O'Rourke Stephen T, Hammad Hana, Delagrange Philippe, Scalbert Elizabeth, Vanhoutte Paul M
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
Br J Pharmacol. 2003 Aug;139(7):1326-32. doi: 10.1038/sj.bjp.0705383.
(1) The present study was designed to test the hypothesis that melatonin inhibits nitrate tolerance in coronary arteries. (2) Rings of porcine coronary arteries were suspended in organ chambers for isometric tension recording. Nitrate tolerance was induced by incubating the tissues with nitroglycerin (10(-4) M) for 90 min, followed by repeated rinsing for 1 h. Control rings that had not been exposed previously to nitroglycerin, but were otherwise treated identically, were studied simultaneously. The rings were contracted with U46619 (1-3 x 10(-9) M) and concentration-response curves to nitroglycerin (10(-9)-10(-4) M) were obtained. (3) Nitrate tolerance was evident by a 15- to 20-fold rightward shift in the concentration-response curve to nitroglycerin in rings with and without endothelium exposed previously to the drug for 90 min. Addition of melatonin (10(-9)-10(-7) M) to the organ chamber during the 90-min incubation period with nitroglycerin partially inhibited nitrate tolerance in coronary arteries with intact endothelium; however, melatonin had no effect on nitrate tolerance in coronary arteries without endothelium. (4) The effect of melatonin on nitrate tolerance in coronary arteries with endothelium was abolished by the melatonin receptor antagonist, S20928 (10(-6) M). In contrast to melatonin, the selective MT(3)-melatonin receptor agonist, 5-MCA-NAT (10(-8)-10(-7) M), had no effect on nitrate tolerance in coronary arteries. (5) The results demonstrate that melatonin, acting via specific melatonin receptors, inhibits nitrate tolerance in coronary arteries and that this effect is dependent on the presence of the vascular endothelium.
(1) 本研究旨在验证褪黑素抑制冠状动脉硝酸酯耐受性的假说。(2) 将猪冠状动脉环悬挂于器官浴槽中进行等长张力记录。通过将组织与硝酸甘油（10⁻⁴ M）孵育90分钟诱导硝酸酯耐受性，随后反复冲洗1小时。同时研究未预先暴露于硝酸甘油但其他处理相同的对照环。用U46619（1 - 3×10⁻⁹ M）使环收缩，并获得硝酸甘油（10⁻⁹ - 10⁻⁴ M）的浓度 - 反应曲线。(3) 在预先将有或无内皮的环暴露于该药物90分钟的情况下，硝酸酯耐受性表现为硝酸甘油浓度 - 反应曲线向右移位15至20倍。在与硝酸甘油孵育90分钟期间向器官浴槽中加入褪黑素（10⁻⁹ - 10⁻⁷ M）可部分抑制完整内皮冠状动脉中的硝酸酯耐受性；然而，褪黑素对无内皮冠状动脉中的硝酸酯耐受性无影响。(4) 褪黑素受体拮抗剂S20928（10⁻⁶ M）消除了褪黑素对有内皮冠状动脉硝酸酯耐受性的影响。与褪黑素相反，选择性MT(3) - 褪黑素受体激动剂5 - MCA - NAT（10⁻⁸ - 10⁻⁷ M）对冠状动脉中的硝酸酯耐受性无影响。(5) 结果表明，褪黑素通过特定的褪黑素受体发挥作用，抑制冠状动脉中的硝酸酯耐受性，且该作用依赖于血管内皮的存在。
