Enhanced GRK2 expression and desensitization of βAr vasodilatation in hypertensive patients

Abstract

Increased levels of G protein coupled receptor kinase GRK2 appear to participate in hypertension presumably through the desensitization of β adrenergic receptors (βARs) that mediate vasodilatation. There are contrasting data on the occurrence of βAR desensitization in the vasculature, we therefore investigated βAR vasodilatation and desensitization in normotensives and in hypertensive humans. In blood lymphocytes, we assessed βAR signaling and GRK2 expression and found βAR signaling alterations and, consistent with desensitization, ncreased GRK2 levels in hypertensives. We studied in vivo vasodilatation to the βAR 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 βAR signaling. Intra-arterial infusion of heparin nhibited lymphocyte GRK2 activity and prevented desensitization of βAR vasodilatation in normotensives. In hypertensives, heparin restored vasodilatation to ISO, to levels observed in normotensives. Our results suggest that βAR 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 βAR vasodilation in hypertensives. We conclude that desensitization participates to impaired βAR vasodilation in hypertension. © 2008 Wiley Periodicals, Inc.