The chronotropic and dromotropic actions of ethmozin and its diethylamine analog ethacizin were studied in the presence and absence of combined muscarinic, beta- and alpha-adrenoreceptor blockade in the intact canine heart in situ (n = 38). Injections of ethacizin, 5, 10 and 25 µg/ml into the sinus node artery caused an immediate and significant (p < 0.001) sinus bradycardia of 2, 6 and 11%, respectively. Injection of 25 and 50 µg/ml of ethacizin into the atrioventricular (AV) node artery significantly (p < 0.001) prolonged AV conduction time with occasional second degree heart block. Conduction delay was located exclusively during the AH interval of the His bundle electrogram. Autonomic blockade did not alter the negative chronotropic or negative dromotropic effects of ethacizin. Ethacizin, 25 µg/ml injected into the sinus node artery immediately reduced the sinus node response to vagal stimulations by 30% and the effect of acetylcholine, 0.1 µg/ml, injected into the sinus node artery by 50%. Ethacizin, 25 µg/ml, injected into the AV node artery immediately reduced the duration of complete AV block elicited by vagal stimulation or intranodal acetylcholine, 0.5 µg/ml, by 90%. Ethacizin caused a minor reduction in sinus node response to right stellate stimulations without, however, altering the sinus node response to intranodal norepinephrine. Ethmozin injections of up to 50 µg/ml, into the sinus and AV node arteries had no chronotropic or dromotropic effects. Ethmozin had a minor and variable vagolytic action but significantly (p < 0.05) reduced the sinus node response to sympathetic nerve stimulation. Hence, ethacizin, in contrast to ethmozin, has a direct depressing action on both the sinus node and the AV junction. Ethacizin also has a transient atropinic action together with a minor sympatholytic effect. Ethmozin has virtually no atropinic action but a moderate sympatholytic effect. Neither agent has any significant adrenolytic effect. © 1986, American College of Cardiology Foundation. All rights reserved.