Abnormalities in dopamine production and receptor function are present in human essential hypertension and rodent models of genetic hypertension; some dopamine receptor genes and their regulators are in loci linked to hypertension. Disruption of the D5 receptor, one of the two D1-like receptors (D1 and D5), in mice produces hypertension. A multi- receptor cascade causes high blood pressure, via central and peripheral mechanisms, when the D5 receptor is disrupted in mice. This widespread abnormality may be related to the increased generation of reactive oxygen species (ROS). The overall hypothesis is that the D5 receptor, which is constitutively unlike the other dopamine receptors, acts to protect against an increase in ROS is constitutively activated unlike the other dopamine receptors, acts to protect against an increase in ROS formation engendered by impairment of D5 receptor function or by hypertension. A consequence of impaired function of the D5 receptor may be an increase in ROS.
Specific aim 1 will establish the mechanism of increased ROS in D5 knockout mice and cells expressing D5 receptor mutants. We will determine the specific increased ROS in D5 knockout mice and cells expressing D5 receptor mutants. We will determine the specific role of: (a) phospholipase D (PLD) in ROS because phosphatidic acid, produced by PLD, is a potent activator of NADPH activity; (b) a reduced activity of protein kinase A (PKA), which thereby fails to terminate NADPH oxidase activity and hence promotes ongoing ROS production. Preliminary data indicates that a polymorphic D5 receptor that failed to increase cAMP production also increased ROS. Therefore, the failure of D5 receptors to generate cAMP/PKA, and thus, inhibition of NADPH oxidase activity, can increase ROS.
Specific aim 2 will establish the mechanism of the deficient antioxidant activity in D5 knockout mice and cells oxidase dismutase.
Specific aim 3 will test the hypothesis that dopamine, via D1/D5 receptors, serve to counter-act the hypertensinogenic effects of angiotensin II. These studies will determine the interactions between AT1 and D1/D5 receptors in the pathogenesis of hypertension. Single nucleotide polymorphisms of the D5 receptor with decreased ability to stimulate cAMP production are present in the human population, thus studies of D5 receptors may shed light into the pathogenesis of human essential hypertension.
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