Ferrari R, Boffa G M, Ceconi C, Curello S, Boraso A, Ghielmi S, Cargnoni A
Cattedra di Cardiologia, Universita degli Studi di Brescia, Italy.
Basic Res Cardiol. 1989 Nov-Dec;84(6):606-22. doi: 10.1007/BF01906946.
In this study we have investigated the possibility that D-600, a phenylalkylamine calcium antagonist, protects the isolated rabbit heart against ischemia and reperfusion-induced damage. D-600 was either subcutaneously injected (2mg/kg, twice daily for 5 to 6 days) in the rabbit before isolation of the heart, or delivered to the isolated hearts in the perfusate (10(-7) M), either at the onset of ischemia and during reperfusion, or only during post-ischemic reperfusion. Ischemia (90 min) was induced by reducing coronary flow from 25 to 1 ml/min, followed by 30 min of reperfusion. Myocardial damage was determined in terms of mechanical function, release of creatine phosphokinase (CPK) and noradrenaline, mitochondrial function, calcium homeostasis, and endogenous stores of ATP and creatine phosphate (CP). Administration of D-600 to the rabbits or to the isolated hearts at the time of ischemia exerted protection. There are four groups of evidence in support of this conclusion: 1) the rise in diastolic pressure during ischemia was diminished with greater recovery of developed pressure during reperfusion; 2) CPK and noradrenaline release during reperfusion were reduced; 3) the oxygen consumption and ATP generating capacities of mitochondria were better maintained; and 4) associated with this preservation of mitochondrial function was the maintenance of near normal calcium homeostasis and of endogenous ATP and CP stores. The two different modalities of administration did not produce substantially different results. When administered to the isolated hearts after the ischemic period, D-600 failed to improve mechanical recovery and release of endogenous substances. However, it reduced mitochondrial calcium overload and improved ATP production. The mechanism of the protective effect of D-600 seems to be multiple: energy-sparing effect, reduction of the toxicity mediated by endogenous catecholamines, and direct inhibition of mitochondrial calcium transport.
在本研究中，我们探讨了苯基烷基胺类钙拮抗剂D - 600保护离体兔心免受缺血及再灌注损伤的可能性。在心脏离体前，给家兔皮下注射D - 600（2mg/kg，每日两次，共5至6天）；或将其加入灌注液中（10⁻⁷M），在缺血开始时及再灌注期间给药，或仅在缺血后再灌注期间给药。通过将冠状动脉血流量从25ml/min降至1ml/min诱导缺血90分钟，随后进行30分钟的再灌注。从机械功能、肌酸磷酸激酶（CPK）和去甲肾上腺素的释放、线粒体功能、钙稳态以及ATP和磷酸肌酸（CP）的内源性储备等方面来确定心肌损伤情况。在缺血时给家兔或离体心脏给予D - 600可起到保护作用。有四类证据支持这一结论：1）缺血期间舒张压的升高有所减轻，再灌注期间收缩压的恢复更好；2）再灌注期间CPK和去甲肾上腺素的释放减少；3）线粒体的氧消耗和ATP生成能力得到更好的维持；4）伴随着线粒体功能的这种保存，接近正常的钙稳态以及内源性ATP和CP储备得以维持。两种不同的给药方式并未产生显著不同的结果。在缺血期后给离体心脏给药时，D - 600未能改善机械功能的恢复及内源性物质的释放。然而，它减少了线粒体钙超载并改善了ATP生成。D - 600的保护作用机制似乎是多方面的：节能效应、减少内源性儿茶酚胺介导的毒性以及直接抑制线粒体钙转运。
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