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 (EREV) 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 mumol/L) had no effect on either inward or outward TI or on the current-voltage relation of TI. However, ISO (0.1 mumol/L) significantly increased both inward and outward TIs without affecting the EREV of TI, if [Na+]o was present. Pretreatment with propranolol (0.2 mumol/L) or atenolol (0.2 mumol/L) abolished the stimulatory effects of ISO. Addition of propranolol (0.2 to 0.5 mumol/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 mumol/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 mumol/L) and quinacrine (20 mumol/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.
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Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Ferrier
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D010766:Phosphorylation; D011433:Propranolol / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D013268:Stimulation, Chemical
D002712:Chlorides; D005576:Colforsin; D012964:Sodium; D011433:Propranolol; D007545:Isoproterenol; D002118:Calcium