ELECTROPHYSIOLOGIC AND ARRHYTHMOGENIC EFFECTS OF THE POTASSIUM CHANNEL AGONIST BRL-38227 IN ANESTHETIZED DOGS

Although potassium channel openers have been demonstrated to induce ar terial vasodilation and shortening of the QT interval, the complete in vivo hemodynamic and electrophysiologic profile of these drugs has no t been fully established. We evaluated the effects of BRL 38227, the a ctive enantiomer of cromakalim, on the electrophysiologic and hemodyna mic parameters in anesthetized dogs. Four intravenous (i.v.) doses (0. 01, 0.03, 0.1, and 0.3 mg/kg) of BRL 38227 (lemakalim) were given to f our different groups of 6 anesthetized and mechanically ventilated dog s. Electrophysiologic and hemodynamic parameters were measured with bi polar catheters positioned in the right atria and the right ventricle and double micromanometers placed in the left ventricle and the aorta. Nine dogs died of ventricular fibrillation (VF; 6 of 6 after 0.3 mg/k g, 2 of 8 dogs after 0.1 mg/kg, and 1 of 7 dogs after 0.03 mg/kg BRL 3 8227). Three dogs had atrial tachycardia (I had atrial flutter and 1 h ad atrial fibrillation after 0.03 mg/kg, and 1 had atrial fibrillation after 0.01 mg/kg BRL 38227). BRL 38227 did not modify heart rate (HR) , corrected sinus recovery time (CSRT), and atrial or atrio-ventricula r (A-V) conduction times. In contrast, PR interval, Luciani-Wenckebach cycle length (LW), HV interval, QRS duration, ventricular effective r efractory period (VERP), QT interval, and monophasic action potential (AP) were significantly shortened in a dose-dependent manner. Left ven tricular end-diastolic pressure (LVEDP) was not modified, whereas LVdP /dt(max) decreased significantly at 0.1 mg/kg BRL 38227. Finally, ther e was a significant dose-dependent decrease in systolic, diastolic, an d mean aortic blood pressure (SBP, DBP, MAP). We conclude that BRL 382 27 shortens the ventricular parameters of conduction velocity and of r epolarization and decreases BP, both in a dose-dependent manner. All d oses were arrhythmogenic, suggesting that BRL 38227 has a low safety m argin.