Milacainide (Ro 22-9194) is structurally related to lidocaine and has a pyridine ring in the side chain. Ro 22-9194 is a new Class I antiarrhythmic agent with a TXA, synthase inhibitory activity. In anesthetized, open-chest dogs Ro 22-9194 transiently decreased arterial blood pressure and affected AV conduction more selectively, with a prolongation of the HV interval, than sinoatrial nodal pacemaker activity. In isolated, blood-perfused atria of dogs, Ro 22-9 194 decreased myocardial contractility more than sinoatrial nodal pacemaker activity. Studies in guinea pig papillary muscles and single ventricular myocytes showed that Ro 22-9194 inhibits sodium channels in a use- and voltage-dependent manner, and belongs to the group comprising intermediate kinetic drugs and activated channel blockers. Epinephrine-, digitalis-, two-stage coronary ligation-, and 3-hr coronary ligation-reperfusion-induced ventricular arrhythmias, or aconitine-induced atrial arrhythmias, in dogs were potently suppressed by Ro 22-9194 administered orally or intravenously. In myocardial ischemia and reperfusion-induced arrhythmias of dogs, Ro 22-9194 had an antifibrillatory effect and prevented an increase in venous levels of TXB, released from the ischemic myocardium.