title: N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress.
abstract: Compelling clinical reports reveal that behavioral stress alone is sufficient to cause reversible myocardial dysfunction in selected individuals. We developed a rodent stress cardiomyopathy model by a combination of prenatal and postnatal behavioral stresses (Stress). We previously reported a decrease in percent fractional shortening by echo, both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the β-adrenergic agonist, isoproterenol (ISO) in Stress rats compared with matched controls (Kan H, Birkle D, Jain AC, Failinger C, Xie S, Finkel MS. J Appl Physiol 98: 77-82, 2005). We now report enhanced catecholamine responses to behavioral stress, as evidenced by increased circulating plasma levels of norepinephrine (P < 0.01) and epinephrine (P < 0.01) in Stress rats vs. controls. Cardiac myocytes isolated from Stress rats also reveal evidence of oxidative stress, as indicated by decreased ATP, increased GSSG, and decreased GSH-to-GSSG ratio in the presence of increased GSH peroxidase and catalase activities (P < 0.01, for each). We also report blunted inotropic and intracellular Ca(2+) concentration responses to extracellular Ca(2+) (P < 0.05), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (20 mM; P < 0.01). Treatment of cardiac myocytes with N-acetylcysteine (NAC) (10(-3) M) normalized calcium handling in response to ISO and extracellular Ca(2+) concentration and inotropic response to caffeine (P < 0.01, for each). NAC also attenuated the blunted inotropic response to ISO and Ca(2+) (P < 0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG, or GSH-to-GSSG ratio. These data support a GSH-independent salutary effect of NAC on intracellular calcium signaling in this rodent model of stress-induced cardiomyopathy.
authors.affiliation: Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia, USA.
authors.forename: Fangping
authors.initials: F
authors.lastname: Chen
authors.forename: Jessalyn M
authors.initials: JM
authors.lastname: Hadfield
authors.forename: Chalak
authors.initials: C
authors.lastname: Berzingi
authors.forename: John M
authors.initials: JM
authors.lastname: Hollander
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.forename: Cody E
authors.initials: CE
authors.lastname: Nichols
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Finkel
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D009202:Cardiomyopathies / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D004837:Epinephrine / Q000097:blood; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000255:Adenosine Triphosphate; D002374:Catalase; D005979:Glutathione Peroxidase; D005978:Glutathione; D007545:Isoproterenol; D002118:Calcium; D019803:Glutathione Disulfide; D000111:Acetylcysteine; D009638:Norepinephrine; D004837:Epinephrine
keywords: N-acetylcysteine; heart function; prenatal stress