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

1 The effects of chronic hypoxia on α 1 ‐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 (pD 2 : 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 α 1 ‐adrenoceptors was increased from 0.54±0.06 μ M in control animals to 1.35±0.14 μ M 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 μ M ) 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 α 1 ‐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 [ 3 H]‐prazosin binding affinity. There was a linear correlation of the maximum contractions to noradrenaline and α 1 ‐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 α 1 ‐adrenoceptor density and the agonist binding affinity.British Journal of Pharmacology (1998) 125 , 136–142; doi: 10.1038/sj.bjp.0702022