Effects of hypoxia/reoxygenation on aortic vasoconstrictor responsiveness.
The purpose of the present study was to assess the effects of hypoxia/reoxygenation (H/R) on vasoconstrictor effectiveness, in vitro. Aortic rings were obtained from rats and placed on isometric force transducers in oxygenated Krebs buffer (95% O2/5% CO2, PO2 > 500 torr). Cumulative concentration/effect relationships to norepinephrine, G-protein activation by AlICl3/NaF, depolarization by KCl or BayK-8644, mobilization of intracellular calcium by caffeine, and protein kinase C activation by l-indolactam were evaluated. Hypoxia (PO2 < 5 torr) was induced by rapidly bubbling the Krebs buffer with 95% N2/5% CO2 for 15 min. Vessel rings were reoxygenated for 30 min and concentration/effect relationships reevaluated. The dissociation constant (KA) for norepinephrine was also determined. The pD2 for maximal norepinephrine responsiveness decreased from 7.7 to 7.3 following H/R. Maximal tension generation was significantly decreased following H/R. Endothelium denudation or nitric oxide synthesis inhibition did not prevent the right shift in norepinephrine concentration/effect relationship caused by H/R. The combination of superoxide dismutase and catalase prevented the dextral shift in the concentration/effect curve. The dissociation constant for norepinephrine increased from 0.16 to 0.32 microM following H/R, suggesting decreased affinity of adrenergic receptor. H/R did not alter AlCl3/NaF, KCl, BayK-8644 or l-indolactam-induced vasoconstriction. Caffeine-induced vasoconstriction was significantly impaired following H/R, suggesting that release of calcium from the sarcoplasmic reticulum is compromised. These results suggest that H/R leads to an endothelium independent, oxidant-mediated decrease in vascular norepinephrine responsiveness that may be related to defects in the mobilization of intracellular calcium from the sarcoplasmic reticulum pool.
Gao
H
H
Department of Physiology and Biophysics, Louisiana State University Medical Center, Shreveport, USA.
Korthuis
R J
RJ
Benoit
J N
JN
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D005609:Free Radicals; D017382:Reactive Oxygen Species; D002110:Caffeine; D002374:Catalase; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine