Abnormal automatic rhythms in ischemic Purkinje fibers are modulated by a specific α1-adrenergic receptor subtype

Abstract

Background. Recent advances in adrenergic pharmacology have made possible the identification of α1-adrenergic receptor subtypes using the specific blockers chloroethylclonidine and WB 4101. Methods and Results. In the present study, we used these two blockers to determine the mechanisms responsible for automatic rhythms occurring during simulated ischemia and reperfusion of isolated canine Purkinje fibers. Experiments were done in the presence of propranolol to minimize β-adrenergic contributions to the rhythms studied. In the control situation, all fibers showed membrane potentials greater than -90 mV and normal automatic rhythms. During simulated ischemia, membrane potential depolarized to the -60 mV range. Abnormal automaticity was seen in 20% of fibers not treated with phenylephrine and in 50% of those superfused with 1×10-7 M phenylephrine. The incidence of abnormal automaticity was reduced to 0% by WB 4101 (which blocks phosphoinositide metabolic effects of α1-adrenergic stimulation in the heart) and was increased to 90% by chloroethylclonidine (which blocks Na-K pump-stimulating effects of α-agonists). Moreover, the ischemic fibers were significantly more hyperpolarized during superfusion with WB 4101 than with chloroethylclonidine. Triggered activity induced by delayed or early afterdepolarizations was not seen in any experiment. Conclusions. Automatic arrhythmias induced by α1-adrenergic stimulation during simulated ischemia may be attributed to a specific α1-adrenergic receptor subtype that is blocked by WB 4101. These results have important implications with respect to the induction of arrhythmias in the setting of ischemia and the means for their prevention or treatment.