Temporal differences in actions of calcium channel blockers on K+ accumulation, cardiac function, and high-energy phosphate levels in ischemic guineapig hearts

We investigated temporal differences in the protective action of three type s of Ca2+ channel blockers in myocardial ischemia, focusing particularly on the blocking ability under depolarizing conditions. The effects of diltiaz em, verapamil, and nifedipine on extracellular potassium concentration ([K](e)), acidosis, and level of metabolic markers were examined during 30-min global ischemia and postischemic left ventricular (LV) function in isolate d guinea pig hearts, Diltiazem and verapamil, but not nifedipine, inhibited the late phase (15-30 min) of [K+](e) elevation, whereas all three blocker s delayed the onset of the early phase (0-8 min) of [K+](e) elevation. Dilt iazem and verapamil inhibited ischemic contracture and improved postischemi c LV function to a greater extent. These differences appeared to be linked to preservation of ATP and creatine phosphate and delay of cessation of ana erobic glycolytic activity. Maneuvers to preserve energy sources during isc hemia (decrease in external Ca2+ concentration or pacing at a lower frequen cy) attenuated the late phase of [K+](e) elevation, Inhibition of LV pressu re was potentiated 12- and 8.2-fold by diltiazem and verapamil, respectivel y, at 8.9 mM K+ as compared with 2.9 mM K+ whereas that by nifedipine was u nchanged. These results indicate that the differential cardioprotection of Ca2+ channel blockers in the late period of ischemia correlates with preser vation of high-energy phosphates as a result of different Ca2+ channel bloc king abilities under high [K+](e) conditions.