title: Chronic hypoxia increases MCA contractile response to U-46619 by reducing NO production and/or activity.
abstract: Chronic hypoxia alters contractile sensitivity of isolated arteries to alpha-adrenergic stimulation and other agonists. However, most studies have been performed in thoracic aortas or other large vessels making little contribution to vascular resistance in their respective circulations. To determine the effect of chronic hypoxia on the vasoconstrictor response in a small, resistance-sized vessel, we studied second and third generation middle cerebral arteries (MCA; approximately 75-microm internal diameter before mounting). MCA were isolated from normoxic (inspired oxygen = 125 Torr) and hypoxic (8 wk at 3,960 m; inspired oxygen = 90 Torr) guinea pigs, and their vasoconstrictor responses were determined to the thromboxane mimetic U-46619 by using dual-pipette video microscopy. Arteries from hypoxic animals had greater contractile sensitivity to U-46619 compared with those of the normoxic animals (-log EC50 = 7.86 +/- 0.11 vs. 7.62 +/- 0.06, respectively, P < 0.05). Addition of the nitric oxide (NO) inhibitor nitro-L-arginine (200 microM) to the vessel bath eliminated the differences in contractile sensitivity between the MCA from the normoxic and chronically hypoxic groups. Supplementation with L-arginine in the drinking water sufficient to raise plasma L-arginine levels 41% reduced MCA contractile sensitivity to U-46619 in the normoxic group (-log EC50 = 7.22 +/- 0.31, P < 0.05 compared with the nonsupplemented normoxic group) but not in the chronically hypoxic group. These results show that chronic hypoxia increases the sensitivity of the MCA to the vasoconstrictor U-46619, likely because of a reduction in NO production and/or activity.
authors.affiliation: Women's Health Research Center, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: A Hugo
authors.initials: AH
authors.lastname: Sillau
authors.forename: Robert E
authors.initials: RE
authors.lastname: McCullough
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dyckes
authors.forename: Margueritte M
authors.initials: MM
authors.lastname: White
authors.forename: Lorna G
authors.initials: LG
authors.lastname: Moore
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000097:blood / Q000494:pharmacology; D001273:Atmosphere Exposure Chambers; D002908:Chronic Disease; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001120:Arginine