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.
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Authors | X Q Hu, S Yang, W J Pearce, L D Longo, L Zhang |
Journal | The 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 |
PMID | 10027834
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Calcium Channels
- Inositol 1,4,5-Trisphosphate Receptors
- Receptors, Adrenergic, alpha-1
- Receptors, Cytoplasmic and Nuclear
- Inositol 1,4,5-Trisphosphate
- Norepinephrine
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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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