Effects of cromakalim, pinacidil and nicorandil on cardiac refractoriness and arterial pressure in open-chest dogs.
The cardiac electrophysiologic effects of the potassium channel activators cromakalim, pinacidil and nicorandil were determined in anesthetized open-chest normotensive dogs using conventional surface electrogram recording techniques. Intravenous administration of cromakalim (0.025-0.5 mg/kg), pinacidil (0.1-2.0 mg/kg) and nicorandil (0.1-2.5 mg/kg) produced large dose-dependent decreases in arterial blood pressure accompanied by smaller reductions of atrial and ventricular effective refractory periods. The shortening of refractoriness was more pronounced in the atrium than in the ventricle and was similar for all three compounds at a given level of hypotension. Effects on other electrophysiological parameters were minimal. Atrial arrhythmias could be induced during electrical pacing at doses of cromakalim and pinacidil producing excessive (greater than or equal to 40%) decreases in mean arterial pressure. No arrhythmias were observed with nicorandil. Induction of the arrhythmias appeared to be closely coupled to the extrastimuli (S2) used to determine refractory periods and was associated with a significant reduction in atrial refractory period (greater than or equal to 30%). No ventricular arrhythmias were observed in this study with any of the compounds tested. Although the plasma levels reached in this study are likely to be higher than those seen clinically, the results nevertheless suggest the potential for cardiac electrophysiologic effects by these agents.
Spinelli
W
W
Wyeth-Ayerst Research, Princeton, NJ 08543.
Follmer
C
C
Parsons
R
R
Colatsky
T
T
D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D019806:Cromakalim; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009431:Neural Conduction / Q000187:drug effects*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D020110:Pinacidil