Ethanol-induced vasoconstriction is mediated via redox-sensitive cyclo-oxygenase-dependent mechanisms

Abstract

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.

Ethanol attenuates peripheral NMDAR-mediated vascular oxidative stress and pressor response

“…5), consistent with our recent findings in the same tissue (McGee & Abdel-Rahman, 2012, 2014) and in other tissues (Gunasekar et al, 1995). In agreement with reported findings (Krenz & Korthuis, 2012; Yogi et al, 2010), ethanol produced modest, but significant increases in ROS, at least partly, via its oxidative metabolites, acetaldehyde and acetate (Deng & Deitrich, 2007; Seitz & Stickel, 2007). Interestingly, despite ethanol’s or NMDA’s ability to increase vascular ROS, ethanol pretreatment significantly attenuated the peripheral NMDAR-mediated increases in ROS.…”

Oxidative Stress-Dependent Cyclooxygenase-2-Derived Prostaglandin F2α Impairs Endothelial Function in Renovascular Hypertensive Rats

“…In addition, COX-derived prostaglandins were suggested to be one major source of EDCF apart from superoxide anions (1,14,39,46). The current study indicates that EDCFs derived from COX-2 were released in response to ROS stimulation based on the following findings.…”

Contribution of oxidative stress and prostanoids in endothelial dysfunction induced by chronic fluoxetine treatment

“…The lucigenin-derived chemiluminescence assay was used to determine O 2 − levels in aortic homogenates as previously described [19][20][21].…”