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J Pharmacol Exp Ther. 2008 Jan;324(1):368-75. Epub 2007 Oct 9.

Endotoxemia-mediated induction of cardiac inducible nitric-oxide synthase expression accounts for the hypotensive effect of ethanol in female rats.

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Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27834, USA.


We have recently shown that intragastric (i.g.) ethanol lowers blood pressure (BP) in conscious female rats via a reduction in cardiac output (CO). However, the mechanisms implicated in these hemodynamic effects of ethanol are not known. Therefore, we tested the hypothesis that ethanol-evoked endotoxemia mediates the reduction in CO via enhanced myocardial inducible nitric-oxide synthase (iNOS) expression. Immunoblot (myocardial iNOS), biochemical (plasma endotoxin and nitrite/nitrate), and integrative [BP, heart rate, CO, stroke volume (SV), and total peripheral resistance (TPR)] studies were conducted in conscious female rats that received i.g. ethanol (1 g/kg) in the absence or presence of 1400W (N-(3-[aminomethyl]benzyl) acetamidine) or ampicillin to selectively inhibit iNOS and to eliminate endogenous endotoxin, respectively. Ethanol-evoked hypotension coincided with reductions in CO and SV and increases in: 1) TPR, 2) plasma endotoxin and nitrite/nitrate, and 3) myocardial iNOS expression. These effects of ethanol were virtually abolished in rats pretreated with ampicillin (200 mg/kg/day for 2 days by gavage) or with 1400W (5 mg/kg i.p.) except for the increase in plasma endotoxin, which persisted in 1400W-pretreated rats. These findings yield insight into the mechanistic role of endotoxin-myocardial iNOS signaling in the cardiodepressant action of ethanol, which accounts for its hypotensive effect in conscious female rats.

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