In vitro and in vivo effects of R023-6152 on heart mitochondrial calcium and energy metabolism.
In vitro and in vivo effects of R023-6152 on heart mitochondrial calcium and energy metabolism.
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R023-6152 对心脏线粒体钙和能量代谢的体外和体内影响。
DOI：
10.1097/00005344-199110000-00001
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发表时间：
1991
影响因子：
3
通讯作者：
Sordahl,LA
中科院分区：
文献类型：
--
作者：
Medh,JD;Rex,KA;Benedict,CR;Sordahl,LA
先前的研究表明，所有化学类别的 Ca 2+ 通道拮抗剂都可以抑制 Na+ 诱导的 Ca 2+ 从线粒体释放。新型硫氮杂酮 Ca 2+ 通道拮抗剂 R023–6152 对离体兔心脏线粒体 Ca 2+ 转运和呼吸活动的影响与地尔硫卓进行了比较。还对体内接受 8023-6152 或地尔硫卓处理的狗的心脏线粒体进行了分离和分析。结果表明，R023–6152 在与地尔硫卓相对相同的浓度 (10–30 μM) 下对 Na+ 诱导的分离线粒体 Ca 2+ 释放产生半最大抑制，但在浓度 (25–100 μM) 下也对线粒体 Ca 2+ 摄取和状态 3 呼吸产生抑制，而地尔硫卓在该浓度下没有作用。与地尔硫卓相比，R023-6152 在接近和抑制线粒体膜中的磷酸盐转运蛋白方面具有更大的亲脂性，这可以解释这些结果。与对照组相比，从接受地尔硫卓和 R023-6152 治疗的狗中分离出的心脏线粒体表现出较低的 3 态呼吸率。我们认为这可能是由于跨肌膜 Ca 2+ 通量减少导致线粒体脱氢酶活性下调所致，而不是由于两种药物的任何直接细胞内作用所致。
Previous studies have shown that Ca 2+ channel antagonists in all chemical classes can inhibit Na+ induced Ca 2+ release from mitochondria. The effects of R023–6152, a new thiazepinone Ca 2+ channel antagonist, on isolated rabbit heart mitochondrial Ca 2+ transport and respiratory activity were compared with those of diltiazem. Heart mitochondria were also isolated and assayed from dogs treated in vivo with either 8023–6152 or diltiazem. The results indicate that R023–6152 produces half-maximal inhibition of Na+-induced Ca 2+ release from isolated mitochondria at relatively the same concentrations (10–30 μM) as diltiazem but also produces inhibition of mitochondrial Ca 2+ uptake and state 3 respiration at concentrations (25–100 μM), at which diltiazem has no effect. The greater lipophilicity of R023–6152 in gaining access to and inhibiting the phosphate transporter in the mitochondrial membrane as compared with that of diltiazem may explain these results. Heart mitochondria isolated from dogs treated with diltiazem and R023–6152 exhibited lower rates of state 3 respiration as compared with controls. We suggest that this may result from a reduction in transsarcolemmal Ca 2+ flux causing a down-regulation in mitochondrial dehydrogenase activity and not from any direct intracellular effects of the two drugs.