title: Nongenomic effects of estrogen mediate the dose-related myocardial oxidative stress and dysfunction caused by acute ethanol in female rats.
abstract: Acute ethanol lowers blood pressure (BP) and cardiac output in proestrus and after chronic estrogen (E2) replacement in ovariectomized (OVX) female rats. However, whether rapid nongenomic effects of estrogen mediate these hemodynamic effects of ethanol remains unanswered. To test this hypothesis, we investigated the effect of ethanol (0.5 or 1.5 g/kg iv) on left ventricular (LV) function and oxidative markers in OVX rats pretreated 30 min earlier with 1 μg/kg E2 (OVXE2) or vehicle (OVX) and in proestrus sham-operated (SO) rats. In SO rats, ethanol caused significant and dose-related reductions in BP, rate of rise in LV pressure (LV dP/dtmax), and LV developed pressure (LVDP). These effects of ethanol disappeared in OVX rats and were restored in OVXE2 rats, suggesting rapid estrogen receptor signaling mediates the detrimental effects of ethanol on LV function. Ex vivo studies revealed that the estrogen-dependent myocardial dysfunction caused by ethanol was coupled with higher LV 1) generation of reactive oxygen species (ROS), 2) expression of malondialdehyde and 4-hydroxynonenal protein adducts, 3) phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), and 4) catalase activity. ERK1/2 inhibition by PD-98059 (1 mg/kg iv) abrogated the myocardial dysfunction, hypotension, and the elevation in myocardial ROS generation caused by ethanol. We conclude that rapid estrogen receptor signaling is implicated in cellular events that lead to the generation of aldehyde protein adducts and Akt/ERK1/2 phosphorylation, which ultimately mediate the estrogen-dependent LV oxidative stress and dysfunction caused by ethanol in female rats.
authors.affiliation: Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: El-Mas
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D016678:Genome / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000378:metabolism
chemical_list: D004967:Estrogens; D000431:Ethanol
keywords: LV dysfunction; estrogen; ethanol; extracellular signal-regulated kinases; oxidative stress