Ferrari R, Cargnoni A, Bernocchi P, Gaia G, Benigno M, Pasini E, Pedersini P, Ceconi C
Cattedra di Cardiologia, Universita' degli Studi di Brescia, Italy.
Cardiovasc Drugs Ther. 1996 Sep;10(4):425-37. doi: 10.1007/BF00051107.
To assess whether the administration of felodipine protects the myocardium in a dose-dependent manner against ischemia and reperfusion, isolated rabbit hearts were infused with three different concentrations of felodipine: 10(-10), 10(-9), and 10(-8) M. Diastolic and developed pressures were monitored; coronary effluent was collected and assayed for CPK activity and for noradrenaline concentration; mitochondria were harvested and assayed for respiratory activity; and ATP production and calcium content and tissue concentration of ATP, creatine phosphate (CP), and calcium were determined. The occurrence of oxidative stress during ischemia and reperfusion was also monitored in terms of tissue content and release of reduced (GSH) and oxidized (GSSG) glutathione. Treatment with felodipine at 10(-10) and 10(-9) M had no effect on the hearts when perfused under aerobic conditions, whilst the higher dose reduced developed pressure from 57.7 +/- 2.6 to 30.0 +/- 2.6 mmHg (p < 0.01). On reperfusion treated hearts recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. Recovery of developed pressure was 100% at 10(-8) M, 55% at 10(-9) M, and 46% at 10(-10) M. The reperfusion-induced tissue and mitochondrial calcium overload, release of CPK and noradrenaline, and oxidative stress were also significantly reduced. The effects of felodipine were dose dependent. Felodipine inhibited the initial rate of ATP-driven calcium uptake but failed to affect the initial rate of mitochondrial calcium transport. It is concluded that felodipine infusion provides dose-dependent protection of the heart against ischemia and reperfusion. Because this protection also occurred at 10(-9) M and 10(-10) M in the absence of a negative inotropic effect during normoxia and of a coronary dilatory effect during ischaemia, it cannot be attributed to an energy-sparing effect or to improvement in oxygen delivery. From our data we can envisage two other major mechanisms-(1) membrane protection and (2) reduction in oxygen toxicity. The ATP-sparing effect occurring at 10(-8) M is likely to be responsible for the further protection.
为评估非洛地平给药是否能以剂量依赖方式保护心肌免受缺血和再灌注损伤，对离体兔心灌注三种不同浓度的非洛地平：10(-10)、10(-9)和10(-8)M。监测舒张期压力和收缩期压力；收集冠状动脉流出液并检测肌酸磷酸激酶（CPK）活性和去甲肾上腺素浓度；收获线粒体并检测呼吸活性；测定ATP生成、钙含量以及ATP、磷酸肌酸（CP）和钙的组织浓度。还根据还原型（GSH）和氧化型（GSSG）谷胱甘肽的组织含量和释放情况监测缺血和再灌注期间氧化应激的发生。在有氧条件下灌注时，10(-10)和10(-9)M的非洛地平处理对心脏无影响，而较高剂量使收缩期压力从57.7±2.6降至30.0±2.6mmHg（p<0.01）。再灌注时，处理过的心脏在左心室功能、ATP和CP储备补充以及线粒体功能方面比未处理的心脏恢复得更好。10(-8)M时收缩期压力恢复率为100%，10(-9)M时为55%，10(-10)M时为46%。再灌注诱导的组织和线粒体钙超载、CPK和去甲肾上腺素释放以及氧化应激也显著降低。非洛地平的作用呈剂量依赖性。非洛地平抑制ATP驱动的钙摄取初始速率，但未影响线粒体钙转运初始速率。得出结论，灌注非洛地平可对心脏提供剂量依赖性的缺血和再灌注保护。由于在常氧期间无负性肌力作用且缺血期间无冠状动脉扩张作用的情况下，10(-9)M和10(-10)M时也出现这种保护作用，因此不能将其归因于能量节省效应或氧输送改善。根据我们的数据，可设想另外两种主要机制——（1）膜保护和（2）氧毒性降低。10(-8)M时出现的ATP节省效应可能是进一步保护的原因。
