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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. |
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