title: Ethanol induces vascular relaxation via redox-sensitive and nitric oxide-dependent pathways.
abstract: We investigated the role of reactive oxygen species (ROS) and nitric oxide (NO) in ethanol-induced relaxation. Vascular reactivity experiments showed that ethanol (0.03-200 mmol/L) induced relaxation in endothelium-intact and denuded rat aortic rings isolated from male Wistar rats. Pre-incubation of intact or denuded rings with l-NAME (non selective NOS inhibitor, 100 μmol/L), 7-nitroindazole (selective nNOS inhibitor, 100 μmol/L), ODQ (selective inhibitor of guanylyl cyclase enzyme, 1 μmol/L), glibenclamide (selective blocker of ATP-sensitive K(+) channels, 3 μmol/L) and 4-aminopyridine (selective blocker of voltage-dependent K(+) channels, 4-AP, 1 mmol/L) reduced ethanol-induced relaxation. Similarly, tiron (superoxide anion (O(2)(-)) scavenger, 1 mmol/L) and catalase (hydrogen peroxide (H(2)O(2)) scavenger, 300 U/mL) reduced ethanol-induced relaxation to a similar extent in both endothelium-intact and denuded rings. Finally, prodifen (non-selective cytochrome P450 enzymes inhibitor, 10 μmol/L) and 4-methylpyrazole (selective alcohol dehydrogenase inhibitor, 10 μmol/L) reduced ethanol-induced relaxation. In cultured aortic vascular smooth muscle cells (VSMCs), ethanol stimulated generation of NO, which was significantly inhibited by l-NAME. In endothelial cells, flow cytometry studies showed that ethanol increased cytosolic Ca(2+) concentration ([Ca(2+)]c), O(2)(-) and cytosolic NO concentration ([NO]c). Tiron inhibited ethanol-induced increase in [Ca(2+)]c and [NO]c. The major new finding of this work is that ethanol induces relaxation via redox-sensitive and NO-cGMP-dependent pathways through direct effects on ROS production and NO signaling. These findings identify putative molecular mechanisms whereby ethanol, at pharmacological concentrations, influences vascular reactivity.
authors.affiliation: Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Juliana T
authors.initials: JT
authors.lastname: Rocha
authors.forename: Ulisses V
authors.initials: UV
authors.lastname: Hipólito
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.forename: Alvaro
authors.initials: A
authors.lastname: Yogi
authors.forename: Mario dos Anjos
authors.initials: Mdos A
authors.lastname: Neto Filho
authors.forename: Lusiane M
authors.initials: LM
authors.lastname: Bendhack
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Tirapelli
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D000431:Ethanol; D006152:Cyclic GMP