Atrial glutathione content, calcium current, and contractility.
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.
College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.
Cynthia A
CA
Carnes
Paul M L
PM
Janssen
Mary L
ML
Ruehr
Hitomi
H
Nakayama
Tomohiro
T
Nakayama
Hannelore
H
Haase
John Anthony
JA
Bauer
Mina K
MK
Chung
Ian M
IM
Fearon
A Marc
AM
Gillinov
Robert L
RL
Hamlin
David R
DR
Van Wagoner
D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D005978:Glutathione / Q000378:metabolism*; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000166:cytology; D032342:Muscle Cells / Q000378:metabolism; D009119:Muscle Contraction; D009200:Myocardial Contraction; D009584:Nitrogen / Q000737:chemistry; D018408:Patch-Clamp Techniques; D013997:Time Factors
D019328:Buthionine Sulfoximine; D005978:Glutathione; D009584:Nitrogen; D002118:Calcium