Hypoxia-induced downregulation of beta-adrenergic receptors in rat heart.
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.
Kacimi
R
R
Institut National de la Recherche Scientifique, U2, Créteil, France.
Richalet
J P
JP
Corsin
A
A
Abousahl
I
I
Crozatier
B
B
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D006352:Heart Ventricles / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D020120:Iodocyanopindolol; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010869:Pindolol / Q000031:analogs & derivatives; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D002395:Catecholamines; D011941:Receptors, Adrenergic; D020120:Iodocyanopindolol; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D009638:Norepinephrine