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Effect of chronic hypoxia on alpha-1 adrenoceptor-mediated inositol 1,4,5-trisphosphate signaling in ovine uterine artery.

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 InsP3 receptor 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 InsP3 synthesis 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.
AuthorsX Q Hu, S Yang, W J Pearce, L D Longo, L Zhang
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 288 Issue 3 Pg. 977-83 (Mar 1999) ISSN: 0022-3565 [Print] United States
PMID10027834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Calcium Channels
  • Inositol 1,4,5-Trisphosphate Receptors
  • Receptors, Adrenergic, alpha-1
  • Receptors, Cytoplasmic and Nuclear
  • Inositol 1,4,5-Trisphosphate
  • Norepinephrine
Topics
  • Animals
  • Arteries (metabolism)
  • Calcium Channels (metabolism)
  • Female
  • Hypoxia (metabolism)
  • Inositol 1,4,5-Trisphosphate (biosynthesis, metabolism)
  • Inositol 1,4,5-Trisphosphate Receptors
  • Norepinephrine
  • Receptors, Adrenergic, alpha-1 (metabolism)
  • Receptors, Cytoplasmic and Nuclear (metabolism)
  • Sheep
  • Signal Transduction
  • Uterus (blood supply)

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