new spiro-cyclic benzopyran activator of the cardiac mito-KATP channel.
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Anti-ischemic properties of a new spiro-cyclic benzopyran activator of the cardiac mito-KATP channel.

机译：心脏线粒体-KATP通道的新型螺环苯并吡喃活化剂的抗缺血特性。

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摘要

Many activators of K(ATP) channels exhibit cardioprotective effects, mainly mediated by channels expressed on mitochondria (mito-K(ATP)). Previous results showed anti-ischemic effects of the spiro-cyclic derivative A, on isolated rat hearts. In this work this molecule was more extensively studied and diazoxide was used as reference mito-K(ATP) opener. The studies were performed on an in vivo rat model of myocardial infarct and on heart-derived H9c2 cells exposed to an anoxic environment. The mechanism of action was further investigated on isolated rat heart mitochondria. In the model of myocardial infarct compound A and diazoxide produced significant cardioprotective effects, antagonised by the selective mito-K(ATP) blocker 5-hydroxydecanoic acid (5-HD). Compound A, like diazoxide, produced modest and non-significant hypotensive responses, while the hyperglycaemic effects of diazoxide were not observed for the new compound. Protective effects of compound A and diazoxide were also recorded in H9c2 cells and again were inhibited by 5-HD. Compound A and diazoxide caused swelling of cardiac mitochondria, in agreement with the profile of mito-K(ATP) openers. Both compounds evoked concentration-dependent Ca2+-release from Ca2+-preloaded mitochondria, prevented mitochondrial Ca2+-uptake and caused mitochondrial membrane depolarisation. These effects were antagonised by ATP, the endogenous K(ATP) inhibitor. In conclusion, compound A exhibits a promising profile of an anti-ischemic agent, with a mechanism likely to be linked to the activation of mito-K(ATP) channels, and, because of its chemical characteristics such as structural rigidity and chirality due to the spiro-cyclic moiety, represents an interesting template for development of analogues further improved in activity and selectivity.
机译：K（ATP）通道的许多激活剂表现出心脏保护作用，主要是由线粒体（mito-K（ATP））上表达的通道介导的。先前的结果表明，螺环衍生物A对离体大鼠心脏具有抗缺血作用。在这项工作中，对该分子进行了更广泛的研究，并将二氮嗪用作参比的mito-K（ATP）开启剂。该研究是在心肌梗塞的体内大鼠模型以及暴露于缺氧环境的心脏来源的H9c2细胞上进行的。进一步研究了离体大鼠心脏线粒体的作用机理。在心肌梗塞模型中，化合物A和二氮嗪产生了显着的心脏保护作用，被选择性的mito-K（ATP）阻断剂5-羟基癸酸（5-HD）拮抗。化合物A与二氮嗪一样，会产生适度且无明显的降压反应，而对于新化合物，未观察到二氮嗪的高血糖作用。在H9c2细胞中也记录了化合物A和二氮嗪的保护作用，并再次被5-HD抑制。化合物A和二氮嗪导致心脏线粒体肿胀，这与mito-K（ATP）开放剂的特征相符。两种化合物都引起了Ca2 +预载线粒体的浓度依赖性Ca2 +释放，阻止了线粒体Ca2 +的吸收并引起线粒体膜去极化。这些作用被内源性K（ATP）抑制剂ATP拮抗。总而言之，化合物A展现出一种有前途的抗缺血药物，其机制可能与mito-K（ATP）通道的激活有关，并且由于其化学特性，例如结构刚性和手性螺环部分代表用于开发类似物的活性和选择性进一步提高的有趣模板。

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