Inducible nitric oxide synthase attenuates adrenergic signaling in alcohol fed rats.
Chronic, excessive alcohol consumption is associated with myocardial dysfunction in humans. The molecular mechanisms and cellular signaling pathways contributing to this cardiac dysfunction remain largely unknown. This study examined the effects of chronic alcohol consumption on myocardial function and cardiac myocyte signaling pathways. Adult male rats were fed a commercially prepared diet containing either ethanol (13 g/kg/d) or isocaloric control diet for 1 month. In vivo hemodynamics were measured in awake rats after inserting a catheter tip in the left ventricle under general anesthesia. Ventricular dysfunction was evidenced in awake, alcohol-fed rats by increased left ventricular end diastolic pressure, decreased systolic developed left ventricular pressure, and decreases in both positive and negative dp/dt compared with controls. Cardiac myocytes isolated from alcohol-fed rats also demonstrated an attenuated response to the beta-adrenergic agonist, isoproterenol, compared to controls. This response was significantly reversed by the nitric oxide synthase (NOS) inhibitor, N-monomethyl-L-arginine (L-NMMA). Western analyses confirmed inducible nitric oxide synthase (iNOS) protein synthesis in cardiac myocytes isolated from alcohol fed rats. It is therefore concluded that chronic alcohol ingestion results in iNOS-mediated attenuation of adrenergic signaling and depression in both systolic and diastolic function in rats.
Khanna
Deepak
D
Department of Medicine, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia, USA.
Kan
Hong
H
Fang
Qiujuan
Q
Xie
Zirong
Z
Underwood
Brandi L
BL
Jain
Abnash C
AC
Williams
H James
HJ
Finkel
Mitchell S
MS
D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D031204:Caloric Restriction / Q000379:methods; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D017725:Ventricular Pressure / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II; D007545:Isoproterenol