We recently reported that troglitazone, an insulin-sensitizing agent, inhibited l-type Ca2+ current (ICa,L) more effectively in streptozotocin (STZ)-induced diabetic ventricular myocytes than in age-matched control myocytes. However, whether this agent would effectively inhibit ICa,L in an animal model of hyperinsulinemia is unknown. Using whole-cell voltage-clamp techniques, ICa,L was measured in ventricular myocytes isolated from 12 to 16 weeks on fructose-enriched feeding and age-matched control rats. Under control conditions, fructose-fed myocytes did not differ from control myocytes in membrane capacitance, current density, or voltage-dependent properties of ICa,L. Troglitazone inhibited ICa,L in both control and fructose-fed myocytes in a concentration-dependent manner. However, this inhibition was less in fructose-fed than in control myocytes; the half-maximum inhibitory concentrations of troglitazone measured at a holding potential of -50 mV were 16.9 and 9.8 μmol/L, respectively. Contrary to the STZ-induced diabetic rat, the suppressive effect of troglitazone on cardiac ventricular ICa,L was attenuated in fructose-fed rats. Persistent elevation of plasma insulin concentration may play a role in these processes.