This study was performed to determine if the changes in cellular coupling induced by simulated ischemia were rate-dependent and if they contributed to the rate-dependent conduction slowing that occurs in this setting. We also sought to determine if the known ability of verapamil to prevent ischemia-induced conduction changes might be related to the preservation of cellular coupling. We studied the effects of increasing stimulation frequency from 0.5 to 2.0 Hz on the simultaneous changes in the maximum rate of rise (Vmax) of the action potential upstroke, conduction velocity, and internal longitudinal resistance (r1) determined by the voltage ratio method in superfused guinea pig papillary muscles under conditions of simulated ischemia (SI). When stimulation frequency was 0.5 Hz, 30 minutes of SI caused a 16.5% decrease in Vmax, a 16% increase in r1, and a 12.9% decrease in conduction velocity. When stimulation frequency was increased to 2.0 Hz, 30 minutes of SI caused a 30% decrease in Vmax, a 72.9% increase in r1, and a 21.4% decrease in conduction velocity. Thus, the changes were rate-dependent. Verapamil (1times10−6M) did not influence the changes in these parameters during SI at 0.5 Hz nor the decrease in Vmaxduring SI at 2.0 Hz, but it did prevent the rate-dependent increase in r1. Veraparail also prevented the rate-dependent decrease in conduction velocity induced by SI. Our results suggest that during simulated ischemia the rate-dependent component of the increase in r1, contributes to the rate-dependence of the conduction slowing. Our results also suggest that the effects of verapamil on ischemia-induced conduction changes are mediated, at least in part, by the prevention of rate-dependent cellular uncoupling.