Inhibitory action of diltiazem on voltage-gated calcium channels in cone photoreceptors
Inhibitory action of diltiazem on voltage-gated calcium channels in cone photoreceptors
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DOI：
10.1016/s0014-4835(03)00027-7
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发表时间：
2003-05-01
影响因子：
3.4
通讯作者：
Barnes, S
中科院分区：
文献类型：
--
作者：
Hart, J;Wilkinson, MF;Barnes, S
苯并硫氮类药物地尔硫卓是一种常用的血管L型钙通道拮抗剂，是临床上重要的抗心绞痛和降压药物。在视网膜，地尔硫还抑制环核苷酸门控(CNG)通道，包括光感受器中的cGMP门控通道，并被认为是视网膜色素变性动物模型的神经保护剂，视网膜色素变性是一种光感受器退行性疾病。与CNG通道相比，地尔硫卓对光感受器钙通道的作用尚未被研究。我们发现D-顺式地尔硫卓可以阻断视锥感光细胞上的钙通道，并且这种药物抑制视锥感光细胞钙通道的效力和效果是非常规的。在5-500um的浓度范围内，地尔硫卓的剂量反应曲线呈双相，高亲和力饱和水平与20-50um范围内的高亲和力饱和水平接近30%(IC_(50)=4.9um)，低亲和力饱和阻断(接近100%)的浓度高达500um(IC_(50)=100.4 um)。当使用Bay K 8644增加钙通道电流时，阻断程度相同，说明阻断程度不是由不同钙通道亚型对地尔硫卓的敏感性不同造成的。钙成像显示，高亲和力钙通道阻滞剂的效果相对较低不是由于携带电荷的二价阳离子的种类，也不是与细胞内容物的透析有关。这些数据支持一种新的观点，即光感受器钙通道具有不同于其他L类型通道的特性，如果这些通道成为测试假定的神经保护疗法的目标，这是一个重要的考虑因素。(C)2003爱思唯尔科学有限公司。保留所有权利。
The benzothiazepine, diltiazem, is commonly used as an inhibitor of vascular L-type Ca channels, and is a clinically important anti-anginal and antihypertensive medication. In the retina, diltiazem also inhibits cyclic-nucleotide gated (CNG) channels, including the cGMP-gated channels in photoreceptors, and has been suggested to be a neuroprotectant in an animal model of retinitis pigmentosa, a degenerative disease of photoreceptors. In contrast to CNG channels, the actions of diltiazem on photoreceptor Ca channels have not been studied. We show that D-cis-diltiazem can block Ca channels in cone photoreceptors and that the potency and efficacy of cone photoreceptor Ca channel inhibition by this drug is unconventional. Over the concentration range of 5-500 muM diltiazem, the dose response curve was biphasic with a high affinity saturation level of similar to30% block in the 20-50 muM range (IC50 = 4.9 muM) and a low affinity saturation block (near 100%) with concentrations up to 500 muM (IC50 = 100.4 muM). The degree of block was found to be equivalent when Bay K 8644 was used to increase Ca channel current, indicating that the levels of block do not result from multiple Ca channel subtypes having differing sensitivities to diltiazem. Calcium imaging showed that the relatively low efficacy of the high-affinity Ca channel block was not due to the species of charge-carrying divalent cation nor that it was associated with dialysis of cellular contents. These data contribute to an emerging perspective that the photoreceptor Ca channel has properties unique from other L-type channels, an important consideration should these channels become a target for testing putative neuroprotective therapies. (C) 2003 Elsevier Science Ltd. All rights reserved.