The direct and indirect chronotropic effects of clonidine (0.001-10 μg/ml) were studied by selective perfusion of the sinus node artery of 20 pentobarbital anesthetized dogs. Concentrations of 0.1, 1.0 and 10 μg/ml produced dose-related reductions in sinus rate of 3.7 ± 0.9 (P<.005) 6.9 ± 1.8 (P<.005) and 15.8 ± 2.3 (P<.0001) beats/min, respectively. Sinus acceleration after right stellate ganglion stimulation at 16 and 32 Hz was significantly (P<.05) inhibited by intranodal clonidine (0.1 μg/ml). The positive chronotropic effect of norepinephrine (0.1 μg/ml, sinus node artery) was not significantly affected by prior administration of clonidine. Atropine (1 mg/kg i.v. or 10 μg/ml, selectively perfused into the sinus node artery) had no effect on the sinus slowing produced by clonidine. Clonidine had an inconsistent effect on the response to vagal stimulation. Clonidine inhibits the heart rate increase after sympathetic nerve stimulation without affecting the heart rate response to norepinephrine infusion. The findings are consistent with previous observations that clonidine can inhibit norepinephrine release and demonstrate that this mechanism of action may occur within the sinus node.