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 (B_max: 325 ± 35 → 378 ± 18 fmol/mg protein), the dissociation constant (K_d) of InsP₃ to its receptors was significantly increased (K_d: 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.