Abstract
Ethanol (EtOH)-evoked oxidative stress, which contributes to myocardial dysfunction in proestrus rats, is mediated by increases in NADPH oxidase (Nox) activity, malondialdehyde (MDA), and ERK1/2 phosphorylation. Whether these biochemical responses, which are triggered by alcohol-derived acetaldehyde in noncardiac tissues, occur in proestrus rats' hearts remains unknown. Therefore, we elucidated the roles of alcohol dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), and catalase, which catalyze alcohol oxidation to acetaldehyde, in these alcohol-evoked biochemical and hemodynamic responses in proestrus rats. Conscious proestrus rats prepared for measurements of left ventricular (LV) function and blood pressure (BP) received EtOH (1.5g/kg, intravenous [i.v.] infusion over 30minutes) or saline 30minutes after an ADH and CYP2E1 inhibitor, 4-methylpyrazole (4-MP) (82mg/kg, intraperitoneal), a catalase inhibitor, 3-AT (0.5g/kg, i.v.), their combination, or vehicle. LV function and BP were monitored for additional 60minutes after EtOH or saline infusion before collecting the hearts for exvivo measurements of LV reactive oxygen species (ROS), Nox activity, MDA, and ERK1/2 phosphorylation. EtOH reduced LV function (dP/dtmax and LV developed pressure) and BP, and increased cardiac Nox activity, ROS and MDA levels, and ERK1/2 phosphorylation. Either inhibitor partially, and their combination significantly, attenuated these responses despite the substantially higher blood EtOH level, and the increased cardiac oxidative stress and reduced BP caused by 3-AT alone or with 4-MP. The inhibitors reduced cardiac MDA level and reversed EtOH effect on cardiac and plasma MDA. EtOH oxidative metabolism plays a pivotal role in the EtOH-evoked LV oxidative stress and dysfunction in proestrus rats. Notably, catalase inhibition (3-AT) caused cardiac oxidative stress and hypotension.
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