Tags

Type your tag names separated by a space and hit enter

Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta.
J Pharmacol Exp Ther. 2005 Dec; 315(3):1058-64.JP

Abstract

Experiments were designed to test the hypothesis that elevated levels of endothelin 1 (ET-1) in the vasculature activate NADPH oxidase and/or uncoupled nitric-oxide synthase (NOS), resulting in O2-* production, and mediate increased constriction. Rat aortic rings were incubated with ET-1 or vehicle in the presence and absence of superoxide dismutase (SOD), ebselen (glutathione peroxidase mimetic), apocynin (NADPH oxidase inhibitor), L-NAME (Nomega-nitro-L-arginine methyl ester) (NOS inhibitor), tetrahydrobiopterin (BH4) (NOS cofactor), or selective ETA and ETB receptor antagonists (BQ-123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] and A-192621 [[2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]], respectively). O2-* production was monitored by oxidized dihydroethidine staining and/or lucigenin chemiluminescence. ET-1 significantly increased O2-* production compared with vehicle. SOD, ebselen, and apocynin inhibited the ET-1-induced increase in O2-* in intact and endothelium-denuded aorta. L-NAME and BH4 inhibited the ET-1-induced increase in O2-* in intact tissue, whereas these two compounds had no effect on ET-1-induced O2-* in endothelium-denuded aorta. Preincubation with BQ-123 or A-192621, individually, had no effect on ET-1-induced O2-*; however combining both antagonists inhibited the ET-1-stimulated increase in O2-*. Rat aortic rings were incubated with ET-1 or vehicle in the presence or absence of sepiapterin (BH4 synthesis substrate) or apocynin and mounted on wire myographs to determine isometric force generation in response to increasing KCl concentrations. ET-1 increased the contractile response to KCl compared with vehicle. Treatment with either sepiapterin or apocynin attenuated the ET-1-mediated increase with no effect of sepiapterin or apocynin alone. These data support the hypothesis that ET-1 increases vascular tone, in part, through ETA/ETB receptor activation of O2-* production from NADPH oxidase and NOS uncoupling.

Authors+Show Affiliations

Vascular Biology Center, Medical College of Georgia, CB-3213, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16144972

Citation

Loomis, E Dabbs, et al. "Endothelin Mediates Superoxide Production and Vasoconstriction Through Activation of NADPH Oxidase and Uncoupled Nitric-oxide Synthase in the Rat Aorta." The Journal of Pharmacology and Experimental Therapeutics, vol. 315, no. 3, 2005, pp. 1058-64.
Loomis ED, Sullivan JC, Osmond DA, et al. Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther. 2005;315(3):1058-64.
Loomis, E. D., Sullivan, J. C., Osmond, D. A., Pollock, D. M., & Pollock, J. S. (2005). Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. The Journal of Pharmacology and Experimental Therapeutics, 315(3), 1058-64.
Loomis ED, et al. Endothelin Mediates Superoxide Production and Vasoconstriction Through Activation of NADPH Oxidase and Uncoupled Nitric-oxide Synthase in the Rat Aorta. J Pharmacol Exp Ther. 2005;315(3):1058-64. PubMed PMID: 16144972.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. AU - Loomis,E Dabbs, AU - Sullivan,Jennifer C, AU - Osmond,David A, AU - Pollock,David M, AU - Pollock,Jennifer S, Y1 - 2005/09/06/ PY - 2005/9/8/pubmed PY - 2006/1/24/medline PY - 2005/9/8/entrez SP - 1058 EP - 64 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 315 IS - 3 N2 - Experiments were designed to test the hypothesis that elevated levels of endothelin 1 (ET-1) in the vasculature activate NADPH oxidase and/or uncoupled nitric-oxide synthase (NOS), resulting in O2-* production, and mediate increased constriction. Rat aortic rings were incubated with ET-1 or vehicle in the presence and absence of superoxide dismutase (SOD), ebselen (glutathione peroxidase mimetic), apocynin (NADPH oxidase inhibitor), L-NAME (Nomega-nitro-L-arginine methyl ester) (NOS inhibitor), tetrahydrobiopterin (BH4) (NOS cofactor), or selective ETA and ETB receptor antagonists (BQ-123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] and A-192621 [[2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]], respectively). O2-* production was monitored by oxidized dihydroethidine staining and/or lucigenin chemiluminescence. ET-1 significantly increased O2-* production compared with vehicle. SOD, ebselen, and apocynin inhibited the ET-1-induced increase in O2-* in intact and endothelium-denuded aorta. L-NAME and BH4 inhibited the ET-1-induced increase in O2-* in intact tissue, whereas these two compounds had no effect on ET-1-induced O2-* in endothelium-denuded aorta. Preincubation with BQ-123 or A-192621, individually, had no effect on ET-1-induced O2-*; however combining both antagonists inhibited the ET-1-stimulated increase in O2-*. Rat aortic rings were incubated with ET-1 or vehicle in the presence or absence of sepiapterin (BH4 synthesis substrate) or apocynin and mounted on wire myographs to determine isometric force generation in response to increasing KCl concentrations. ET-1 increased the contractile response to KCl compared with vehicle. Treatment with either sepiapterin or apocynin attenuated the ET-1-mediated increase with no effect of sepiapterin or apocynin alone. These data support the hypothesis that ET-1 increases vascular tone, in part, through ETA/ETB receptor activation of O2-* production from NADPH oxidase and NOS uncoupling. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16144972/Endothelin_mediates_superoxide_production_and_vasoconstriction_through_activation_of_NADPH_oxidase_and_uncoupled_nitric_oxide_synthase_in_the_rat_aorta_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16144972 DB - PRIME DP - Unbound Medicine ER -