title: Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients.
abstract: Increased levels of G protein coupled receptor kinase GRK2 appear to participate in hypertension presumably through the desensitization of beta adrenergic receptors (betaARs) that mediate vasodilatation. There are contrasting data on the occurrence of betaAR desensitization in the vasculature, we therefore investigated betaAR vasodilatation and desensitization in normotensives and in hypertensive humans. In blood lymphocytes, we assessed betaAR signaling and GRK2 expression and found betaAR signaling alterations and, consistent with desensitization, ncreased GRK2 levels in hypertensives. We studied in vivo vasodilatation to the betaAR agonist isoproterenol (ISO) injected in the brachia artery in control conditions and during the concomitant infusion of heparin, a known in vitro nonspecific GRK inhibitor. ISO induced a dose-dependent vasorelaxation that was attenuated in hypertensives indicating a loss of betaAR signaling. Intra-arterial infusion of heparin nhibited lymphocyte GRK2 activity and prevented desensitization of betaAR vasodilatation in normotensives. In hypertensives, heparin restored vasodilatation to ISO, to levels observed in normotensives. Our results suggest that betaAR desensitization does indeed occur at the vascular levels in vivo, and that heparin by acting as a GRK inhibitor prevents this in normotensives and restores impaired betaAR vasodilation in hypertensives. We conclude that desensitization participates to impaired betaAR vasodilation in hypertension.
authors.affiliation: Dipartimento di Medicina Clinica Scienze Cardiovascolari ed Immunologiche, Federico II University of Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Izzo
authors.forename: Ersilia
authors.initials: E
authors.lastname: Cipolletta
authors.forename: Michele
authors.initials: M
authors.lastname: Ciccarelli
authors.forename: Alfonso
authors.initials: A
authors.lastname: Campanile
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Palumbo
authors.forename: Antonio
authors.initials: A
authors.lastname: Vasta
authors.forename: Salvatore
authors.initials: S
authors.lastname: Formisano
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
mesh_terms: D000328:Adult; D005260:Female; D005542:Forearm / Q000098:blood supply; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012039:Regional Blood Flow; D015398:Signal Transduction; D014664:Vasodilation
chemical_list: D011943:Receptors, Adrenergic, beta; D006493:Heparin; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D007545:Isoproterenol