García J L, Fernández N, García-Villalón A L, Monge L, Gómez B, Diéguez G
Deparatmento de Fisiología, Facultad de Medicina, Universidad Autónoma, Madrid, Spain.
Eur J Pharmacol. 1996 Nov 14;315(2):179-86. doi: 10.1016/s0014-2999(96)00625-5.
The role of endothelin ETA and ETB receptors as well as of nitric oxide (NO) and prostanoids in the effects of endothelin-1 on the coronary circulation was studied in anesthetized goats. Where blood flow in the left circumflex coronary artery (coronary blood flow) (electromagnetically measured), systemic arterial pressure, left ventricle pressure and d P/dt, and heart rate were recorded. Endothelin-1 (0.01-0.3 nmol), intracoronarily injected, produced marked, dose-dependent reductions in basal coronary blood flow, ranging from 5% for 0.01 nmol to 75% for 0.3 nmol; 0.1 and 0.3 nmol endothelin-1 also reduced systolic ventricle pressure and dP/dt. The effects of endothelin-1 on coronary blood flow were diminished during intracoronary infusion of BQ-123 (cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp). specific antagonist for endothelin ETA receptors. 2-16 nmol/min) in a dose-dependent way, but not during the infusion of BQ-788 (N-[N-[N-[(2.6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-1-leucyl]-1- (methoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium, specific antagonist for endothelin ETB receptors. 2-4 nmol/min). IRL 1620 (Suc-[Glu9, Ala11.15]endothelin-1-(8-21), specific agonist for endothelin ETB receptors. 0.01-0.3 nmol), intracoronarily injected. slightly reduced basal coronary blood flow only when 0.1 and 0.3 nmol were applied (maximal reduction about 25%); 0.3 nmol IRL 1620 also reduced systolic ventricle pressure and dP/dt. The effects of IRL 1620 were not modified by BQ-123 or BQ-788. NG-nitro-1-arginine methyl ester (L-NAME, inhibitor of NO synthesis, 47 mg/kg by i.v. route) reduced resting coronary blood flow by 10% and increased mean systemic arterial pressure and systolic ventricle pressure by 22 and 20%. respectively, without changing systolic ventricle dP/dt and heart rate. With L-NAME, the reductions of coronary blood flow by endothelin-1 were potentiated (P < 0.05), and those by IRL 1620 were not changed (P > 0.05). Meclofenamate (cyclooxygenase inhibitor, 4-6 mg/kg by i.v. route) modified neither the basal values of hemodynamic variables nor the coronary effects of endothelin-1 and IRL 1620. Therefore, endothelin-1 produces marked coronary vasoconstriction, which may be mediated by endothelin ETA receptors, with no participation of endothelin ETB receptors. NO, but not prostanoids, may produce a basal coronary vasodilator tone and may inhibit endothelin-1-induced coronary vasoconstriction. Also, it is suggested that the coronary vasoconstriction by endothelin-1 may impair cardiac performance due to heart ischemia.
在麻醉山羊身上研究了内皮素ETA和ETB受体以及一氧化氮（NO）和前列腺素在内皮素-1对冠状动脉循环作用中的角色。记录了左旋冠状动脉中的血流（冠状动脉血流量）（通过电磁测量）、体动脉压、左心室压力和dP/dt以及心率。冠状动脉内注射内皮素-1（0.01 - 0.3 nmol）可使基础冠状动脉血流量产生显著的剂量依赖性降低，范围从0.01 nmol时的5%到0.3 nmol时的75%；0.1和0.3 nmol的内皮素-1也降低了收缩期心室压力和dP/dt。在冠状动脉内输注BQ - 123（环-（D - 天冬氨酸 - 脯氨酸 - D - 缬氨酸 - 亮氨酸 - D - 色氨酸），内皮素ETA受体特异性拮抗剂，2 - 16 nmol/min）期间，内皮素-1对冠状动脉血流量的影响以剂量依赖性方式减弱，但在输注BQ - 788（N - [N - [N - [(2,6 - 二甲基 - 1 - 哌啶基)羰基] - 4 - 甲基 - 1 - 亮氨酰] - 1 - (甲氧基羰基) - D - 色氨酸 - D - 去甲亮氨酸单钠盐，内皮素ETB受体特异性拮抗剂，2 - 4 nmol/min）期间未减弱。冠状动脉内注射IRL 1620（苏氨酸 - [谷氨酸9，丙氨酸11,15]内皮素-1 - (8 - 21)，内皮素ETB受体特异性激动剂，0.01 - 0.3 nmol），仅在应用0.1和0.3 nmol时才轻微降低基础冠状动脉血流量（最大降低约25%）；0.3 nmol的IRL 1620也降低了收缩期心室压力和dP/dt。BQ - 123或BQ - 788未改变IRL 1620的作用。NG - 硝基 - L - 精氨酸甲酯（L - NAME，NO合成抑制剂，静脉注射47 mg/kg）使静息冠状动脉血流量降低10%，使平均体动脉压和收缩期心室压力分别升高22%和20%，而不改变收缩期心室dP/dt和心率。使用L - NAME时，内皮素-1对冠状动脉血流量的降低作用增强（P < 0.05），而IRL 1620的作用未改变（P > 0.05）。甲氯芬那酸（环氧化酶抑制剂，静脉注射4 - 6 mg/kg）既未改变血流动力学变量的基础值，也未改变内皮素-1和IRL 1620对冠状动脉的作用。因此，内皮素-1可产生显著的冠状动脉血管收缩，这可能由内皮素ETA受体介导，内皮素ETB受体未参与。NO而非前列腺素可能产生基础冠状动脉血管舒张张力，并可能抑制内皮素-1诱导的冠状动脉血管收缩。此外，提示内皮素-1引起的冠状动脉血管收缩可能由于心脏缺血而损害心脏功能。
