Fukai T, Egashira K, Hata H, Numaguchi K, Ohara Y, Takahashi T, Tomoike H, Takeshita A
Research Institute of Angiocardiography, Kyushu University School of Medicine, Fukuoka, Japan.
Circulation. 1993 Oct;88(4 Pt 1):1922-30. doi: 10.1161/01.cir.88.4.1922.
Coronary spasm may be caused by endothelial dysfunction, vascular smooth muscle hyperreactivity, or both. We aimed to determine the relative role of endothelial dysfunction and vascular smooth muscle hyperreactivity in the pathogenesis of coronary artery spasm in the swine model in vivo.
In Göttingen miniature pigs given a high cholesterol diet, a segment of the left coronary artery was denuded and irradiated with x-ray (total, 30 Gy). Three months after endothelial denudation and irradiation, vasomotor responses of the denuded and control sites to agonists were assessed by quantitative arteriography. Serotonin (10 micrograms/kg) provoked coronary spasm at the denuded site (diameter reduction, 79 +/- 6%) associated with ST elevation but not at the nondenuded control site (21 +/- 6%). Intracoronary infusion of N omega-nitro-L-arginine methyl ester (LNNA, an inhibitor of endothelium-derived nitric oxide) of 1 and 3 mg/kg potentiated constriction evoked with serotonin (1, 3, 10 micrograms/kg) at the control site but did not alter it at the denuded site. However, serotonin-induced constriction after LNNA was still less at the control site (31 +/- 3%) than at the denuded site (80 +/- 5%). Endothelium-dependent vasodilation with substance P (0.1, 1, 10 ng/kg), which was inhibited by LNNA, was less (P < .01) at the denuded site than at the control site, whereas vasodilation with the nitrovasodilator SIN-1 (0.1, 1, 10 ng/kg) was comparable between the two sites. Histological study revealed regenerated endothelial cells and intimal thickening at the denuded site.
The results suggest that the denuded segment of the coronary artery with regenerated endothelium was associated with defective endothelium-dependent vasodilation mediated by nitric oxide and vascular smooth muscle hyperreactivity to serotonin. However, provocation of coronary spasm with serotonin resulted primarily from vascular smooth muscle hyperreactivity but not by defective nitric oxide production in this swine model.
冠状动脉痉挛可能由内皮功能障碍、血管平滑肌反应性亢进或两者共同引起。我们旨在确定内皮功能障碍和血管平滑肌反应性亢进在猪体内冠状动脉痉挛发病机制中的相对作用。
给哥廷根小型猪喂食高胆固醇饮食，然后剥脱一段左冠状动脉内皮并用X射线照射（总量30 Gy）。内皮剥脱和照射3个月后，通过定量血管造影评估剥脱部位和对照部位对激动剂的血管舒缩反应。血清素（10微克/千克）在剥脱部位引发冠状动脉痉挛（直径缩小79±6%），伴有ST段抬高，但在未剥脱的对照部位未引发（21±6%）。冠状动脉内注入1毫克/千克和3毫克/千克的Nω-硝基-L-精氨酸甲酯（LNNA，一种内皮源性一氧化氮抑制剂）可增强对照部位血清素（1、3、10微克/千克）诱发的收缩，但对剥脱部位无影响。然而，LNNA处理后血清素诱导的对照部位收缩（31±3%）仍低于剥脱部位（80±5%）。P物质（0.1、1、10纳克/千克）引起的内皮依赖性血管舒张在剥脱部位比对照部位弱（P<0.01），且被LNNA抑制，而硝基血管扩张剂SIN-1（0.1、1、10纳克/千克）引起的血管舒张在两个部位相当。组织学研究显示剥脱部位有再生的内皮细胞和内膜增厚。
结果表明，具有再生内皮的冠状动脉剥脱段与一氧化氮介导的内皮依赖性血管舒张缺陷以及血管平滑肌对血清素反应性亢进有关。然而，在该猪模型中，血清素诱发冠状动脉痉挛主要源于血管平滑肌反应性亢进，而非一氧化氮生成缺陷。
