G protein-coupled receptor (GPCR) kinase 2 (GRK2) is a serine/theorinine kinase that phosphorylates and desensitizes agonist-bound GPCRs. GRK2 is increased in expression and activity in lymphocytes and vascular smooth muscle (VSM) in human hypertension and animal models of the disease. Inhibition of GRK2 using the carboxyl-terminal portion of the protein (GRK2ct) has been an effective tool to restore compromised -adrenergic receptor (AR) function in heart failure and improve outcome. A well-characterized dysfunction in hypertension is attenuation of AR-mediated vasodilation. Therefore, we tested the role of inhibiting GRK2 using the GRK2ct or VSM-selective GRK2 gene ablation in a renal artery stenosis model of elevated BP (two kidney, one clip; 2K1C). 2K1C resulted in a 30% increase in conscious BP, a 3-fold increase in plasma norepinephrine levels and a 50% increase in VSM GRK2 mRNA levels. BP remained increased despite VSM-specific GRK2 inhibition, by either GRK2 knockout (GRK2KO) or peptide inhibition (GRK2ct). Although AR-mediated dilation in vivo and in situ was enhanced, ₁AR-mediated vasoconstriction was also increased. Further pharmacological studies using ₁AR antagonists revealed that GRK2 inhibition of expression (GRK2KO) or activity (GRK2ct) enhanced _1DAR vasoconstriction. This is the first study to suggest that VSM _1DARs are a GRK2 substrate in vivo.