Park S J, Lee J J, Kirchengast M, Boulanger C M, Vanhoutte P M
Department of Medicine, Baylor College of Medicine, Houston, TX 77030-3498.
Cardiovasc Res. 1995 Jan;29(1):95-101.
The aim was to evaluate the effect of the combined 5-hydroxytryptamine-2 (5-HT2) receptor antagonist and calcium channel inhibitor LU49938 ((2S)-5-[N-methyl-N-(n-hexyl)] amino-2-isopropyl-2(3.4.5-trimethoxyphenyl)-valeronitrilhydrochloride ) on the endothelium dependent responsiveness of porcine coronary arteries with native and regenerated endothelium.
Male Yorkshire pigs were assigned randomly to one of four groups: (1) controls; (2) pigs receiving LU49938 daily (5 mg.kg-1) for four weeks; (3) pigs undergoing balloon de-endothelialisation of the left anterior descending coronary artery; and (4) pigs undergoing balloon de-endothelialisation and receiving LU49938 daily. At four weeks, quantitative coronary angiography, organ chamber experiments, and morphometric studies of the tissues were performed.
Treatment with LU49938 did not affect the endothelium dependent responses in native porcine coronary arteries. Intracoronary injection of serotonin caused significantly greater coronary vasoconstriction in group 3 compared with group 4. The cross sectional area of the intima and media of previously de-endothelialised left anterior descending coronary artery increased significantly in group 3, but not in group 4. In arteries with regenerated endothelium, augmented endothelium dependent contractions were noted not only in response to serotonin, but also in response to platelets, noradrenaline, and endothelin-1. The endothelium dependent relaxations to platelets, serotonin, and UK14304 were impaired in the regenerated endothelium, but not those to adenosine diphosphate and SIN-1. However, following four weeks of treatment with LU49938, the pertussis toxin sensitive endothelium dependent responses were restored. The augmented endothelium dependent contraction to endothelin-1 was not altered by the treatment.
Chronic treatment with LU49938 restores endothelium dependent, pertussis toxin sensitive, G protein mediated responses in the regenerated endothelium of the porcine coronary artery, and inhibits the intimal thickening following arterial injury.
评估5-羟色胺-2（5-HT2）受体拮抗剂与钙通道抑制剂LU49938（(2S)-5-[N-甲基-N-(正己基)]氨基-2-异丙基-2(3,4,5-三甲氧基苯基)-戊腈盐酸盐）联合应用对具有天然内皮和再生内皮的猪冠状动脉内皮依赖性反应性的影响。
将雄性约克夏猪随机分为四组：（1）对照组；（2）每天接受LU49938（5mg·kg-1）治疗四周的猪；（3）左前降支冠状动脉接受球囊去内皮术的猪；（4）左前降支冠状动脉接受球囊去内皮术并每天接受LU49938治疗的猪。四周时，进行定量冠状动脉造影、器官腔室实验和组织形态计量学研究。
LU49938治疗对天然猪冠状动脉的内皮依赖性反应无影响。与第4组相比，第3组冠状动脉内注射血清素引起的冠状动脉收缩明显更强烈。第3组中，先前去内皮的左前降支冠状动脉内膜和中膜的横截面积显著增加，而第4组未增加。在具有再生内皮的动脉中，不仅对血清素，而且对血小板、去甲肾上腺素和内皮素-1的反应，内皮依赖性收缩均增强。再生内皮对血小板、血清素和UK14304的内皮依赖性舒张受损，但对二磷酸腺苷和SIN-1的舒张未受损。然而，用LU49938治疗四周后，百日咳毒素敏感的内皮依赖性反应得以恢复。治疗并未改变对内皮素-1增强的内皮依赖性收缩。
LU49938长期治疗可恢复猪冠状动脉再生内皮中内皮依赖性、百日咳毒素敏感的G蛋白介导的反应，并抑制动脉损伤后的内膜增厚。
