Ethanol-induced vasoconstriction is mediated via redox-sensitive cyclo-oxygenase-dependent mechanisms.
The present study investigated the role of ROS (reactive oxygen species) and COX (cyclo-oxygenase) in ethanol-induced contraction and elevation of [Ca2+]i (intracellular [Ca2+]). Vascular reactivity experiments, using standard muscle bath procedures, showed that ethanol (1-800 mmol/l) induced contraction in endothelium-intact (EC50: 306+/-34 mmol/l) and endothelium -denuded (EC50: 180+/-40 mmol/l) rat aortic rings. Endothelial removal enhanced ethanol-induced contraction. Preincubation of intact rings with L-NAME [NG-nitro-L-arginine methyl ester; non-selective NOS (NO synthase) inhibitor, 100 micromol/l], 7-nitroindazole [selective nNOS (neuronal NOS) inhibitor, 100 micromol/l], oxyhaemoglobin (NO scavenger, 10 micromol/l) and ODQ (selective inhibitor of guanylate cyclase enzyme, 1 micromol/l) increased ethanol-induced contraction. Tiron [O2- (superoxide anion) scavenger, 1 mmol/l] and catalase (H2O2 scavenger, 300 units/ml) reduced ethanol-induced contraction to a similar extent in both endothelium-intact and denuded rings. Similarly, indomethacin (non-selective COX inhibitor, 10 micromol/l), SC560 (selective COX-1 inhibitor, 1 micromol/l), AH6809 [PGF2alpha (prostaglandin F2alpha)] receptor antagonist, 10 micromol/l] or SQ29584 [PGH2(prostaglandin H2)/TXA2 (thromboxane A2) receptor antagonist, 3 micromol/l] inhibited ethanol-induced contraction in aortic rings with and without intact endothelium. In cultured aortic VSMCs (vascular smooth muscle cells), ethanol stimulated generation of O2- and H2O2. Ethanol induced a transient increase in [Ca2+]i, which was significantly inhibited in VSMCs pre-exposed to tiron or indomethacin. Our data suggest that ethanol induces vasoconstriction via redox-sensitive and COX-dependent pathways, probably through direct effects on ROS production and Ca2+ signalling. These findings identify putative molecular mechanisms whereby ethanol, at high concentrations, influences vascular reactivity. Whether similar phenomena occur in vivo at lower concentrations of ethanol remains unclear.
Yogi
Alvaro
A
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada.
Callera
Glaucia E
GE
Hipólito
Ulisses V
UV
Silva
Catiane R
CR
Touyz
Rhian M
RM
Tirapelli
Carlos R
CR
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
D017382:Reactive Oxygen Species; D013481:Superoxides; D000431:Ethanol; D014700:Verapamil; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium