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 transduce rs in oxygenated Krebs buffer (95% O-2/5% CO2, PO2 > 500 torr). Cumula tive concentration/effect relationships to norepinephrine, G-protein a ctivation by AlCl3/NaF, depolarization by KCl or BayK-8644, mobilizati on of intracellular calcium by caffeine, and protein kinase C activati on by l-indolactam were evaluated. Hypoxia (PO2 < 5 torr) was induced by rapidly bubbling the Krebs buffer with 95% N-2/5% CO2 for 15 min. V essel rings were reoxygenated for 30 min and concentration/effect rela tionships reevaluated. The dissociation constant (K-A) for norepinephr ine was also determined. The pD(2) for maximal norepinephrine responsi veness decreased from 7.7 to 7.3 following H/R. Maximal tension genera tion was significantly decreased following WR. Endothelium denudation or nitric oxide synthesis inhibition did not prevent the right shift i n norepinephrine concentration/effect relationship caused by WR. The c ombination 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 mu M following WR, suggest ing decreased affinity of adrenergic receptor. WR did not alter AlCl3/ NaF, KCl, BayK-8644 or l-indolactam-induced vasoconstriction. Caffeine -induced vasoconstriction was significantly impaired following WR, sug gesting that release of calcium from the sarcoplasmic reticulum is com promised. These results suggest that WR leads to an endothelium indepe ndent, oxidant-mediated decrease in vascular norepinephrine responsive ness that may be related to defects in the mobilization of intracellul ar calcium from the sarcoplasmic reticulum pool.