The actions of 2-methylhistamine (H1 agonist), 4- methylhistamine (H2 agonist), and histamine were studied by selective perfusion of the sinus node artery and atrioventricular node artery in 75 dogs anesthetized with pentobarbital sodium. 2-Methylhistamine and histamine had variable and inconsistent effects on the sinus rate. 4-Methylhistamine (100μg/ml) produced acceleration of the sinus rate from 158 ± 4 to 173 ± 5 beats per minute (P < 0.05) when perfused via the sinus node artery. The effects of the histamine agonists on atrioventricular junctional rhythms were similar to the effects on sinus rhythm. The response of the sinus node to vagal stimulation was attenuated by selective perfusion with histamine; however, the direct negatively chronotropic action of acetylcholine was not affected by histamine. Neither 2-methylhistamine nor 4-methylhistamine affected the response of the sinus node to vagal stimulations. Both 4-methylhistamine and histamine (but not 2-methylhistamine) attenuated (P < 0.05) the response of the sinus node to stimulation of the right stellate ganglion. The positively chronotropic effects of directly perfused norepinephrine were unaffected by histamine or 4-methylhistamine. These results suggest a neural depressing action of histamine on autonomic efferent fibers. In the atrioventricular junction, both histamine and 2-methylhistamine (but not 4-methylhistamine) had negatively dromotropic effects. Cimetidine (an H2 antagonist) had no significant direct effects on the sinus rate or atrioventricular conduction and failed to prevent the acceleration of the sinus rate produced by local perfusion with 4-methylhistamine.