Fontaine E R, Viau S, Jasmin G, Dumont L
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Québec, Canada.
J Cardiovasc Pharmacol. 1998 Jul;32(1):12-20. doi: 10.1097/00005344-199807000-00003.
Coronary dysfunctions identified in the presence of chronic heart failure are an important pathophysiologic abnormality that influences the prognosis of the disease. Because the endothelin pathway plays a significant role in the increased peripheral vascular tone associated with heart failure, we hypothesized that the endothelin pathway may be involved in the abnormal coronary vasomotion associated with this pathologic condition. Experiments were carried out in failing hearts (UM-X7.1 cardiomyopathic hamsters, aged 225-250 days) and normal hearts (Syrian LVG hamsters, also aged 225-250 days). Isolated hearts were perfused at constant flow and exposed to the blocker of the generation of endothelin-1 (ET-1), phosphoramidon (10 microM infusion), as well as to the selective ET(A)-receptor antagonist BQ 123 (10 microM infusion) and to a selective ET(B)-receptor antagonist BQ 788 (1 microM infusion). Coronary and cardiac effects of exogenous ET-1 (0.01-100 pmol) were also studied. Phosphoramidon, BQ 788, and BQ 123 did not altered coronary perfusion pressure either in normal or in failing hearts, whereas cardiac contractility was significantly impaired in the presence of phosphoramidon and BQ 123. Coronary sensitivity to exogenous ET-1 did not demonstrate a significant difference between normal and failing hearts [median effective concentration (EC50), 7 pmol in failing hearts vs. 12 pmol in normal hearts; p = NS]. In the presence of exogenous ET-1, cardiac contractility was significantly increased in both groups. In normal hearts, the exogenous ET-1-induced increase in coronary perfusion pressure was completely antagonized by BQ 123, whereas combined administration of BQ 788 and BQ 123 was necessary to induce complete inhibition in failing hearts. The positive inotropic effect elicited by exogenous ET-1 (EC50) was completely abolished in the presence of BQ 123, whereas BQ 788 had no significant effect. Results indicate that the endothelin pathway does not play a significant role in the altered coronary vasomotion observed in this model of chronic heart failure. On the contrary, the endothelin pathway appears to participate in the maintenance of myocardial contractility. According to these observations, administration of an inhibitor of ET-1 synthesis, as well as the use of an ET(A)-receptor antagonist, may be contraindicated in the presence of poor left ventricular function because the endothelin pathway contributes significantly to the maintenance of cardiac contractility.
在慢性心力衰竭情况下发现的冠状动脉功能障碍是一种重要的病理生理异常，会影响该疾病的预后。由于内皮素途径在与心力衰竭相关的外周血管张力增加中起重要作用，我们推测内皮素途径可能参与了与这种病理状况相关的异常冠状动脉血管运动。实验在衰竭心脏（225 - 250日龄的UM - X7.1心肌病仓鼠）和正常心脏（同样225 - 250日龄的叙利亚LVG仓鼠）中进行。将离体心脏以恒定流量灌注，并暴露于内皮素 - 1（ET - 1）生成阻滞剂磷酰胺素（10微摩尔输注），以及选择性ET(A)受体拮抗剂BQ 123（10微摩尔输注）和选择性ET(B)受体拮抗剂BQ 788（1微摩尔输注）。还研究了外源性ET - 1（0.01 - 100皮摩尔）对冠状动脉和心脏的影响。磷酰胺素、BQ 788和BQ 123在正常心脏和衰竭心脏中均未改变冠状动脉灌注压力，而在存在磷酰胺素和BQ 123时心脏收缩力显著受损。正常心脏和衰竭心脏对外源性ET - 1的冠状动脉敏感性未显示出显著差异[半数有效浓度（EC50），衰竭心脏中为7皮摩尔，正常心脏中为12皮摩尔；p = 无显著差异]。在存在外源性ET - 1时，两组的心脏收缩力均显著增加。在正常心脏中，外源性ET - 1诱导的冠状动脉灌注压力增加被BQ 123完全拮抗，而在衰竭心脏中需要联合给予BQ 788和BQ 123才能诱导完全抑制。外源性ET - 1（EC50）引发的正性肌力作用在存在BQ 123时完全被消除，而BQ 788没有显著作用。结果表明，内皮素途径在这种慢性心力衰竭模型中观察到的冠状动脉血管运动改变中不发挥重要作用。相反，内皮素途径似乎参与了心肌收缩力的维持。根据这些观察结果，在左心室功能不佳的情况下，给予ET - 1合成抑制剂以及使用ET(A)受体拮抗剂可能是禁忌的，因为内皮素途径对心脏收缩力的维持有显著贡献。
