Tanguay M, Jasmin G, Blaise G, Dumont L
Départment of Pharmacology, Faculty of Medicine, University of Montreal, Quebec, Canada.
J Cardiovasc Pharmacol. 1996 Aug;28(2):232-9. doi: 10.1097/00005344-199608000-00008.
Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.
由于心力衰竭时钙拮抗剂的负性肌力作用增强存在争议，其他机制可能解释其在此种情况下疗效不佳的原因。我们推测，内皮功能障碍导致的冠状动脉敏感性改变可能与之有关。我们的目标是评估心力衰竭对冠状动脉及心脏对钙拮抗剂地尔硫䓬敏感性的影响。在来自心肌病仓鼠（UM-X7.1）的等容搏动、灌注的衰竭心脏以及正常仓鼠的心脏中，评估左心室舒张末压（LVP）和冠状动脉血流量（CF）。在对照条件下以及存在特异性一氧化氮（NO）合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME，30 μM）和环氧化酶抑制剂吲哚美辛（10 μM）的情况下，绘制地尔硫䓬对冠状动脉扩张及其负性肌力作用的浓度-反应曲线。地尔硫䓬负性肌力作用的浓度-反应曲线在正常心脏和衰竭心脏中相似（IC50分别为1.2 μM和2.3 μM）。相比之下，地尔硫䓬在衰竭心脏中的冠状动脉扩张作用受损（地尔硫䓬诱导冠状动脉扩张的EC50从正常心脏的90 nM增加至衰竭心脏的1.1 μM，p < 0.01）。通过NO合酶和环氧化酶途径评估内皮功能障碍在心力衰竭时观察到的冠状动脉对 地尔硫䓬“脱敏”中的作用。在存在L-NAME的情况下，衰竭心脏的地尔硫䓬浓度-反应曲线未改变，而吲哚美辛使心力衰竭时冠状动脉对地尔硫䓬的反应恢复正常。这些发现表明，冠状动脉对 地尔硫䓬的“脱敏”是通过环氧化酶途径产生和/或释放一种或多种血管收缩因子而发生的。心力衰竭与心脏对地尔硫䓬的敏感性增加无关，而是与冠状动脉敏感性改变有关。这些发现表明，冠状动脉脱敏可能在心力衰竭时地尔硫䓬疗效不佳中起作用，并有助于更好地理解调节钙拮抗剂在心力衰竭中作用的因素。
