Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion.
Norepinephrine (NE)-induced desensitization of the adrenergic receptor pathway may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanisms 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 (LV) hypertrophy, whereas hypoxia resulted in right (RV) hypertrophy, the selective hypertrophic response of hypoxia and NE was also evaluated. In hypoxia, alpha(1)-adrenergic receptors (AR) density increased by 35%, only in the 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 apparent affinity. Stimulated maximal activity of adenylate cyclase decreased in both ventricles with hypoxia (LV, 41%; RV, 36%) but only in LV with NE infusion (42%). The functional activities of G(i) and G(s) proteins in cardiac membranes were assessed by incubation with pertussis toxin (PT) and cholera toxin (CT). PT had an important effect in abolishing the decrease in isoproterenol-induced stimulation of adenylate cyclase in hypoxia; however, pretreatment of the NE ventricle cells with PT failed to restore this stimulation. Although CT attenuates the basal activity of adenylate cyclase in the RV and the isoproterenol-stimulated activity in the LV, pretreatment of NE or hypoxic cardiac membranes with CT has a less clear effect on the adenylate cyclase pathway. The present study has demonstrated that 1) NE does not mimic the effects of hypoxia at the cellular level, i.e., hypoxia has specific 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).
León-Velarde
F
F
Laboratoire Réponses cellulaires et fonctionnelles à l'hypoxie, Association pour la Recherche en Physiologie de l'Environuement, Faculté de Médecine, Université Paris XIII, 93017 Bobigny, France.
Bourin
M C
MC
Germack
R
R
Mohammadi
K
K
Crozatier
B
B
Richalet
J P
JP
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D002908:Chronic Disease; D005576:Colforsin / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006339:Heart Rate; D006352:Heart Ventricles / Q000201:enzymology / Q000294:innervation / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology*; D037342:Pertussis Toxin; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012969:Sodium Fluoride / Q000494:pharmacology; D013566:Sympathomimetics / Q000494:pharmacology*; D014316:Tritium; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D015430:Weight Gain
D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D013566:Sympathomimetics; D010566:Virulence Factors, Bordetella; D014316:Tritium; D005576:Colforsin; D006160:Guanosine Triphosphate; D012969:Sodium Fluoride; D002772:Cholera Toxin; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; C033394:CGP 12177; D009638:Norepinephrine