Influence of oxygen on endothelium-derived relaxing factor/nitric oxide and K(+)-dependent regulation of vascular tone.
We investigated the effect of hypoxia on acetylcholine (ACh) stimulated, endothelium-derived relaxing factor/nitric oxide (EDRF/NO)-dependent relaxation, and on basal tension in rat aortic rings. ACh (10(-9)-10(-6) M)-mediated relaxation at high [95%, Emax -76.2 +/- 4.5% of phenylephrine (PE)-induced constriction] and normal (20%, Emax -81.2 +/- 3.6%) O2 levels was inhibited by hypoxia (5%, Emax -36.2 +/- 7.2%); residual hypoxic relaxation was blocked by the K+ channel antagonist glibenclamide. To address whether O2 influenced EDRF/NO and K+ channel contributions to basal tone, the effect of stepwise reduction of available O2 (95, 20, 5, and 0%) was studied in intact and endothelial cell (EC)-denuded rings. The effects in these rings were compared with results of the same progressive reduction in O2 in the presence of the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) or glibenclamide (10(-4) M). EC-intact and EC-denuded rings constricted to 0.80 +/- 0.10 and 1.41 +/- 0.15 g, respectively. Reducing O2 to 20% had no significant effect on vascular tension, but 5% caused constriction (p < 0.05) in EC-intact rings (0.90 +/- 0.15 g). This hypoxic vasoconstriction was blocked by L-NAME, but not by glibenclamide, suggesting that hypoxic vasoconstriction was mediated by withdrawal of EDRF/NO. In contrast, EC-denuded rings showed a significant relaxant response at 5% O2. When O2 was then reduced further (95% N2/5% CO2), both EC-intact and EC-denuded rings relaxed, and this relaxation reached baseline tension (0.10 +/- 0.1 g).(ABSTRACT TRUNCATED AT 250 WORDS)
Vallet
B
B
Laboratoire de Pharmacologie, Faculté de Médecine, CHRU de Lille, France.
Winn
M J
MJ
Asante
N K
NK
Cain
S M
SM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D005905:Glyburide / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
D015221:Potassium Channels; D010656:Phenylephrine; D009569:Nitric Oxide; D001120:Arginine; D000109:Acetylcholine; D010100:Oxygen; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester