title: Mechanism for the cardioprotective effects of the calcium channel blocker clentiazem during ischemia and reperfusion.
abstract: To elucidate whether or not Ca channel blockers have an intrinsic benefit that cannot be attributed to the reduction of Ca2+ entry by pretreatment, time-averaged intracellular Ca2+ concentration ([Ca2+]i) and energy-related phosphates were measured in isolated ferret hearts using nuclear magnetic resonance. In the drug-free ischemic group, [Ca2+]i increased significantly during 30 min of global ischemia at 30 degrees C and during 0-5 min of reperfusion. After 30 min of reperfusion, isovolumic left ventricular developed pressure recovered only to 63+/-7% of the pre-ischemic level (mean+/-SEM; N=5). Pretreatment with the Ca channel blocker clentiazem (10(-7) mol/L) itself depressed developed pressure by 53+/-9%. In the clentiazem group, [Ca2+]i showed no significant changes during ischemia or reperfusion. Recovery of developed pressure (87+/-8% of untreated level) was significantly higher than in the non-treated group (p<0.05). Nevertheless, when the negative inotropism of clentiazem was offset by increasing [Ca]o from 2 to 3 mmol/L, no beneficial effects of clentiazem were observed; [Ca2+]i increased significantly during 0-5 min of reperfusion, and developed pressure recovered only 60+/-7% of untreated level. These results indicate that reduction of Ca2+ entry from the extracellular space to the myocyte, as reflected by negative inotropism during pretreatment, is required for clentiazem to protect myocardium in a model of global ischemia and reperfusion.
authors.affiliation: Division of Tracer Kinetics, Biomedical Research Center, Osaka University Medical School, Suita, Japan. kusuoka@tracer.med.osaka-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Kusuoka
authors.forename: M C
authors.initials: MC
authors.lastname: Corretti
authors.forename: Y
authors.initials: Y
authors.lastname: Koretsune
authors.forename: E
authors.initials: E
authors.lastname: Marban
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005289:Ferrets; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D002121:Calcium Channel Blockers; C056595:clentiazem; D004110:Diltiazem; D002118:Calcium