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Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, Direction des Sciences du Vivant-Commissariat a l'Énergie Atomique, 91406 Orsay, France
Chronic hypoxia
induces an overall sympathetic hyperactivation associated with a
myocardial 
-receptor desensitization. The mechanisms
involved in this desensitization were evaluated in 32 male Wistar rats
kept in a hypobaric pressure chamber
(PO2 = 40 Torr, atmospheric pressure = 450 Torr) for 5 days. In hypoxic compared with normoxic conditions,
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
measured by [3H]NE was
decreased by 32% in the right ventricle (RV) and by 35% in the left
ventricle (LV), and
[3H]mazindol in vitro
binding showed a decrease in uptake-1 carrier protein density by 38%
in the RV and by 41% in the LV. In vitro binding assays with
[3H]CGP-12177 indicate
-adrenoceptor density reduced by 40% in the RV and by 32% in the
LV, and this was due to reduced
1-subtype fraction (competition
binding experiments with practolol). Hypoxia reduced the production of
cAMP induced by isoproterenol (36% decrease in the RV and 41%
decrease in the LV), 5'-guanylylimododiphosphate (40% decrease
in the RV and 42% decrease in the LV), and forskolin (39% decrease in
the RV and 41% decrease in the LV) but did not alter the effect of
MnCl2 and NaF. Quantitation of
inhibitory G-protein 
-subunit by immunochemical analysis showed a
46% increase in the cardiac-specific isoform
Gi
2 in
hypoxic hearts. The present data demonstrate that in rats 5-day hypoxia
leads to changes in pre- and postsynaptic myocardial adrenergic
function. The myocardial desensitization associated with both a
reduction in externalized 1-adrenoceptor and an increase
in inhibitory G-protein subunit may be caused by increased synaptic NE
levels due to impaired uptake-1 system.
adrenergic neurotransmitters; uptake 1; adenylate cyclase
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