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 conduction and refractoriness in comparison to its vasodilator activity in anesthetized, open-chest dogs. We assessed effects during both intrinsic sinus rhythm and during constant atrial pacing. RWJ 29009 markedly increased coronary blood flow and decreased mean arterial blood pressure (MAP) dose dependently (0.3-10 micrograms/kg intravenously, i.v.). RWJ 29009 had no effect on PR interval but decreased AV-nodal conduction time (AH) and Wenkebach cycle length slightly. RWJ 29009 decreased QT interval, left ventricular (LV) monophasic action potential duration (APD), and ventricular and atrial refractory period. These effects were consistent with shortening of cardiac repolarization. RWJ 29009 had no effect on QRS or His-Purkinje conduction time. Cromakalim had a qualitatively similar profile but was much less potent (3-300 micrograms/kg i.v.). In addition, the effects of cromakalim on repolarization parameters were somewhat less marked than those of RWJ 29009. Nicardipine also markedly increased coronary blood flow and decreased arterial pressure (10-300 micrograms/kg i.v.). Unlike the potassium channel activators, nicardipine (100-300 micrograms/kg), did not affect cardiac repolarization, but increased PR and AH interval, and Wenkebach cycle length (WENK) and reduced heart rate (HR) consistent with calcium channel blockade. These results indicate that RWJ 29009, like cromakalim, increases coronary blood flow at low doses without substantial electrophysiologic effects. Electrophysiologic effects observed at higher doses indicated a shortening of repolarization, expectedly produced by potassium channel activation in cardiac tissue.
Damiano
B P
BP
R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania.
Stump
G L
GL
Cheung
W M
WM
Salata
J J
JJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011714:Pyrans; D011758:Pyrroles / Q000494:pharmacology; D013876:Thiophenes; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D010881:Piperidones; D015221:Potassium Channels; D011714:Pyrans; D011758:Pyrroles; D013876:Thiophenes; D014665:Vasodilator Agents; D019806:Cromakalim; C078276:RWJ 26629; D009529:Nicardipine