Adrenergic Induction of Delayed Afterdepolarizations in Ventricular Myocardial Cells: β Induction and α Modulation

Abstract

Adrenergic Afterdepolarizations in Ventricular Cells. Introduction: The purpose of these studies was to expose canine multicellular ventricular endocardial preparations and disaggregated myocytes to adrenergic agonists and antagonists, and to investigate the generation of delayed afterdepolarizations and triggered action potentials. Methods and Results: We used multicellular preparations and disaggregated myocytes from canine ventricles. The threshold concentration for induction of delayed afterdepolarizations in isolated myocytes for norepinephrine was between 1 × 10−8 M and 5 × 10−5 M, with 50% of the cells showing delayed afterdepolarizations at 4.3 × 10−8 M. Higher concentrations of epinephrine are required with 50% of the cells responding to 8.3 × 10−8 M. The threshold concentrations for induction of delayed afterdepolarizations in myocardial cells of multicellular preparations were an order of magnitude higher. Delayed afterdepolarizations could not be induced in Purkinje fibers with concentrations up to 10−4 M with norepinephrine. Adrenergic delayed afterdepolarizations were inhibited promptly by reduction of pO2 in superfusate that was equilibrated with N2 (95%) in place of O2. The amplitudes of adrenergic delayed afterdepolarizations and the propensity to triggered action potentials were inversely related to cycle length down to the shortest cycle length tested (330 msec). Adrenergic delayed afterdepolarizations were induced by isoproterenol but not by α‐adrenergic agonists (methoxamine or phenylephrine). They were inhibited by a β antagonist (propranolol) but not by α antagonists (prazosin or yohimbine). Delayed afterdepolarizations induced by isoproterenol were inhibited by α agonists (methoxamine or phenylephrine). The α‐adrenergic inhibitory effects on β‐adrenergic delayed afterdepolarizations could be reversed by prazosin, but not by yohimbine. Conclusions: We conclude the natural catecholamines norepinephrine and epinephrine generate delayed afterdepolarizations in myocardial cells, but not in Purkinje cells, by activating β receptors, but activation of α1 receptors inhibits adrenergic delayed afterdepolarizations. Individual myocytes exhibit widely varying sensitivities for induction of adrenergic delayed afterdepolarizations, but some cells respond to concentrations similar to those that may exist in vivo. Therefore, sympathetic activation in vivo may generate delayed afterdepolarizations, triggered action potentials, and arrhythmias.