Supraventricular tachydysrhythmias are a commonly encountered clinical problem after cardiothoracic surgery. Current choices for acute drug therapy of these dysrhythmias include intravenous verapamil as well as esmolol, but no data yet exist comparing the relative negative dromotropic (atrioventricular [A-V] nodal blocking) and negative inotropic effects of these agents. The purpose of this study was to compare the effects of esmolol with those of verapamil on systemic hemodynamics, coronary blood flow, and cardiac contractility at doses that produce a similar ventricular response rate in an animal model of a supraventricular tachydysrhythmia. Rapid electrical stimulation (800 impulses/min) of the left atrium in 14 dogs resulted in a rapid and irregularly irregular ventricular rhythm. Esmolol or verapamil were administered by bolus and then infusion to incrementally slow the average ventricular rate. Regional myocardial contractility was measured using the end-systolic pressure-length relationship (Ees). At drug doses that produced similar decreases in ventricular rate, esmolol produced a greater decrease in contractility (Ees: 284 ± 46 to 40 ± 22 mmHg/mm, LV dp/dt:2,400 ± 450 to 1,360 ± 450 mmHg/sec) compared with that following verapamil (Ees: 297 ± 57 to 116 ± 25 mmHg/mm, LV dp/dt: 2,040 ± 580 to 1,950 ± 520 mmHg/sec). This was accompanied by a modest decrease in cardiac output in the esmolol group (2,880 ± 940 to 2,290 ± 730 ml/min) compared with an unchanged cardiac output as ventricular rate slowed in verapamil-treated animals. Stroke volume increased significantly in the verapamil-treated animals (10.9 ± 4.0 to 18.5 ± 4.6 ml), but remained unchanged following esmolol. Neither drug produced adverse effects on perfusion pressure nor left anterior descending coronary blood flow in the doses employed in this model. The differential effects of esmolol and verapamil on contractility may have important implications when used to control the ventricular response to supraventricular tachydysrhythmias in the presence of impaired ventricular function.