Bosnjak John J, Terata Ken, Miura Hiroto, Sato Atsushi, Nicolosi Alfred C, McDonald Monica, Manthei Sara A, Saito Takashi, Hatoum Ossama A, Gutterman David D
Medical College of Wisconsin, Cardiovascular Center, Milwaukee, Wisconsin 53226, USA.
Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1080-6. doi: 10.1152/ajpheart.00465.2002. Epub 2002 Dec 19.
Thrombin (Thromb), activated as part of the clotting cascade, dilates conduit arteries through an endothelial pertussis toxin (PTX)-sensitive G-protein receptor and releases nitric oxide (NO). Thromb also acts on downstream microvessels. Therefore, we examined whether Thromb dilates human coronary arterioles (HCA). HCA from right atrial appendages were constricted by 30-50% with endothelin-1. Dilation to Thromb (10(-4)-1 U/ml) was assessed before and after inhibitors with videomicroscopy. There was no tachyphylaxis to Thromb dilation (maximum dilation = 87.0%, ED(50) = 1.49 x 10(-2)). Dilation to Thromb was abolished with either hirudin or denudation but was not affected by PTX. Neither N(omega)-nitro-l-arginine methyl ester (n = 7), indomethacin (n = 9), (1)H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (n = 6), tetraethylammonium chloride (n = 5), nor iberiotoxin (n = 4) reduced dilation to Thromb. However, KCl (maximum dilation = 89 +/- 5 vs. 20 +/- 10%; P < 0.05; n = 7), tetrabutylammonium chloride (maximum dilation = 79 +/- 7 vs. 21 +/- 4%; P < 0.05; n = 5), and charybdotoxin (maximum dilation = 89 +/- 4 vs. 10 +/- 2%; P < 0.05; n = 4) attenuated dilation to Thromb. In contrast to animal models, Thromb-induced dilation in human arterioles is independent of G(i)-protein activation and NO release. However, Thromb dilation is endothelium dependent, is maintained on consecutive applications, and involves activation of K(+) channels. We speculate that an endothelium-derived hyperpolarizing factor contributes to Thromb-induced dilation in HCA.
凝血酶（Thromb）作为凝血级联反应的一部分被激活后，通过内皮百日咳毒素（PTX）敏感的G蛋白受体使传导动脉扩张，并释放一氧化氮（NO）。凝血酶也作用于下游微血管。因此，我们研究了凝血酶是否能使人类冠状动脉小动脉（HCA）扩张。来自右心耳的HCA被内皮素-1收缩30%-50%。在使用抑制剂前后，通过视频显微镜评估对凝血酶（10(-4)-1 U/ml）的扩张反应。对凝血酶扩张不存在快速耐受现象（最大扩张率=87.0%，半数有效量（ED(50)）=1.49×10(-2)）。水蛭素或去内皮处理可消除对凝血酶的扩张反应，但不受PTX影响。N(ω)-硝基-L-精氨酸甲酯（n = 7）、吲哚美辛（n = 9）、（1）H-[1,2,4]恶二唑并-[4,3-a]喹喔啉-1-酮（n = 6）、四乙铵氯化物（n = 5）以及iberiotoxin（n = 4）均未降低对凝血酶的扩张反应。然而，氯化钾（最大扩张率=89±5%对20±10%；P<0.05；n = 7）、四丁铵氯化物（最大扩张率=79±7%对21±4%；P<0.05；n = 5）以及蝎毒素（最大扩张率=89±4%对10±2%；P<0.05；n = 4）减弱了对凝血酶的扩张反应。与动物模型不同，凝血酶诱导的人类小动脉扩张不依赖于G(i)蛋白激活和NO释放。然而，凝血酶扩张依赖于内皮，连续应用时可维持，且涉及钾通道的激活。我们推测一种内皮源性超极化因子有助于凝血酶诱导的HCA扩张。
