G protein-coupled receptor (GPCR) kinases (GRKs) regulate the sensitivity of GPCRs, including dopamine receptors. The GRK4 locus is linked to, and some of its polymorphisms are associated with, human essential hypertension. Transgenic mice overexpressing human (h) GRK4 A142V on a mixed genetic background (C57BL/6J and SJL/J) have impaired renal D1R function and increased blood pressure. We now report that hGRK4 A142V transgenic mice, in C57BL/6J background, are hypertensive and have higher blood pressures than hGRK4 wild-type transgenic and non-transgenic mice. The hypertensive phenotype is stable because blood pressures in transgenic founders and F6 offspring are similarly increased. To determine whether the hypertension is associated with increased production of reactive oxygen species (ROS), we measured renal NADPH oxidase (Nox2 and Nox 4) and heme-oxygenase (HO-1 and HO-2) protein expressions and urinary excretion of 8-isoprostane and compared the effect of Tempol on blood pressure in hGRK4 A142V transgenic mice and D₅R knockout (D_5-/-) mice in which hypertension is mediated by increased ROS. The expressions of Nox isoforms and HO-2, and the urinary excretion of 8-isoprostane, were similar in hGRK4 A142V transgenic mice and their controls. HO-1 expression was increased in hGRK4 A142V relative to hGRK4 wild-type transgenic mice. In contrast to the hypotensive effect of Tempol in D_5-/- mice, it had no effect in hGRK4 A142V transgenic mice. We conclude that the elevated blood pressure of hGRK4 A142V transgenic mice is due mainly to the effect of hGRK4 A142V transgene acting via D₁R and increased ROS production is not a contributor.