D₅dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure

Abstract

Activation of D 1 -like receptors (D 1 and/or D 5 ) induces antioxidant responses; however, the mechanism(s) involved in their antioxidant actions are not known. We hypothesized that stimulation of the D 5 receptor inhibits NADPH oxidase activity, and thus the production of reactive oxygen species (ROS). We investigated this issue in D 5 receptor-deficient (D 5 −/−) and wild-type (D 5 +/+) mice. NADPH oxidase protein expression (gp91 phox , p47 phox , and Nox 4) and activity in kidney and brain, as well as plasma thiobarbituric acid-reactive substances (TBARS) were higher in D 5 −/− than in D 5 +/+ mice. Furthermore, apocynin, an NADPH oxidase inhibitor, normalized blood pressure, renal NADPH oxidase activity, and plasma TBARS in D 5 −/− mice. In HEK-293 cells that heterologously expressed human D 5 receptor, its agonist fenoldopam decreased NADPH oxidase activity, expression of one of its subunits (gp91 phox ), and ROS production. The inhibitory effect of the D 5 receptor activation on NADPH oxidase activity was independent of cAMP/PKA but was partially dependent on phospholipase D2. The ability of D 5 receptor stimulation to decrease ROS production may explain, in part, the antihypertensive action of D 5 receptor activation.