Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion

Norepinephrine (NE)-induced desensitization of the adrenergic receptor path way may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanis ms involved in this desensitization were evaluated in male Wistar rats kept in a hypobaric chamber (380 Torr) and in rats infused with NE (0.3 mg.kg(- 1).h(-1)) for 21 days. Because NE treatment resulted in left ventricular (L V) hypertrophy, whereas hypoxia resulted in right (RV) hypertrophy, the sel ective hypertrophic response of hypoxia and NE was also evaluated. In hypox ia, alpha (1)-adrenergic receptors (AR) density increased by 35%, only in t he LV. In NE, alpha (1)-AR density decreased by 43% in the RV. Both hypoxia and NE decreased beta -AR density. No difference was found in receptor app arent affinity. Stimulated maximal activity of adenylate cyclase decreased in both ventricles with hypoxia (LV, 41%; RV, 36%) but only in LV with NE i nfusion (42%). The functional activities of G(i) and G(s) proteins in cardi ac membranes were assessed by incubation with pertussis toxin (PT) and chol era toxin (CT). PT had an important effect in abolishing the decrease in is oproterenol-induced stimulation of adenylate cyclase in hypoxia; however, p retreatment of the NE ventricle cells with PT failed to restore this stimul ation. Although CT attenuates the basal activity of adenylate cyclase in th e RV and the isoproterenol-stimulated activity in the LV, pretreatment of N E or hypoxic cardiac membranes with CT has a less clear effect on the adeny late cyclase pathway. The present study has demonstrated that 1) NE does no t mimic the effects of hypoxia at the cellular level, i.e., hypoxia has spe cific effects on cardiac adrenergic signaling, and 2) changes in alpha- and beta -adrenergic pathways are chamber specific and may depend on the type of stimulation (hypoxia or adrenergic).