PT  - JOURNAL ARTICLE
AU  - Xiang-Qun Hu
AU  - Shumei Yang
AU  - William J. Pearce
AU  - Lawrence D. Longo
AU  - Lubo Zhang
TI  - Effect of Chronic Hypoxia on <em>Alpha</em>-1 Adrenoceptor-Mediated Inositol 1,4,5-Trisphosphate Signaling in Ovine Uterine Artery
DP  - 1999 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 977--983
VI  - 288
IP  - 3
4099  - http://jpet.aspetjournals.org/content/288/3/977.short
4100  - http://jpet.aspetjournals.org/content/288/3/977.full
SO  - J Pharmacol Exp Ther1999 Mar 01; 288
AB  - The present study examined the effect of chronic hypoxia on coupling efficiency of alpha-1 adrenoceptors to inositol 1,4,5-trisphosphate (InsP3) signaling in ovine uterine artery. Chronic hypoxia did not change the time course of InsP3 formation, but significantly decreased the potency (pD2: 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 InsP3 synthesis. The coupling efficiency of alpha-1 adrenoceptors to InsP3 synthesis (picomoles InsP3 per femtomoles receptor) was decreased 45% by chronic hypoxia. In addition, simultaneous measurement of norepinephrine-induced contractions and InsP3 synthesis indicated that for a given amount of InsP3 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 InsP3). InsP3 receptors were characterized using radioligand binding techniques. Although the density of InsP3 receptors was not changed by chronic hypoxia (Bmax: 325 ± 35 → 378 ± 18 fmol/mg protein), the dissociation constant (Kd) of InsP3 to its receptors was significantly increased (Kd: 5.20 ± 0.40 → 7.81 ± 0.34 nM). Analysis of InsP3receptor occupancy-tension development relationship indicated no difference in intrinsic ability of the InsP3-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 InsP3synthesis in the uterine artery. In addition, the tissue contractile sensitivity to InsP3 is reduced, which is mediated predominantly by a decrease in InsP3 binding affinity to InsP3 receptors. The American Society for Pharmacology and Experimental Therapeutics