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(Circulation Research. 1995;76:664-674.)
© 1995 American Heart Association, Inc.

Articles

Contribution of Na⁺-Ca²⁺ Exchange to Stimulation of Transient Inward Current by Isoproterenol in Rabbit Cardiac Purkinje Fibers

Xinqiang Han, Gregory R. Ferrier

From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.

Abstract Cellular mechanisms underlying ß-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 µmol/L) had no effect on either inward or outward TI or on the current-voltage relation of TI. However, ISO (0.1 µmol/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 µmol/L) or atenolol (0.2 µmol/L) abolished the stimulatory effects of ISO. Addition of propranolol (0.2 to 0.5 µmol/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 µmol/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 µmol/L) and quinacrine (20 µmol/L). These results suggest that ß-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.

Key Words: ß-adrenoceptors • nonspecific cationic currents • Cl^- current • Na⁺-Ca²⁺ exchange • oscillatory afterpotentials

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