EFFECTS OF 5-DAY HYPOXIA ON CARDIAC ADRENERGIC NEUROTRANSMISSION IN RATS

Chronic hypoxia induces an overall sympathetic hyperactivation associa ted with a myocardial beta-receptor desensitization. The mechanisms in volved in this desensitization were evaluated in 32 male Wistar rats k ept in a hypobaric pressure chamber (Po-2 = 40 Torr, atmospheric press ure = 450 Torr) for 5 days. In hypoxic compared with normoxic conditio ns, plasma norepinephrine (NE) levels were higher(2.1 +/- 0.7 vs. 0.6 +/- 0.2 ng/ml) with no difference in the plasma epinephrine levels (2. 2 +/- 0.7 vs. 1.8 +/- 0.3 ng/ml). In hypoxia neuronal NE uptake measur ed by [H-3]NE was decreased by 32% in the right ventricle (RV) and by 35% in the left ventricle (LV), and [H-3]mazindol in vitro binding sho wed a decrease in uptake-1 carrier protein density by 38% in the RV an d by 41% in the LV. In vitro binding assays with [H-3]CGP-12177 indica te beta-adrenoceptor density reduced by 40% in the RV and by 32% in th e LV, and this was due to reduced beta(1)-subtype fraction (competitio n binding experiments with practolol). Hypoxia reduced the production of cAMP induced by isoproterenol (36% decrease in the RV and 41% decre ase in the LV), 5'-guanylylimododiphosphate (40% decrease in the RV an d 42% decrease in the LV), and forskolin (39% decrease in the RV and 4 1% decrease in the LV) but did not alter the effect of MnCl2 and NaF. Quantitation of inhibitory G-protein alpha-subunit by immunochemical a nalysis showed a 46% increase in the cardiac-specific isoform Gi(alpha 2) in hypoxic hearts. The present data demonstrate that in rats 5-day hypoxia leads to changes in pre- and postsynaptic myocardial adrenerg ic function. The myocardial desensitization associated with both a red uction in externalized beta(1)-adrenoceptor and an increase in inhibit ory G-protein subunit may be caused by increased synaptic NE levels du e to impaired uptake-1 system.