IN-VIVO CARDIAC ELECTROPHYSIOLOGIC EFFECTS OF RWJ-29009, A NEW POTASSIUM-CHANNEL ACTIVATOR, IN COMPARISON TO CROMAKALIM AND NICARDIPINE

RWJ 29009 is a new potassium channel activator with prominent coronary and peripheral vasodilating actions. Because of the potential direct cardiac electrophysiologic actions of increased potassium conductance in myocardium, we evaluated the effects of RWJ 29009 on cardiac conduc tion and refractoriness in comparison to its vasodilator activity in a nesthetized, open-chest dogs. We assessed effects during both intrinsi c sinus rhythm and during constant atrial pacing. RWJ 29009 markedly i ncreased coronary blood flow and decreased mean arterial blood pressur e (MAP) dose dependently (0.3-10 mug/kg intravenously, i.v.). RWJ 2900 9 had no effect on PR interval but decreased AV-nodal conduction time (AH) and Wenkebach cycle length slightly. RWJ 29009 decreased QT inter val, left ventricular (LV) monophasic action potential duration (APD), and ventricular and atrial refractory period. These effects were cons istent with shortening of cardiac repolarization. RWJ 29009 had no eff ect on QRS or His-Purkinje conduction time. Cromakalim had a qualitati vely similar profile but was much less potent (3-300 mug/kg i.v.). In addition, the effects of cromakalim on repolarization parameters were somewhat less marked than those of RWJ 29009. Nicardipine also markedl y increased coronary blood flow and decreased arterial pressure (10-30 0 mug/kg i.v.). Unlike the potassium channel activators, nicardipine ( 100-300 mug/kg), did not affect cardiac repolarization, but increased PR and AH interval, and Wenkebach cycle length (WENK) and reduced hear t rate (HR) consistent with calcium channel blockade. These results in dicate that RWJ 29009, like cromakalim, increases coronary blood flow at low doses without substantial electrophysiologic effects. Electroph ysiologic effects observed at higher doses indicated a shortening of r epolarization, expectedly produced by potassium channel activation in cardiac tissue.