The authors determined whether increasing alpha1-adrenergic blockade resulted in progressively less arrhythmic activity in the canine halothane-epinephrine arrhythmia model. Dogs (n = 7) were anesthetized with halothane (1.5%) in oxygen. Stepwise increases in steady-state plasma levels of either of two alpha1-adrenoceptor antagonists (droperidol, doxazosin) were produced by applying Wagnerian principles to the known pharmacokinetic parameters of these drugs. At each steady state plasma level of these antagonists, the extent of the alpha1-adrenergic blockade produced was assessed by defining a phenylephrine (PE) dose pressor response curve. The degree of alpha1-blockade produced was quantitated as the dose of PE that caused a 25-mmHg increase in mean arterial pressure (ED25) as derived by polynomial regression analysis. By analysis of variance (ANOVA) the ED25increased significantly for each targeted steady state plasma level of either droperidol (P< 0.001) or doxazosin (P< 0.001). For an assessment of the antiarrhythmic activity of these alpha1-antagonists, the arrhythmogenic dose of epinephrine (ADE) was determined at each of the states of alpha1-adrenergic blockade previously defined. By ANOVA there was a significant increase in the ADE over the range of alpha blockade produced for either droperidol (P< 0.001) or doxazosin (P< 0.001). A close correlation (r2) existed between the ED25and the ADE for the target steady state levels that were achieved for either droperidol (0.99) or doxazosin (0.74). These data support the contention that the antiarrhythmic activity of these antagonists is on the basis of their alpha, adrenergic blockade, and the authors suggest that this antiarrhythmic action is mediated by blockade of the myocardial alpha, adrenoceptors.