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 nulear magnetic resonance. In the drug-free ischemic group, [Ca²⁺]_i increased significantly during 30 min 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. (Jpn Circ J 1998; 62: 611 - 616)