D5 dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure

D-5 dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure. Am J Physiol Regul Integr Comp Physiol 290: R96 - R104, 2006; doi: 10.1152/ ajpregu. 00434.2005. - 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 D5 receptor, its agonist fenoldopam decreased NADPH oxidase activity, expression of one of its subunits (gp91(phox)), and ROS production. The inhibitory effect of the D5 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.