Pathogenesis and prevention of myocardial injury induced by coronary artery spasm

1.猪冠状动脉痉挛模型的特点：观察前列环素和白三烯在猪冠状动脉痉挛模型中的作用。对34头小型猪进行左冠状动脉内皮剥脱术，然后进行高胆固醇喂养。剥离后3个月，用组胺反复引起冠状动脉剥脱部分的冠脉痉挛，观察前列腺素和LTS对冠脉痉挛的作用。冠脉内注射稳定的TX；A2类似物200微克，不能引起冠状动脉痉挛，但非选择性地使冠状动脉收缩33%。持续静脉滴注前列环素(50 ng/kg/min)不能预防组胺诱发的冠脉痉挛，但预先静脉注射苯海拉明(1 mg/kg)可有效预防冠脉痉挛。因此，在这头猪…中更典型的是，前列腺素可能在冠状动脉痉挛的发生中不起主要作用。冠状动脉内注射1和10剂量的LTC_4和LT_4&GT；g可引起心电图ST段抬高，冠状动脉造影显示充盈延迟。然而，这些LT并没有引起心外膜冠状动脉任何部位的血管收缩。55712 mg/kg能完全消除LT诱导的心肌缺血，但不能阻止组胺诱导的冠脉痉挛。因此，在我们的猪冠状动脉痉挛模型中，LTS在小血管水平上收缩冠状动脉，使灌流的心肌缺血，但它们在组胺诱导的痉挛中并不起主要作用。冠脉痉挛体外研究的可行性：我们在小型猪去内皮和喂饲胆固醇3个月后，就痉挛的程度和部位，测试了组胺在体外是否可以复制类似于体内的组胺增强血管收缩的作用。用Krebs-Henseleit液恒压灌流，复制冠脉痉挛模型。灌流液中不含钙离子的组胺诱发的痉挛有一定的预防作用。平滑肌收缩的细胞生物学分析：用放射配基结合技术检测来自猪冠状动脉和主动脉的细胞膜提取物的α、β和H_1受体特性。(&lt；II&gt；)用生理负荷的Quin II微量荧光分光光度法建立了测定培养的平滑肌细胞胞浆&lt；Ca~(++)&Gt；动力学的新方法。较少

1. Characteristics of Coronary Artery Spasm in Our Swine Model: The role of prostanoids and leukotriene (LT) in a swine model of coronary artery spasm was examined. Thirty four miniature pigs underwent endothelial denudation of the left coronary artery followed by high cholesterol feeding. Three months after the denudation, when coronary artery spasm was repeatedly provoked along the denuded portion of the coronary artery by histamine, the role of prostanoids and LTs on coronary artery spasm was examined in 18 and 16 pigs, respectively. ( <i> ) Intracoronary administration of thiothromboxane <A_2> , 200 <micro> g, a stable Tx <A_2> analog, failed to provoke coronary artery spasm, but nonselectively constricted the coronary artery by 33%. Continuous intravenous infusion of prostacyclin, 50 ng/kg per min, failed to prevent histamine-induced coronary artery spasm, yet the spasm was all but prevented by intravenous pretreatment with diphenhydramine at a dose of 1 mg/kg. Thus, in this swine … More model, prostanoids may not play a primary role in the occurrence of coronary artery spasm. ( <ii> ) Intracoronary administration of <LTC_4> and <LTD_4> in doses of 1 and 10 <micro> g caused ECG-ST elevation along with delayed filling of the coronary artery angiographically. Nevertheless, those LTs did not provoke augmented vasconstriction in any site of the epicardial coronary arteries. FPL-55712, 0.1 mg/kg by which LT-induced myocardial ischemia was completely abolished, did not prevent histamine-induced coronary artery spasm. Accordingly, in our swine model of coronary spasm, LTs constricted coronary arteries at the level of small vessels and rendered the perfused myocardium ischemic, yet they did not play a primary role in the provocation of histamine-induced spasm.2. Feasibility of in vitro Studies of Coronary Spasm: We tested whether augmented vasoconstriction is reproducible by histamine in vitro similar to in vivo with regard to the degree and location of the spasm in miniature pigs, after endothelial denudation and cholesterol feeding for 3 months. Coronary artery spasm was reproduced in isolated hearts under constant pressure perfusion with Krebs-Henseleit solution. Absence of <Ca^(++)> in the perfused sobution prevented the histamine-induced spasm.3. Cell Biological Analysis of Smooth Muscle Contraction: ( <i> ) Receptor characteristics of the cell membrane extracts derived from the porcine coronary artery and aorta were examined with regard to alpha, beta and <H_1> receptors using a radioligand binding technique. ( <ii> ) The new method for determining cytosolic <Ca^(++)> kinetics in the cultured smooth muscle cell was established using micro-fluorometric measurement of Quin II loaded physiologically. Less