746-1 Antifibrillatory Effect of HE-93, a New K+Channel and β Adrenergic Blocker in Conscious Dogs with a Healed Myocardial Infarction

Abstract

IKr potassium (K+) channel blockade is ineffective in preventing ventricular fibrillation (VF) due to a combination of high sympathetic activity and acute myocardial ischemia. This may be partly due to the fact that electrical sympathetic stimulation reduces action potential prolongation due to IKr blockade by more than 50%. Therefore, full efficacy of K+channel blockade may require antagonism of adrenergic influences on refractoriness. HE-93, a new K+channel blocker with β adrenergic blocking activity, was tested in 13 dogs with a healed anterior myocardial infarction (MI) that developed VF during two minutes of circumflex artery occlusion (CAO) during sub-maximal treadmill exercise. HE-93 lengthened QTc by 6% (P = 0.035) and reduced heart rate at rest (-9%, P < 0.05), during exercise (-7%; P < 0.05) and at 30 seconds into CAO from 235 ± 8 to 205 ± 6 b/min, (-13%, P < 0.0005). Eleven dogs (85%) were protected from VF. In 7 of the 11 protected dogs, VF did not recur in consecutive tests over a month after HE-93 administration. This is surprising considering the 91% reproducibility previously observed in 74 dogs using this same preparation and warrants further investigation. In 6 anesthetized dogs, HE-93 prolonged left ventricular monophasic action potential (MAP) duration at paced 360 msec cycle length from 179 ± 6 to 233 ± 5 msec (30%, P < 0.001) and completely prevented the effects of sympathetic stimulation on MAP duration. HE-93 exerts a powerful antifibrillatory effect that seems to be long lasting. The combination of β adrenergic antagonism and K+channel blockade overcomes the limitations encountered with traditional IKr blockers in preventing VF due to acute myocardial ischemia accompanied with reflex sympathetic activation.