Grover G J, Sleph P G
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
J Cardiovasc Pharmacol. 1989 Aug;14(2):331-40.
This study was performed to determine if cardiodepression can be dissociated from cardioprotection with calcium antagonists and which one (diltiazem, nifedipine, or verapamil) can maximally protect ischemic myocardium at a given level of cardiodepression. Isolated rat hearts were subjected to 0.1, 0.5, or 1.0 microM diltiazem, verapamil, or nifedipine 10 min before global ischemia. Ischemia was maintained for 25 min, at which time reperfusion was instituted for 30 min. Pre- and postischemia function, flow, and lactate dehydrogenase (LDH) release were measured. All three drugs reduced preischemic function and improved postischemic function and reflow in a dose-dependent fashion. LDH release and contracture were also mitigated with all drugs. When the efficacy of these drugs was expressed as the ratio of LDH release versus preischemic, postdrug function (ability of drug to reduce LDH release at a given level of cardiodepression), diltiazem had a significantly lower ratio as compared with verapamil or nifedipine. When similar experiments were performed with various concentrations of calcium in the perfusion buffer (2.50, 1.25, 0.75, 0.50, 0.41 mM CaCl2) administered 10 min before ischemia and reperfusion with normal (1.25 mM) buffer, preischemic function was reduced in a concentration-dependent fashion. Despite severe reductions in function at the concentration of 0.50 mM CaCl2, LDH release was not reduced. The concentration of 0.41 mM CaCl2, which depressed function to the same degree as 0.50 mM CaCl2, reduced LDH release. This reduction in LDH release, however, was not as great as that which occurred with the high dose of the calcium antagonists. Reperfusion with 0.41 mM calcium buffer, however, nearly abolished LDH release. Thus, although all three calcium antagonists reduced the severity of ischemia, diltiazem reduces it with the lowest cost in cardiac function. Reduction in extracellular calcium reduces cardiac function, but reductions in severity of ischemia, as measured by LDH release, do not parallel these changes.
本研究旨在确定钙拮抗剂引起的心脏抑制是否可与心脏保护作用相分离，以及在给定的心脏抑制水平下，哪种药物（地尔硫䓬、硝苯地平或维拉帕米）能最大程度地保护缺血心肌。在全心缺血前10分钟，将离体大鼠心脏分别置于0.1、0.5或1.0微摩尔/升的地尔硫䓬、维拉帕米或硝苯地平中。缺血持续25分钟，之后进行30分钟的再灌注。测量缺血前后的心脏功能、血流量以及乳酸脱氢酶（LDH）释放量。所有三种药物均以剂量依赖的方式降低缺血前的心脏功能，并改善缺血后的心脏功能及再灌注血流量。所有药物还减轻了LDH释放和心肌挛缩。当将这些药物的疗效表示为LDH释放量与缺血前、用药后心脏功能的比值（即药物在给定心脏抑制水平下降低LDH释放的能力）时，与维拉帕米或硝苯地平相比，地尔硫䓬的比值显著更低。当在缺血和再灌注前10分钟，用不同浓度的钙（2.50、1.25、0.75、0.50、0.41毫摩尔/升氯化钙）灌注缓冲液进行类似实验，并在再灌注时使用正常（1.25毫摩尔/升）缓冲液时，缺血前的心脏功能呈浓度依赖性降低。尽管在0.50毫摩尔/升氯化钙浓度下心脏功能严重降低，但LDH释放并未减少。0.41毫摩尔/升氯化钙浓度使心脏功能降低的程度与0.50毫摩尔/升氯化钙相同，但降低了LDH释放。然而，这种LDH释放的降低程度不如高剂量钙拮抗剂所引起的降低程度大。然而，用0.41毫摩尔/升钙缓冲液进行再灌注时，几乎完全消除了LDH释放。因此，尽管所有三种钙拮抗剂都减轻了缺血的严重程度，但地尔硫䓬在心脏功能方面以最低的代价减轻了缺血。细胞外钙的减少会降低心脏功能，但以LDH释放量衡量的缺血严重程度的降低与这些变化并不平行。
