Abstract 89: Enhanced TP Sensitivity and HO-dependent CO Release Mediates H2O2-Induced Vasoconstriction and Dilation: A Response Affected by Antioxidants
Hydrogen peroxide (H2O2) is a non-radical oxidant and is employed to ascertain the role of redox mechanisms in regulation of vascular tone. Where both dilation and constriction have been reported in response to this oxidant; we examined the hypothesis that the ability of H2O2 to affect vasoconstriction or dilatation is conditioned by redox mechanisms and may be amenable to modulation by antioxidants. Freshly isolated rat renal interlobular (RIA) or mesenteric (MA) arteries were used for investigation of the effect of H2O2 on their internal diameter (ID), in the absence or presence of antioxidants including, tempol, PEG-SOD, BHT and biliverdin (BV). In arteries without antioxidant pretreatment, H2O2 (1.0 and 10.0 μM) reduced (p< 0.05) the ID of RIA (90.0±0.6 to 85.0±1.9 and 71.6±1.4 μm, respectively) and MA (90.4±2.3 to 85.0±2.1 and 74.2±1.8 μm, respectively); a response obliterated by all antioxidants used (p<0.05). However, in contrast to tempol and PEG-SOD, antioxidants targeting lipid peroxides and OH. (BHT, BV) not only blocked constriction but also uncovered vasodilation in response to H2O2 (91.3±2.5 to 95.2±2.4 and 102.5±2.8 μm, with BHT), which was also endothelium dependent [Δ ID- BHT+H2O2 (10 μM): 11.85±0.73 vs. in endothelium denuded: 0.80±0.49 μm, p<0.05]. Without enhancing vascular TxB2 synthesis (2.01±0.72 vs. 1.87±0.41 ng/mg/hr) H2O2 caused vasoconstriction which was blocked (p<0.05) by inhibitors of the COX-TXA2 pathway (indomethacin, SQ29548). However, H2O2 treatment sensitized the arteries to a TP agonist- U46619 (EC50: 0.63±0.07 vs. 0.17±0.08 nmol/l, in arteries without and with H2O2, respectively), an effect reversed by PEG-SOD pretreatment. The dilatory response to H2O2 was accompanied by enhanced vascular heme oxygenase (HO)-dependent CO generation (BHT: 157.2±19.9 vs. BHT+H2O2: 301.25±25.3, p<0.05 and BV: 162.6±17.3 vs. BV + H2O2: 255.9±19.9, p<0.05 as opposed to tempol: 135.0±19.9 vs. tempol + H2O2: 125.3±18.6 pmol/mg/hr) and was abolished (p<0.05) by either an inhibitor of HO or in RIA from animals treated with HO-1& 2 AS-ODN. These results demonstrate that H2O2 has antioxidant-modifiable pleotropic vascular effects brought about by enhanced TP sensitivity to constrictor agonist(s) or dilatory HO-derived products.
- © 2012 by American Heart Association, Inc.