Mechanism for the cardioprotective effects of the calcium channel blocker clentiazem during ischemia and reperfusion

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 30min of global ischemia at 30°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.