Effects of ouabain and isoproterenol on left ventricular diastolic function during low-flow ischemia in isolated, blood-perfused rabbit hearts.
Effects of ouabain and isoproterenol on left ventricular diastolic function during low-flow ischemia in isolated, blood-perfused rabbit hearts.
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哇巴因和异丙肾上腺素对离体、血液灌注兔心脏低流量缺血期间左心室舒张功能的影响。
DOI：
10.1161/01.res.63.2.457
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发表时间：
1988
影响因子：
20.1
通讯作者：
Apstein,CS
中科院分区：
文献类型：
--
作者：
Lorell,BH;Isoyama,S;Grice,WN;Weinberg,EO;Apstein,CS
心肌缺血会导致收缩和舒张功能障碍。临床上可以使用具有不同亚细胞机制的多种正性肌力药物来尝试逆转缺血性收缩衰竭。我们测试了以下假设：两种正性肌力药物异丙肾上腺素（一种 β 肾上腺素能激动剂）和哇巴因（一种钠泵抑制剂）尽管具有相同的正性肌力作用，但在缺血性衰竭期间可能对左心室 (LV) 舒张功能产生不同的影响。离体等容（LV 球囊）血液灌注兔心脏以恒定的生理心率 (4 Hz) 起搏，不给予任何药物（对照，n = 7）、异丙肾上腺素（n = 7）或哇巴因（n = 7），然后进行 6 分钟的低流量缺血（基线冠状动脉流量减少 75%）。选择异丙肾上腺素和哇巴因的剂量，以在基线灌注条件下在每只心脏中产生同等的适度正性肌力作用（LV + dP/dt 增加 15%）。在缺血期间，收缩力显着下降，与对照组相比，异丙肾上腺素和哇巴因均未表现出正性肌力作用。然而，这些药物对缺血期间的舒张室扩张性（通过恒定左心室容量下的舒张末压进行评估）具有显着不同的影响。在对照组和异丙肾上腺素组中，舒张室扩张性在缺血期间没有变化。相比之下，哇巴因治疗导致缺血期间舒张室扩张性显着降低。这种变化在 10 分钟再灌注期间并不完全可逆。间接评估了哇巴因相对于异丙肾上腺素降低舒张室扩张性的机制。通过氧供/需失衡评估，哇巴因组和异丙肾上腺素组遭受同等程度的缺血；缺血期间，各药物组在心肌灌注率、心肌需氧量的决定因素（心率、左心室展开压、左心室压力+dP/dt）、心肌耗氧量、乳酸生成以及ATP和磷酸肌酸含量方面没有差异。因此，我们推断哇巴因组舒张期扩张性的更大下降并不是由于缺血的代谢严重程度更大。这些观察结果与哇巴因诱导的细胞溶质钙超载机制一致，导致整个舒张期持续活跃的肌丝张力发展，导致哇巴因组缺血期间舒张室扩张性观察到的下降。（摘要截断为 400 字）
Myocardial ischemia causes both systolic and diastolic dysfunction. A variety of positive inotropic agents with different subcellular mechanisms may be used clinically in an attempt to reverse ischemic contractile failure. We tested the hypothesis that two inotropic agents, isoproterenol (a beta-adrenergic agonist) and ouabain (a sodium pump inhibitor), might have different effects on left ventricular (LV) diastolic function during ischemic failure despite an equivalent inotropic effect. Isolated isovolumic (balloon-in-LV) blood perfused rabbit hearts were paced at constant physiological heart rate (4 Hz), given either no drug (controls, n = 7), isoproterenol (n = 7), or ouabain (n = 7), and then subjected to 6 minutes of low flow ischemia (75% reduction of baseline coronary flow). The doses of isoproterenol and ouabain were selected to produce equivalent modest inotropic effects (15% increase in LV + dP/dt) in each heart during baseline perfusion conditions. During the ischemic period, there was a marked decrease in contractility, and neither isoproterenol nor ouabain demonstrated a positive inotropic effect relative to the control group. However, these agents had markedly different effects on diastolic chamber distensibility (assessed by end-diastolic pressure at constant LV volume) during ischemia. In the control and isoproterenol groups, diastolic chamber distensibility did not change during the ischemic period. In contrast, ouabain treatment resulted in a marked decrease in diastolic chamber distensibility during ischemia; this change was not completely reversible during the 10-minute reperfusion period. The mechanism by which ouabain decreased diastolic chamber distensibility relative to isoproterenol was assessed indirectly. The ouabain and isoproterenol groups were subjected to equivalent degrees of ischemia as assessed by oxygen supply/demand imbalance; during ischemia, each drug group did not differ with regard to myocardial perfusion rates, determinants of myocardial oxygen demand (heart rate, LV developed pressure, LV + dP/dt), myocardial oxygen consumption, lactate production, and ATP and creatine phosphate content. We therefore inferred that the greater decrease in diastolic distensibility in the ouabain group was not due to a greater metabolic severity of ischemia. These observations are consistent with a mechanism of cytosolic calcium overload induced by ouabain, resulting in persistent active myofilament tension development throughout diastole, to cause the observed decrease in diastolic chamber distensibility during ischemia in the ouabain group.(ABSTRACT TRUNCATED AT 400 WORDS)