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

1. The effects of chronic hypoxia on alpha1-adrenoceptor-mediated contractions were investigated in foetal umbilical vessels obtained from near-term (approximately 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 KCI were not affected by chronic hypoxia. 3. In umbilical vein, the apparent dissociation constant (KA) of noradrenaline to alpha1-adrenoceptors was increased from 0.54+/-0.06 microM in control animals to 1.35+/-0.14 microM 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 GTPgammaS (100 microM) 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 (pKi: 7.80+/-0.17 vs 7.20+/-0.16). 4. Chronic hypoxia significantly decreased alpha1-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 alpha1-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 alpha1-adrenoceptor density and the agonist binding affinity.