Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients.
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.
Izzo
Raffaele
R
Dipartimento di Medicina Clinica Scienze Cardiovascolari ed Immunologiche, Federico II University of Naples, Italy.
Cipolletta
Ersilia
E
Ciccarelli
Michele
M
Campanile
Alfonso
A
Santulli
Gaetano
G
Palumbo
Gianluigi
G
Vasta
Antonio
A
Formisano
Salvatore
S
Trimarco
Bruno
B
Iaccarino
Guido
G
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
D011943:Receptors, Adrenergic, beta; D006493:Heparin; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D007545:Isoproterenol