Combined Catalase and ADH Inhibition Ameliorates Ethanol‐Induced Myocardial Dysfunction Despite Causing Oxidative Stress in Conscious Female Rats

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2017-09, Vol.41 (9), p.1541-1550
• Main Authors: Yao, Fanrong, Abdel‐Rahman, Abdel A.
• Format: Article
• Language: English
• Subjects: Acetaldehyde; Alcohol; Alcohol Dehydrogenase; Amitrole - pharmacology; Animals; Blood pressure; Blood Pressure - drug effects; Cardiomyopathies - chemically induced; Cardiomyopathies - physiopathology; Cardiomyopathies - prevention & control; Catalase; Catalase - antagonists & inhibitors; Central Nervous System Depressants - antagonists & inhibitors; Central Nervous System Depressants - blood; Central Nervous System Depressants - toxicity; Cytochrome P4502E1; Enzyme Inhibitors - therapeutic use; Estrus cycle; Ethanol; Ethanol - antagonists & inhibitors; Ethanol - blood; Ethanol - toxicity; Female; Heart; Heart diseases; Hemodynamic responses; Hypotension; Intravenous administration; Malondialdehyde; Myocardial Dysfunction; NAD(P)H oxidase; Neurophysins - antagonists & inhibitors; Oxidative metabolism; Oxidative Stress; Oxidative Stress - drug effects; Phosphorylation; Proestrus; Protein Precursors - antagonists & inhibitors; Pyrazoles - therapeutic use; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Rodents; Vasopressins - antagonists & inhibitors; Ventricle; Ventricular Function, Left
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.13442

Background 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. Methods Conscious proestrus rats prepared for measurements of left ventricular (LV) function and blood pressure (BP) received EtOH (1.5 g/kg, intravenous [i.v.] infusion over 30 minutes) or saline 30 minutes after an ADH and CYP2E1 inhibitor, 4‐methylpyrazole (4‐MP) (82 mg/kg, intraperitoneal), a catalase inhibitor, 3‐AT (0.5 g/kg, i.v.), their combination, or vehicle. LV function and BP were monitored for additional 60 minutes after EtOH or saline infusion before collecting the hearts for ex vivo measurements of LV reactive oxygen species (ROS), Nox activity, MDA, and ERK1/2 phosphorylation. Results 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. Conclusions 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. Ethanol (EtOH; 1.5 g/kg) caused oxidative stress‐mediated myocardial dysfunction in conscious proestrus rats via increases in cardiac NADPH oxidase activity, malondialdehyde levels, and ERK1/2 phosphorylation. Inhibition of EtOH metabolizing enzymes (alcohol dehydrogenase, cytochrome P4502E1 and catalase) by 3‐AT, 4‐MP alone or their combination partially and significantly attenuated these responses. The current findings suggest that oxidative EtOH metabolism plays a pivotal role in the EtOH‐evoked myocardial oxidative stress and dysfunction in estrogen replet