Effects of Ca2+ channel blockers on Ca2+ loading induced by metabolic inhibition and hyperkalemia in cardiomyocytes.

The effects of the L-type (nifedipine and verapamil) and the T-type (mibefradil) Ca2+ channel blockers on the increase in intracellular Ca2+ concentration ([Ca2+]i) induced by NaCN metabolic inhibition and hyperkalemia were examined in chicken cardiomyocytes using fluorescence imaging with Fura-2. NaCN induced a slow and sustained rise in [Ca2+]i, which was not affected by pretreating the cells for 5 min with nifedipine, verapamil, or mibefradil at 100 nM or 10 microM. Pretreatment of the cells with 10 microM nifedipine, verapamil, or mibefradil for 5 min remarkably inhibited the K+-induced increase in [Ca2+]i. These inhibitory effects diminished after 48-h pretreatment with nifedipine or verapamil but not with mibefradil. Ryanodine also induces an increase in [Ca2+]i, and this effect was enhanced by 48-h pretreatment of the cells with 10 microM verapamil but not with 10 microM mibefradil. We conclude that the NaCN-induced increase in [Ca2+]i is independent of the Ca2+ influx though the L-type or T-type Ca2+ channels. Chronic inhibition of the L-type Ca2+ channels but not T-type channels may enhance the ryanodine receptor-mediated Ca2+ release, which may be responsible for the development of tolerance to their inhibitory effects on K+-induced increase in [Ca2+]i.