Ventricular hypertrophy is associated with several electrophysiologic abnormalities. However, little is known about the pharmacodynamics of antiarrhythmic drugs in the setting of ventricular hypertrophy. We studied the myocardial accumulation and pharmacodynamics of quinidine in 10 control rabbit hearts and 10 with isoproterenol-induced hypertrophy. Hearts were perfused in the working heart configuration. Electrophysiologic measurements were made at low afterload (30 cm H2O) and high afterload (60 cm H2O) at baseline and during quinidine perfusion (972 ng/ml). The myocardial quinidine concentration measured at the end of each experiment was significantly lower in the hypertrophied hearts (25.0 +/- 11.7 micrograms/g) as compared with the control hearts (51.2 +/- 12.7 micrograms/g, p < 0.001). The left ventricular (LV) monophasic action potential (MAP) duration was significantly shorter in the hypertrophied hearts as compared with control hearts at low afterload (166 +/- 27 vs. 192 +/- 24 ms, p < 0.01) and at high afterload (141 +/- 7 vs. 171 +/- 24 ms, p < 0.01). Quinidine prolonged MAP duration to a similar extent in both hypertrophied and control hearts; the MAP prolongation occurred at both low (192 +/- 21 vs. 223 +/- 25 ms, p < 0.02) and high afterloads (179 +/- 15 vs. 216 +/- 20 ms, p < 0.01) in the hypertrophied and control hearts, respectively. However, the ratios of the changes in electrophysiologic parameters to quinidine myocardial concentrations were greater in the hypertrophied hearts than in control hearts (p < 0.05). Therefore, AP duration (APD) is significantly shortened in isoproterenol-induced hypertrophy. The magnitude of quinidine effects on MAP duration and ventricular effective refractory period (VERP) are similar in hypertrophied hearts and control hearts, but the myocardial concentration-effect relations are increased significantly in hypertrophied hearts.