The density of potassium channels, including the inward rectifying current (IK1), the delayed rectifying current and the transient outward current have been reported to be decreased in cardiac hypertrophy. However, it is not known whether the effects of specific ionic channel blockers are altered in this setting. The effects of barium chloride, which inhibits IK1, of dofetilide, which inhibits the rapidly activating component of the delayed rectifying current, and 4-aminopyridine, which inhibits the transient outward current, were studied in isolated perfused working rabbit hearts. Cardiac hypertrophy was induced in rabbits by aortic banding. Hearts were removed 43 +/- 8 days after surgery, and electrophysiologic parameters were measured at low (30 cm H2O) and high (100 cm H2O) afterload at base line and during perfusion of barium, dofetilide or 4-aminopyridine. The hearts from banded rabbits weighed more (13.0 +/- 2.3 g) than those from the sham controls (10.0 +/- 1.6 g; P < .001). The action potential duration at 90% repolarization (APD90) was greater in hypertrophied hearts (198 +/- 16 msec) at base line than in control hearts (182 +/- 20 msec; P < .01). Barium (0.025 mM) caused greater prolongation of APD90 in hypertrophied hearts than in control hearts at both low afterload (214 +/- 9 msec vs. 195 +/- 20 msec) and high afterload (200 +/- 10 msec vs. 166 +/- 22 msec, P < .01). This interaction of barium's effects on APD90 and hypertrophy was highly statistically significant (P < .001). In contrast, dofetilide (15 nM) and 4-aminopyridine (1.0 mM) caused similar changes in APD90 in hypertrophied hearts and in control hearts at low afterload and high afterload (P = NS). In isolated ventricular myocytes, IK1 and transient outward densities, but not the rapidly activating component of the delayed rectifying current were decreased in hypertrophied cells compared with control cells (P < .05). Thus the increased effects of barium on prolongation of APD in hypertrophy are probably due to the decreased density of IK1 in hypertrophy and perhaps, in part, to a change in the balance of repolarizing currents that occurs in hypertrophy.