This study was designed to determine whether the various classes of Ca2+ channel blockers have differential protective effects on isolated adult rat ventricular myocytes exposed to high K+ under anoxic (100% N2) conditions. Calcium-tolerant myocytes were incubated under control (4mM K+) aerobic conditions and then subjected to high K+ (75 mM) and N2. The cells were assessed by morphological criteria (i.e. absence of blebbing, granulation etc.), maintenance of ATP levels, exclusion of trypan blue, and the presence or absence of spontaneous contractile activity. Under control conditions, the cells were quiescent and declined at a rate of approximately 10%/h. In the absence of O2, the rate of cell decline was significantly faster. Verapamil, diltiazem and the dihydropyridines had no significant effects on cell decline under these conditions. Cells exposed to 75 mM K0+ exhibited contractile activity and accelerated rate of decline under anoxic conditions; these effects were independent of lowering Na0+ to 75mM. Cells in high K0+ and N2 were significantly protected (i.e. contractile activity and rate of decline were decreased) by verapamil, less so by diltiazem, and not at all by the dihydropyridines. The uptake of 45Ca2+ into cells in high K0+ was not significantly altered by verapamil or diltiazem. Caffeine induced the immediate cessation of contractile activity of cells incubated in high K0+, but did not affect the accelerated rate of cell declined under anoxic conditions. Verapamil and diltiazem still conferred significant protection in this non-beating cell preparation. Neither verapamil nor diltiazem had any effect on the oscillation frequency of skinned heart cells.(ABSTRACT TRUNCATED AT 250 WORDS)