Endotoxemia-mediated induction of cardiac inducible nitric-oxide synthase expression accounts for the hypotensive effect of ethanol in female rats.
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.
El-Mas
Mahmoud M
MM
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Fan
Ming
M
Abdel-Rahman
Abdel A
AA
D000578:Amidines / Q000494:pharmacology; D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D019446:Endotoxemia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D004731:Endotoxins / Q000097:blood; D000431:Ethanol / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume / Q000187:drug effects
D000578:Amidines; D000900:Anti-Bacterial Agents; D001596:Benzylamines; D004731:Endotoxins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009566:Nitrates; D009573:Nitrites; D000431:Ethanol; D000667:Ampicillin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat