CONTRIBUTION OF NA+-CA2+ EXCHANGE TO STIMULATION OF TRANSIENT INWARD CURRENT BY ISOPROTERENOL IN RABBIT CARDIAC PURKINJE-FIBERS

Cellular mechanisms underlying beta-adrenergic stimulation of the arrhythmogenic transient inward current (TI) were investigated by using a two-microelectrode voltage-clamp technique in rabbit cardiac Purkinje fibers. TI induced by elevating [Ca2+](o) to 30 mmol/L and substituting [Na+](o) with N-methyl-D-glucamine (NMG) chloride had a distinct reversal potential (E(REV)) of -25 mV, suggesting that Na+-Ca2+ exchange was not the charge carrier for TI. In the absence of [Na+](o), isoproterenol (ISO, 0.01 to 5.0 mu mol/L) had no effect on either inward or outward TI or on the current-voltage relation of TI. However, ISO (0.1 mu mol/L) significantly increased both inward and outward TIs without affecting the E(REV) of TI, if [Na+](o) was present. Pretreatment with propranolol (0.2 mu mol/L) or atenolol (0.2 mu mol/L) abolished the stimulatory effects of ISO. Addition of propranolol (0.2 to 0.5 mu mol/L) after the effects of ISO had developed caused only partial reversal of TI stimulation. This indicates persistence of stimulatory effects downstream from the initial agonist-receptor interaction. Forskolin (1 mu mol/L), a direct adenylate cyclase activator, also strongly increased both inward and outward TI in the presence of [Na+](o). These effects also were abolished when [Na+](o) was substituted by NMG. Inward and outward TIs enhanced by either ISO or forskolin were reversed by two putative Na+-Ca2+ exchange blockers, dodecylamine (20 mu mol/L) and quinacrine (20 mu mol/L). These results suggest that beta-adrenergic stimulation of TI is mediated by the Na+-Ca2+ exchange; stimulation likely involves phosphorylation of the exchanger or some factor that modulates exchanger activity.