Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats.
Chronic hypoxia induces an overall sympathetic hyperactivation associated with a myocardial beta-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 beta-adrenoceptor density reduced by 40% in the RV and by 32% in the LV, and this was due to reduced beta1-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 alpha-subunit by immunochemical analysis showed a 46% increase in the cardiac-specific isoform Gialpha2 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 beta1-adrenoceptor and an increase in inhibitory G-protein subunit may be caused by increased synaptic NE levels due to impaired uptake-1 system.
Mardon
K
K
Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, Direction des Sciences du Vivant-Commissariat a l'Energie Atomique, 91406 Orsay, France.
Merlet
P
P
Syrota
A
A
Mazière
B
B
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001273:Atmosphere Exposure Chambers; D001667:Binding, Competitive / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D004837:Epinephrine / Q000097:blood; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000294:innervation / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D009929:Organ Size / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D009638:Norepinephrine; D004837:Epinephrine