Effect of Chronic Hypoxia on Alpha-1 Adrenoceptor-Mediated Inositol 1,4,5-Trisphosphate Signaling in Ovine Uterine Artery

• Published in: The Journal of pharmacology and experimental therapeutics 1999-03, Vol.288 (3), p.977-983
• Main Authors: Hu, X Q, Yang, S, Pearce, W J, Longo, L D, Zhang, L
• Format: Article
• Language: English
• Subjects: Animals; Arteries - metabolism; Calcium Channels - metabolism; Female; Hypoxia - metabolism; Inositol 1,4,5-Trisphosphate - biosynthesis; Inositol 1,4,5-Trisphosphate - metabolism; Inositol 1,4,5-Trisphosphate Receptors; Norepinephrine; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; Sheep; Signal Transduction; Uterus - blood supply
• ISSN: 0022-3565; 1521-0103

The present study examined the effect of chronic hypoxia on coupling efficiency of alpha -1 adrenoceptors to inositol 1,4,5-trisphosphate (InsP 3 ) signaling in ovine uterine artery. Chronic hypoxia did not change the time course of InsP 3 formation, but significantly decreased the potency (pD 2 : 6.17 ± 0.09 → 5.26 ± 0.12) and the maximal response (220.7 ± 21.7 → 147.7 ± 15.3 pmol/mg protein) of norepinephrine-induced InsP 3 synthesis. The coupling efficiency of alpha -1 adrenoceptors to InsP 3 synthesis (picomoles InsP 3 per femtomoles receptor) was decreased 45% by chronic hypoxia. In addition, simultaneous measurement of norepinephrine-induced contractions and InsP 3 synthesis indicated that for a given amount of InsP 3 generated, the contractile force of the uterine artery was significantly less in chronically hypoxic than in control tissues (0.27 ± 0.01 versus 0.35 ± 0.02 g tension/pmol InsP 3 ). InsP 3 receptors were characterized using radioligand binding techniques. Although the density of InsP 3 receptors was not changed by chronic hypoxia ( B max : 325 ± 35 → 378 ± 18 fmol/mg protein), the dissociation constant ( K d ) of InsP 3 to its receptors was significantly increased ( K d : 5.20 ± 0.40 → 7.81 ± 0.34 nM). Analysis of InsP 3 receptor occupancy-tension development relationship indicated no difference in intrinsic ability of the InsP 3 -receptor complex in eliciting contractions between the control and hypoxic tissues. Our results suggest that chronic hypoxia attenuates coupling efficiency of alpha -1 adrenoceptors to InsP 3 synthesis in the uterine artery. In addition, the tissue contractile sensitivity to InsP 3 is reduced, which is mediated predominantly by a decrease in InsP 3 binding affinity to InsP 3 receptors.