Cardioprotective aspects of calcium antagonists.
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.
Nayler
W G
WG
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Australia.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003327:Coronary Disease / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D008297:Male; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D014700:Verapamil; D002118:Calcium