The interaction of verapamil with three known positive inotropic stimuli, ouabain, dopamine and postextrasystolic potentiation (PESP), was studied in 10 conscious dogs. Implanted sonomicrometer crystals and solid state pressure transducers were used to evaluate left atrial (LA) and left ventricular (LV) function while heart rate was held constant by atrial pacing. Ouabain (0.025 mg/kg) and dopamine (3-5 micrograms/kg/min) were administered in amounts sufficient to increase LV dP/dt by about 20%. PESP was achieved by using a programmed stimulator to introduce atrial premature beats. Each of these inotropic interventions caused significant (P less than .05) increases in LV dp/dt, LV fractional shortening, LA fractional shortening LV-velocity of circumferential fiber shortening (Vcf) and LA-Vcf. Administration of a single i.v. dose of verapamil (0.03 mg/kg) caused no change in base-line mechanical and hemodynamic parameters. However, when verapamil was given during the increased inotropic state resulting from ouabain or dopamine administration, significant (P less than .05) decreases occurred in LV dP/dt, LV fractional shortening, LA fractional shortening, LV-Vcf and LA-VCf. Verapamil did not alter the positive inotropic response to PESP in the LV or LA. Thus, a dose of verapamil that did not change resting indices of myocardial contractility depressed function significantly during positive inotropic responses to ouabain and dopamine. This negative inotropic effect seemed to be selective because verapamil did not alter the response to PESP.