SKF-525A不抑制大鼠胸主动脉、狗肠系膜和股动脉内皮源性松弛因子的释放。

Blood vessels Pub Date : 1991-01-01 DOI:10.1159/000158894
J M Xie, Y Wang, S S Greenberg
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引用次数: 1

摘要

SKF-525A (proadifen)抑制乙酰胆碱、花生四烯酸和钙离子载体A23187诱导的内皮依赖性松弛。这表明SKF-525A是内皮衍生放松因子(EDRF)的抑制剂,EDRF可能是花生四烯酸代谢的产物,通过细胞色素P-450依赖途径形成,或者EDRF的释放依赖于细胞色素P-450。我们用大鼠胸主动脉和狗肠系膜和股动脉分离环以及灌注-灌注生物测定法来验证这一假设。分别用EC50浓度的去甲肾上腺素(0.1 nmol/l)或U46619 (0.05 mumol/l)对内皮完整的大鼠胸主动脉和狗肠系膜、股动脉环进行预收缩,分别在SKF-525A (50 mumol/l)加入前、加入后30 min和冲洗后30 min获得对乙酰胆碱(ACh)、弛豫素、三磷酸腺苷(ATP)或硝酸甘油(GTN)的松弛。SKF-525A抑制乙酰胆碱诱导的大鼠主动脉环内皮依赖性松弛和乙酰胆碱和ATP诱导的狗肠系膜和股动脉内皮依赖性松弛,但不影响对缓激肽或GTN的松弛。SKF-525A对乙酰胆碱和atp诱导的松弛的抑制作用在其从肌室洗脱后部分逆转。用布洛芬(1mumol /l)预处理血管不会减弱skf - 525a介导的对任何激动剂的松弛抑制。犬股动脉(供体)选择性暴露于SKF-525A (50 μ mol/l)中60分钟,不影响内皮摩擦冠状动脉(生物测定组织)对基础EDRF的松弛反应,也不影响供体组织对乙酰胆碱(10-1,000 pmol)、ATP (1-100 nmol)或缓激肽(3-100 pmol)刺激的流出物的松弛反应。结果表明,SKF-525A通过与内皮生成EDRF无关的平滑肌机制对内皮依赖性松弛表现出可逆的抑制作用。
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SKF-525A does not inhibit release of endothelium-derived relaxing factor from rat thoracic aorta and dog mesenteric and femoral artery.

SKF-525A (proadifen) inhibits endothelium-dependent relaxations induced by acetylcholine, arachidonic acid and the calcium ionophore A23187. This suggests that SKF-525A is an inhibitor of endothelium-derived relaxing factor (EDRF) and that EDRF may be a product of arachidonic acid metabolism formed via a cytochrome P-450-dependent pathway or that EDRF release is dependent on cytochrome P-450. We tested this postulate using both isolated rings of rat thoracic aorta and dog mesenteric and femoral artery and the perfusion-superfusion bioassay. Rings of rat thoracic aorta and dog mesenteric and femoral artery with intact endothelium were precontracted with an EC50 concentration of norepinephrine (0.1 nmol/l) or U46619 (0.05 mumol/l) and the relaxation to acetylcholine (ACh), bradykinin, adenosine triphosphate (ATP) or nitroglycerin (GTN) were obtained before, 30 min after addition of, and 30 min after washout of SKF-525A (50 mumol/l). SKF-525A inhibited ACh-induced endothelium-dependent relaxation of rat aortic rings and endothelium-dependent relaxation of the dog mesenteric and femoral artery produced by ACh and ATP, but did not affect relaxation to bradykinin or GTN. The inhibitory effect on SKF-525A on ACh and ATP-induced relaxation was partially reversed upon its washout from the muscle chamber. Pretreatment of the blood vessels with ibuprofen (1 mumol/l) did not attenuate SKF-525A-mediated inhibition of the relaxations to any agonist. Selective exposure of dog femoral artery (donor) to SKF-525A (50 mumol/l) for 60 min did not affect the relaxation responses of endothelium-rubbed coronary artery (bioassay tissue) to basal EDRF nor to the effluent from donor tissues stimulated with ACh (10-1,000 pmol), ATP (1-100 nmol) or bradykinin (3-100 pmol). The results show that SKF-525A exhibited a reversible inhibition of endothelium-dependent relaxation by a smooth muscle mechanism unrelated to the generation of EDRF from endothelium.

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