Effects of cytochrome P450 inhibitors on agonist-induced Ca2+ responses and production of NO and PGI2 in vascular endothelial cells
Effects of cytochrome P450 inhibitors on agonist-induced Ca2+ responses and production of NO and PGI2 in vascular endothelial cells
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细胞色素 P450 抑制剂对激动剂诱导的 Ca2+ 反应以及血管内皮细胞中 NO 和 PGI2 产生的影响
DOI：
10.1023/a:1024136318779
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发表时间：
2003
影响因子：
4.3
通讯作者：
H. Hayashi
中科院分区：
文献类型：
--
作者：
K. Takeuchi;Hiroshi Watanabe;Q. Tran;Mariko Ozeki;A. Uehara;H. Katoh;H. Satoh;H. Terada;K. Ohashi;H. Hayashi
内皮依赖性血管舒张因子如一氧化氮（NO）、前列腺素I2（PGI 2）和内皮源性超极化因子（EDHF）的产生部分受到血管内皮细胞（EC）内Ca 2+浓度（[Ca 2 +]i）变化的调节。细胞色素P450（CYP 450）是EDHF的候选者之一，它通过环氧二十碳三烯酸介导内皮依赖性超极化。在这项研究中，我们测试的假设，ESTA可能参与EC Ca 2+信号，ESTA活动可能与生产的血管舒张因子以外的EDHF。为此，在原代培养的猪主动脉内皮细胞上测试了结构上不同的血管内皮抑制剂，包括SKF 525 A、益康唑和咪康唑。细胞内Ca ~（2+）浓度用荧光指示剂fura-2/AM测定。缓激肽（BK，10 nM）和毒胡萝卜素（TG，1 μM）引起[Ca 2 +]i的大的双相增加，这包括从细胞内储存的Ca 2+释放和跨质膜Ca 2+进入。SKF 525 A呈剂量依赖性（30-100 μM）抑制BK和TG刺激的Ca 2+内流，但不抑制细胞内Ca 2+库释放。益康唑（10 μM）和咪康唑（10 μM）对Ca 2+内流的影响与SKF 525 A相同。通过测量cGMP和6-keto-PGF 1 α浓度评估，SKF 525 A还剂量依赖性地抑制BK刺激的NO和PGI 2的产生。这些数据表明，除了其调节EDHF的生产，ESTA也有助于通过修改EC Ca 2+信号调节其他内皮依赖性血管舒张因子。
Production of endothelium-dependent vascular relaxing factors, such as nitric oxide (NO) and prostaglandin I2 (PGI2), and endothelium-derived hyperpolarizing factor (EDHF), is regulated in part by changes in intracellular Ca2+ concentration ([Ca2+]i) in vascular endothelial cells (ECs). Cytochrome P450 (CYP), shown to mediate endothelium-dependent hyperpolarization via epoxyeicosatrienoic acids, is one of the candidates for EDHF. In this study we tested the hypotheses that CYP might be involved in EC Ca2+ signaling and that CYP activity might be linked with production of vasodilating factors other than EDHF. To this end, structurally different CYP inhibitors including SKF 525A, econazole and miconazole were tested on primary cultured porcine aortic endothelial cells. Intracellular Ca2+ concentration was measured using the fluorescent Ca2+ indicator fura-2/AM. Bradykinin (BK, 10 nM) and thapsigargin (TG, 1 μM) provoked large biphasic increases in [Ca2+]i, which consist of Ca2+ release from intracellular stores and transplasmalemmal Ca2+ entry. SKF 525A dose-dependently (30–100 μM) inhibited BK- and TG-stimulated Ca2+ entry, but not intracellular Ca2+ store release. Econazole (10 μM) and miconazole (10 μM) had the same effect as SKF 525A on the Ca2+ entry. SKF 525A also dose-dependently inhibited BK-stimulated production of NO and PGI2, assessed by measuring cGMP and 6-keto-PGF1α concentration. These data suggest that, in addition to its regulation of EDHF production, CYP also contributes to the regulation of other endothelium-dependent vasorelaxing factors by modifying EC Ca2+ signaling.
培养的人内皮细胞中凝血酶诱导的前列环素产生与肌醇三磷酸和胞质游离钙水平之间的相关性。
DOI：
--
发表时间：
1987
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Jaffe,EA;Grulich,J;Weksler,BB;Hampel,G;Watanabe,K
通讯作者：
Watanabe,K