title: Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.
abstract: The goal of this study was to determine the mechanism of beta-adrenergic receptor desensitization after chronic elevation of circulating NE levels. Osmotic minipumps containing either NE or saline were implanted subcutaneously in dogs for 3-4 wk. Physiologic desensitization to isoproterenol was confirmed in conscious dogs, i.e., left ventricular dP/dt increased in response to isoproterenol (0.4 micrograms/kg per min) by 5,625 +/- 731 mmHg/s in control dogs with saline pumps, and significantly less, P less than 0.01, by 2,093 +/- 263 mmHg/s in dogs with NE pumps. Myocardial beta-adrenergic receptor density as determined with 125I-cyanopindolol binding was 49% higher (p less than 0.05) in the NE pump group. However, beta-adrenergic receptor agonist binding with isoproterenol demonstrated a significant shift into the low affinity state for the animals with NE pumps. Basal, GTP plus isoproterenol, 5'-guanylylimidodiphosphate, sodium fluoride, and forskolin-stimulated adenylate cyclase activity in the NE pump group were significantly depressed (P less than 0.05) by amounts ranging from 20 to 40%. The functional activity of the guanine nucleotide binding protein Gs was also reduced (P less than 0.05) in animals with NE pumps. Thus, the process of desensitization in response to chronic elevation of NE levels in intact, normal dogs does not involve a decrease in beta-adrenergic receptor density. Rather, it is characterized by reduced adenylate cyclase activation and uncoupling of the beta-adrenergic receptor in association with decreased activity of the GTP-coupling protein Gs.
authors.affiliation: Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston 02114.
authors.forename: D E
authors.initials: DE
authors.lastname: Vatner
authors.forename: S F
authors.initials: SF
authors.lastname: Vatner
authors.forename: J
authors.initials: J
authors.lastname: Nejima
authors.forename: N
authors.initials: N
authors.lastname: Uemura
authors.forename: E E
authors.initials: EE
authors.lastname: Susanni
authors.forename: T H
authors.initials: TH
authors.lastname: Hintze
authors.forename: C J
authors.initials: CJ
authors.lastname: Homcy
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D004285:Dogs; D004361:Drug Tolerance; D019204:GTP-Binding Proteins / Q000502:physiology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006352:Heart Ventricles / Q000033:anatomy & histology; D006439:Hemodynamics / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D009638:Norepinephrine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D009929:Organ Size; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D012969:Sodium Fluoride / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D016276:Ventricular Function
chemical_list: D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; C047975:cyanopindolol; D006160:Guanosine Triphosphate; D012969:Sodium Fluoride; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol; D009638:Norepinephrine