Effects of the potassium channel blocking agent ambasilide on ventricular arrhythmias induced by acute myocardial ischemia and sympathetic activation.
The ineffectiveness of traditional antiarrhythmic agents in preventing sudden cardiac death has increased the interest in drugs that prolong refractoriness. Ambasilide is a new potassium channel blocking agent that appears to prolong refractoriness at short and long cycle lengths. We assessed the effects of ambasilide, 5 mg/kg intravenous (i.v.) bolus plus 5 mg.kg-1.hr-1 i.v. infusion, in 16 anesthetized cats in which ventricular arrhythmias could be induced reproducibly by the combination of acute myocardial ischemia and increased sympathetic activity. Ambasilide decreased heart rate and blood pressure and prolonged QRS duration (26%, p < 0.05), QTc (17%, p < 0.0001), and JTc (16%, p < 0.005). Ambasilide also shifted the strength-interval curve for ventricular refractoriness by 17 to 22 msec to the right (p < 0.001). Ventricular fibrillation was observed in 7 animals and never occurred after ambasilide (p < 0.001); however, 4 (57%) of these cats had sustained ventricular tachycardia requiring cardiac massage. Ambasilide prevented nonsustained ventricular tachycardia in 2 (40%) of 5 animals. The antiarrhythmic effect of ambasilide persisted when heart rate was kept constant by atrial pacing. In no case was proarrhythmia observed. Ambasilide had a significant electrophysiologic effect at the ventricular level in the cat because it did prolong QTc and ventricular refractoriness. Therefore ambasilide showed an antifibrillatory effect but provided only a partial protection against lethal arrhythmias induced by acute myocardial ischemia and sympathetic activation.
Stramba-Badiale
M
M
Instituto di Clinica Medica Generale e Terapia Medica, Università di Milano, Italy.
Pessano
P
P
Kirchengast
M
M
Schwartz
P J
PJ
D000208:Acute Disease; D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002415:Cats; D003327:Coronary Disease / Q000150:complications*; D004558:Electric Stimulation; D004594:Electrophysiology; D006439:Hemodynamics / Q000187:drug effects; D013233:Stellate Ganglion / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
D062365:Aminobenzoates; D000889:Anti-Arrhythmia Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C075113:ambasilide