Oxidative Stress and Autonomic Dysregulation Contribute to the Acute Time-Dependent Myocardial Depressant Effect of Ethanol in Conscious Female Rats.

Background The molecular mechanisms of the acute hypotensive and indirectly assessed cardiac depressant effect of ethanol ( Et OH)-evoked myocardial depression and hypotension in female rats are not known. We tested the hypothesis that a time-dependent myocardial depression caused by Et OH is initiated by its direct and indirect (cardiac vagal dominance) effects and is exacerbated by gradual development of oxidative stress. Methods In conscious female rats, we directly measured left ventricular developed pressure ( LVDP), the maximal rise of ventricular pressure over time (d P/d t_max), blood pressure ( BP), heart rate ( HR), and sympathovagal activity following intragastric Et OH (1 g/kg) or water over 90 minutes. Catalytic activity of acetaldehyde ( ACA)-generating (alcohol dehydrogenase [ADH] and catalase) and eliminating aldehyde dehydrogenase [ALDH2] enzymes along with mediators of oxidative stress were measured in myocardial tissues collected at 30, 60, or 90 minutes after Et OH or water. Results Et OH reduced myocardial function ( LVDP and d P/d t_max) within 5 to 10 minutes before the steady fall in BP in conscious proestrus rats. Further, Et OH shifted the sympathovagal balance, analyzed by spectral analysis of high frequency and low frequency of interbeat intervals, toward vagal dominance. Prior vagal blockade (atropine) or antioxidant (tempol) treatment attenuated Et OH-evoked myocardial depression and hypotension. Ex vivo studies revealed time-dependent: (i) enhancement of ADH, but not ALDH2 activity (indicative of elevated ACA levels), (ii) increases in phosphorylated Akt and ERK1/2, NADPH-oxidase activity, reactive oxygen species, malondialdehyde, and 4-hydroxy-2-nonenal-modified proteins. These molecular responses along with reduced myocardial catalase activity were most evident at 90 minutes post- Et OH when the reductions in cardiac function and BP reached their nadir. Conclusions Vagal dominance and time-dependent myocardial oxidative stress along with the accumulation of cardiotoxic aldehydes mediate Et OH-evoked myocardial dysfunction and hypotension in conscious proestrus female rats. [ABSTRACT FROM AUTHOR]