The effects of intracoronary (i.c.) cromakalim (1 microgram/kg/min) or pinacidil (3 micrograms/kg/min) were evaluated to assess the effects of blood flow on arrhythmogenesis in a canine model of CsCl-induced triggered activity. CsCl (1 M) was administered i.c. through the left anterior descending coronary artery (LAD) at volumes of 0.1, 0.2, 0.5, 0.75, 1.0, and 2.0 ml. In the vehicle group, CsCl produced significant increases in percentage of ectopy from control (ED50 = 0.56 mM). Under conditions of uncontrolled LAD flow, pretreatment with either cromakalim or pinacidil significantly reduced ectopy as compared with vehicle (ED50 = 1.12 and 1.55 mM, respectively). Both cromakalim and pinacidil produced a three-fold increase in blood flow. Under conditions of controlled flow, cromakalim and pinacidil failed to reduce ectopy (ED50 = 0.54 and 0.66 mM, respectively). Doses of cromakalim that elicited a modest (10%) increase in coronary flow also failed to suppress ectopy (ED50 = 0.56 mM). Ectopy was reduced when flow was increased threefold from control using a carotid-LAD shunt without drug. In contrast, diltiazem (3 micrograms/kg/min), a calcium channel antagonist, reduced ectopy even though flow was held constant (ED50 > 2 mM). Cromakalim, pinacidil, and diltiazem significantly decreased mean blood pressure (BP) 20, 19, and 10%, respectively. These studies suggest that the antiarrhythmic activity of both cromakalim and pinacidil in this model is not directly mediated, but instead is indirectly mediated through an increase in coronary blood flow. In contrast, diltiazem was shown to have direct antiarrhythmic effects.