Hypoxia-induced downregulation of beta-adrenergic receptors in rat heart.

Abstract

To test the desensitization hypothesis of cardiac beta-adrenergic receptors (beta-AR) in chronic hypoxia, the effect of 1, 3, 7, 15, and 21 days of exposure to hypobaric hypoxia (380 Torr) was evaluated in Wistar rats. Exposure to hypoxia for 1-15 days did not induce any change in right and left ventricular beta-AR density (Bmax) determined with [125I]iodocyanopindolol or in antagonist affinity. After 21 days, Bmax decreased by 24% in the left ventricle. In contrast, no change in beta-AR was shown in the right hypertrophied ventricle. Agonist affinity in the left ventricle was not altered, as shown by the analysis of displacement curves of isoproterenol (normoxia 185 +/- 26 nM, hypoxia 170 +/- 11 nM). Moreover, there was no significant decrease in adenylate cyclase activity (pmol.mg-1.min-1) in the left ventricle. In the right ventricle, a 21-day exposure to hypoxia led to a decrease in basal and maximal activity when stimulated by isoproterenol. A decrease in tissue norepinephrine content was observed after 7 days of hypoxia. In conclusion, these data support the beta-AR downregulation hypothesis as one of the mechanisms of myocardial adaptation to high altitude occurring after 2-3 wk of exposure to hypoxia. The regulation pathways of beta-AR may differ between left nonhypertrophied and right hypertrophied ventricles. No evidence of profound abnormality of signal transduction was shown.