Atrial Glutathione Content, Calcium Current, and Contractility

Abstract

Atrial fibrillation (AF) is characterized by decreased L-type calcium current (I Ca,L ) in atrial myocytes and decreased atrial contractility. Oxidant stress and redox modulation of calcium channels are implicated in these pathologic changes. We evaluated the relationship between glutathione content (the primary cellular reducing moiety) and I Ca,L in atrial specimens from AF patients undergoing cardiac surgery. Left atrial glutathione content was significantly lower in patients with either paroxysmal or persistent AF relative to control patients with no history of AF. Incubation of atrial myocytes from AF patients (but not controls) with the glutathione precursor N-acetylcysteine caused a marked increase in I Ca,L . To test the hypothesis that glutathione levels were mechanistically linked with the reduction in I Ca,L , dogs were treated for 48 h with buthionine sulfoximine, an inhibitor of glutathione synthesis. Buthionine sulfoximine treatment resulted in a 24% reduction in canine atrial glutathione content, a reduction in atrial contractility, and an attenuation of I Ca,L in the canine atrial myocytes. Incubation of these myocytes with exogenous glutathione also restored I Ca,L to normal or greater than normal levels. To probe the mechanism linking decreased glutathione levels to down-regulation of I Ca , the biotin switch technique was used to evaluate S-nitrosylation of calcium channels. S-Nitrosylation was apparent in left atrial tissues from AF patients; the extent of S-nitrosylation was inversely related to tissue glutathione content. S-Nitrosylation was also detectable in HEK cells expressing recombinant human cardiac calcium channel subunits following exposure to nitrosoglutathione. S-Nitrosylation may contribute to the glutathione-sensitive attenuation of I Ca,L observed in AF. Atrial fibrillation (AF)2 is characterized by rapid electrical activation of the atria. Persistent AF results in phenotypic electrical and structural remodeling of the atria. Calcium influx via I Ca triggers calcium release from intracellular stores and is an essential first step in excitation-contraction coupling and a critical determinant of atrial contractility. In atrial myocytes from patients with persistent AF (1) or from animals with pacinginduced AF (2), calcium current density is significantly decreased. The time course of contractile impairment following the onset of AF (3) or rapid atrial pacing (4) parallels the down-regulation of I Ca , and contractile recovery proceeding cardioversion follows a time course similar to that of reverse electrical remodeling (4). Reports characterizing the impact of AF on the expression of the calcium channel pore subunit in human AF and in experimental models have had conflicting results (5, 6); the mechanisms by which I Ca,L down-regulation occurs are not fully resolved.In a porcine model of rapid atrial pacing, superoxide production is increased (7), and nitric oxide production is decreased (8). Oxidant-generating pathways can shift the myocyte intracellular redox environment from...

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