The effects of pentobarbital on heart rate, reflexly mediated vagal activity and the automaticity (intrinsic rate) of the sinoatrial (SA) node were investigated in rabbits. When administered in three cumulative doses (10 mg/kg i.v. each) at 15 min intervals, each dose produced transient hypotension which was not modified by prior muscarinic receptor blockade (MRB), beta-receptor blockade (BRB), or combined MRB and BRB. Subanesthetic doses (10 mg/kg) of pentobarbital produced tachycardia in normal rabbits, as well as in rabbits with prior BRB. After pentobarbital, MRB failed to increase the heart rate, indicating total loss of resting vagal tone. Failure to induce tachycardia in rabbits with prior MRB indicated the absence of sympathetic stimulation in pentobarbital-induced tachycardia. In rabbits with prior BRB, pentobarbital enhanced the hypotensive effects of acetylcholine and nitroglycerin and abolished nitroglycerin-induced tachycardia without significant effects on the magnitude of reflex bradycardia produced by norepinephrine. Pentobarbital had minimal, transient depressant effects on the intrinsic rate of the SA node. These results indicate that pentobarbital produces total loss of resting vagal tone without major impairment of reflex vagal activation.