Date of Graduation


Document Type


Degree Type



Davis College of Agriculture, Natural Resources and Design


Animal and Nutritional Sciences

Committee Chair

Mitchell S. Finkel.


Compelling clinical reports indicate that emotional/behavioral stress alone is sufficient to cause profound, but completely reversible myocardial dysfunction in selected individuals. A rodent cardiomyopathy model was previously reported by combining pre-natal and post-natal behavioral/restraint stress (Stress). A decrease in % FS (the ratio between the diameter of the left ventricle when it is relaxed and when it is contracted) by echocardiogram was previously reported, along with both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the beta adrenergic agonist, isoproterenol (ISO) in Stress compared with matched Controls. The p38mitogen-activated protein (MAP) kinase inhibitor, SB203580, both prevented and reversed the baseline reduction in systolic and diastolic dysfunction, as well as the blunted ISO response in cardiac myocytes from Stress animals in vitro and in vivo. p38 MAP kinase has been reported to be activated by oxidative stress. Previous work showed that the sulhydryl donor and substrate for glutathione, N-acetylcysteine (NAC), reversed myocardial dysfunction in 2 different genetic proteinopathy models (Syrian Hamster and Tat mouse). In the current studies, cardiac myocytes isolated from Stress revealed evidence of mitochondrial dysfunction and oxidative stress as indicated by decreased ATP concentration and decreased GSH/GSSG ratio, respectively. Stress cardiac myocytes also displayed blunted inotropic and [Ca2+ ]i responses to extracellular Ca2+ ([Ca 2+]out) and ISO (p<0.05, for each), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (10mM),which causes sacroplasmic reticulum Ca2+ depletion (p<0.01). Treatment of cardiac myocytes with NAC (10-3 M) normalized calcium handling in response to ISO and [Ca2+]out and inotropic response to caffeine (p<0.01, for each). NAC also normalized the blunted inotropic response to ISO and Ca2+ (p<0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG or GSH/GSSG ratio. These data indicate that NAC may reverse cardiac myocyte dysfunction by a glutathione-independent effect on intracellular calcium signaling. Elucidating the molecular mechanisms responsible for the salutary effects of NAC may provide novel insights into potential therapeutic targets for the reversal of myocardial dysfunction in patients with cardiomyopathies and heart failure.