Eberli F R, Apstein C S, Ngoy S, Lorell B H
Cardiac Muscle Research Laboratory, Boston University School of Medicine, MA.
Circ Res. 1992 May;70(5):931-43. doi: 10.1161/01.res.70.5.931.
Hearts with compensatory pressure-overload hypertrophy show an increased intracardiac activation of angiotensin II that may contribute to ischemic diastolic dysfunction. We studied whether pressure-overload hypertrophy in response to aortic banding would result in exaggerated diastolic dysfunction during low-flow ischemia and whether the specific inhibition of the cardiac angiotensin converting enzyme by enalaprilat would modify systolic and diastolic function during ischemia and reperfusion in either hypertrophied or nonhypertrophied hearts. Isolated, red blood cell-perfused isovolumic nonhypertrophied and hypertrophied rat hearts were subjected to enalaprilat (2.5 x 10(-7) M final concentration) infusion during 20 minutes of baseline perfusion and during 30 minutes of low-flow ischemia and 30 minutes of reperfusion. Coronary flow per gram was similar in nonhypertrophied and hypertrophied hearts during baseline perfusion, ischemia, and reperfusion. At baseline, left ventricular developed pressure was higher in hypertrophied than nonhypertrophied hearts in untreated groups (224 +/- 8 versus 150 +/- 9 mm Hg; p less than 0.01) and in enalaprilat-treated groups (223 +/- 9 versus 145 +/- 8 mm Hg; p less than 0.01). During low-flow ischemia, left ventricular developed pressure was depressed but similar in all groups. All groups showed deterioration of diastolic function; however, left ventricular end-diastolic pressure increased to a significantly higher level in untreated hypertrophied than in nonhypertrophied hearts (65 +/- 7 versus 33 +/- 3 mm Hg; p less than 0.001). Enalaprilat had no effect in nonhypertrophied hearts, but it significantly attenuated the greater increase in left ventricular end-diastolic pressure in hypertrophied hearts treated with enalaprilat compared with no drug (65 +/- 7 versus 50 +/- 5 mm Hg; p less than 0.01). The beneficial effect could not be explained by differences in coronary blood flow per gram left ventricular weight, glycolytic flux as reported by lactate production, myocardial water content, oxygen consumption, and tissue levels of glycogen and high energy phosphate compounds. During reperfusion, all hearts showed a partial recovery of developed pressure to 70-74% of initial values. No effect of enalaprilat could be detected during reperfusion on systolic and diastolic function or restoration of tissue levels of high energy compounds. In conclusion, our experiments show that hypertrophied red blood cell-perfused hearts manifest a severe impairment of left ventricular diastolic relaxation in response to low-flow ischemia in comparison with control hearts. Further, our experiments support the hypothesis that the enhanced conversion of angiotensin I to angiotensin II in rats with pressure-overload hypertrophy contributes to the enhanced sensitivity of hypertrophied hearts to diastolic dysfunction during low-flow ischemia.
具有代偿性压力超负荷肥大的心脏显示出心脏内血管紧张素 II 的激活增加，这可能导致缺血性舒张功能障碍。我们研究了主动脉缩窄引起的压力超负荷肥大是否会在低流量缺血期间导致舒张功能障碍加剧，以及依那普利拉对心脏血管紧张素转换酶的特异性抑制是否会改变肥大或非肥大心脏在缺血和再灌注期间的收缩和舒张功能。在基线灌注的 20 分钟、低流量缺血的 30 分钟和再灌注的 30 分钟期间，对分离的、用红细胞灌注的非肥大和肥大大鼠心脏输注依那普利拉（终浓度为 2.5×10⁻⁷ M）。在基线灌注、缺血和再灌注期间，非肥大和肥大心脏每克的冠状动脉血流量相似。在基线时，未治疗组中肥大心脏的左心室舒张末压高于非肥大心脏（224±8 与 150±9 mmHg；p<0.01），依那普利拉治疗组中也是如此（223±9 与 145±8 mmHg；p<0.01）。在低流量缺血期间，左心室舒张末压降低，但所有组相似。所有组均显示舒张功能恶化；然而，未治疗的肥大心脏中左心室舒张末压升高到显著高于非肥大心脏的水平（65±7 与 33±3 mmHg；p<0.001）。依那普利拉对非肥大心脏没有影响，但与未用药相比，它显著减轻了依那普利拉治疗的肥大心脏中左心室舒张末压的更大升高（65±7 与 50±5 mmHg；p<0.01）。这种有益作用不能用每克左心室重量的冠状动脉血流量、乳酸产生所报告的糖酵解通量、心肌含水量、氧消耗以及糖原和高能磷酸化合物的组织水平差异来解释。在再灌注期间，所有心脏的舒张末压均部分恢复到初始值的 70-74%。在再灌注期间未检测到依那普利拉对收缩和舒张功能或高能化合物组织水平恢复的影响。总之，我们的实验表明，与对照心脏相比，肥大的红细胞灌注心脏在低流量缺血时表现出左心室舒张松弛的严重受损。此外，我们的实验支持以下假设，即压力超负荷肥大大鼠中血管紧张素 I 向血管紧张素 II 的转化增强导致肥大心脏在低流量缺血期间对舒张功能障碍的敏感性增强。
