The effects of normothermic and hypothermic cardiopulmonary bypass, crossclamping of the aortic root, cold cardioplegia, as well as epicardial application of iced slush, on the efficacy of the efferent sympathetic nervous system to augment the heart and the efferent parasympathetic nervous system to depress the heart were studied in anesthetized dogs. Cardiac rate and force are augmented by stimulation of the intrathoracic efferent sympathetic nervous system and reduced by stimulation of the intrathoracic efferent parasympathetic nervous system. After cardiopulmonary bypass, which included systemic and topical hypothermia, aortic crossclamping, and crystalloid cardioplegia, the augmentor effects of the efferent sympathetic nervous system were obtunded whereas the depressor effects exerted by the efferent parasympathetic nervous system were not. Direct cardiac myocyte augmentor responses induced by isoproterenol were unaffected by these interventions. Normothermic cardiopulmonary bypass, hypothermic cardiopulmonary bypass, crossclamping of the aorta, or cold cardioplegia did not result in blunting of the efferent sympathetic cardiac nervous system. Significant blunting of cardiac augmentation induced by the efferent sympathetic nervous system occurred after topical application of iced slush alone. These data demonstrate that blunting of the efferent sympathetic, but not parasympathetic, innervation of the heart occurs after cardiopulmonary bypass, which presumably is primarily due to altering the function of subepicardial efferent sympathetic axons by topical hypothermia and not due to altered cardiac myocyte function. These data imply that after cardiopulmonary bypass involving the procedures described, the ability of the efferent sympathetic nervous system to support cardiac rate and force is transiently impaired.