Effects of long-term high-altitude hypoxemia on alpha(1)-adrenergic receptors in the ovine uterine artery

To elucidate the effects of chronic hypoxia on alpha(1)-adrenergic receptor-mediated contractions of the uterine artery, we examined norepinephrine-induced contractions in tissues obtained from near-term (similar to 140 days gestation) pregnant ewes maintained near sea level(similar to 300 m) and at high altitude (3,820 m) from 30 days gestation. Compared with the sea-level controls, contractions induced by norepinephrine in main and fourth-branch uterine arteries of the high-altitude animals were significantly depressed. The norepinephrine dose-response curves were shifted to the right and the concentrations at which 50% of the maximal response was attained were increased 3.2- and 5.7-fold in the main and fourth-branch uterine arteries, respectively. The maximal responses were decreased 22 and 36% in main and fourth-branch uterine arteries, respectively. The dissociation constants of norepinephrine were increased from 0.77 to 1.53 mu M and from 0.72 to 2.05 mu M in main and fourth-branch uterine arteries, respectively. Radioligand binding studies with [H-3]prazosin revealed a decrease in the density of alpha(1)-adrenergic receptors in both vessels from high-altitude animals. We conclude that chronic hypoxia depresses alpha(1)-adrenergic receptor-induced contractions of conduit- and resistance-type uterine arteries. The depressed contractility is mediated, at least in part, by decreases in alpha(1)-adrenergic receptor density and agonist binding affinity.