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Research ArticleArticle

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

Xiang-Qun Hu, Shumei Yang, William J. Pearce, Lawrence D. Longo and Lubo Zhang
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 977-983;
Xiang-Qun Hu
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Shumei Yang
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William J. Pearce
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Lawrence D. Longo
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Lubo Zhang
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Lubo Zhang, Center for Perinatal Biology, Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350. E-mail:lzhang{at}ccmail.llu.edu

  • ↵1 This work was supported in part by National Institutes of Health Grants HL-54094, HL-57787 (to L.Z.), HD-31226 (to L.D.L.), HL-54120 (to W.J.P.), a Grant-in-Aid from the American Heart Association 96007560 (to L.Z.), and by Loma Linda University School of Medicine.

  • Abbreviations:
    InsP3, inositol 1
    4,5-trisphosphate
    TCA
    trichloroacetic acid
    cGMP
    cyclic GMP
    • Received June 30, 1998.
    • Accepted October 5, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

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

Xiang-Qun Hu, Shumei Yang, William J. Pearce, Lawrence D. Longo and Lubo Zhang
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 977-983;

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Research ArticleArticle

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

Xiang-Qun Hu, Shumei Yang, William J. Pearce, Lawrence D. Longo and Lubo Zhang
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 977-983;
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