Effect of chronic hypoxia on adrenoceptor responses of ovine foetal umbilical vessels

Abstract

1. The effects of chronic hypoxia on α1-adrenoceptor-mediated contractions were investigated in foetal umbilical vessels obtained from near-term (~ 140 day gestation) pregnant sheep maintained near sea level (~ 300 m) and at high altitude (3820 m) from 30 day gestation. 2. Chronic hypoxia significantly decreased contractile sensitivity of the umbilical vein to noradrenaline (pD2: 6.22 ± 0.19 vs 5.67 ± 0.09) and reduced the maximum response by 43%. Noradrenaline-induced contraction of the umbilical artery was abolished. In contrast, contractions to KCl were not affected by chronic hypoxia. 3. In umbilical vein, the apparent dissociation constant (K(A)) of noradrenaline to α1-adrenoceptors was increased from 0.54 ± 0.06 μM in control animals to 1.35 ± 0.14 μM in chronically hypoxic animals. In accordance, radioligand binding of agonist showed high and low affinity binding sites for noradrenaline in both normoxic and chronically hypoxic tissues. Addition of GTPγS (100 μM) abolished apparent high affinity binding sites. Whereas proportional binding sites were not changed by chronic hypoxia, the apparent high affinity of noradrenaline was significantly decreased (pK(i): 7.80 ± 0.17 vs 7.20 ± 0.16). 4. Chronic hypoxia significantly decreased α1-adrenoceptor density (fmol mg protein-1) in umbilical vein (24.6 ± 3.2 vs 12.3 ± 3.1) and the artery (7.1 ± 0.4 vs 3.1 ± 0.9) with no change in [3H]-prazosin binding affinity. There was a linear correlation of the maximum contractions to noradrenaline and α1-adrenoceptor density. 5. We conclude that chronically hypoxic-induced depression in contractions of ovine foetal umbilical vessels to noradrenaline is mediated predominantly by decreases in α1-adrenoceptor density and the agonist binding affinity.