Nayler W G
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Australia.
J Cardiovasc Pharmacol. 1991;18 Suppl 6:S10-4.
The use of calcium antagonists as cardioprotective agents is based on the assumption that uncontrolled Ca2+ gain is a key factor in causing cell death and tissue necrosis. This uncontrolled gain in Ca2+ is the ultimate expression of a series of metabolic events triggered by inadequate perfusion. One of the early events is a rise in cytosolic Ca2+ (Cai2+). Using 1,2-bis(e-amino-5-fluorophenoxy)ethan-N1N1N11N11tetraacetic acid and nuclear magnetic resonance spectroscopy to monitor this early rise in Cai2+, it is possible to show that, in isolated perfused rat hearts, Cai2+ increases (p less than 0.01) within the initial 10 min of ischemia and that the increase progresses with time. Possible causes of this early rise in Cai2+ include activation of the endothelin-1 receptors with the subsequent inositol triphosphate-induced activation of sarcoplasmic (SR) Ca2+ release, enhanced Ca(2+)-induced Ca2+ release from the SR reticulum, displacement of bound Ca2+ by the accumulating protons and entry of Ca2+ in exchange for Na+, or through the voltage-sensitive Ca2+ channels. Using the d and l isomers of verapamil it is possible to show that verapamil slows the early rise in Cai2+, the l isomer being more effective (p less than 0.01) than the d isomer. This, in addition to its established energy-sparing effect, may contribute to the effectiveness of verapamil as a cardioprotective agent when used prophylactically.
钙拮抗剂作为心脏保护剂的应用基于这样一种假设，即不受控制的Ca2+内流是导致细胞死亡和组织坏死的关键因素。这种不受控制的Ca2+内流是灌注不足引发的一系列代谢事件的最终表现。早期事件之一是胞质Ca2+（Cai2+）升高。使用1,2-双（e-氨基-5-氟苯氧基）乙烷-N1N1N11N11-四乙酸和核磁共振波谱来监测Cai2+的这种早期升高，可以表明，在离体灌注的大鼠心脏中，Cai2+在缺血最初10分钟内升高（p<0.01），且这种升高随时间进展。Cai2+早期升高的可能原因包括内皮素-1受体激活，随后肌醇三磷酸诱导肌浆网（SR）Ca2+释放、SR网中Ca(2+)诱导的Ca2+释放增强、积累的质子置换结合的Ca2+以及Ca2+与Na+交换进入，或通过电压敏感性Ca2+通道进入。使用维拉帕米的d和l异构体可以表明，维拉帕米减缓了Cai2+的早期升高，l异构体比d异构体更有效（p<0.01）。这除了其已确定的节能作用外，可能有助于解释维拉帕米预防性使用时作为心脏保护剂的有效性。
