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(Hypertension. 2009;54:1077.)
© 2009 American Heart Association, Inc.

Original Articles

Intrarenal Dopamine Attenuates Deoxycorticosterone Acetate/High Salt–Induced Blood Pressure Elevation in Part Through Activation of a Medullary Cyclooxygenase 2 Pathway

From the Nashville Veterans’ Administration Hospital and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Raymond C. Harris, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, TN 37232. E-mail ray.harris{at}vanderbilt.edu

Locally produced dopamine in the renal proximal tubule inhibits salt and fluid reabsorption, and a dysfunctional intrarenal dopaminergic system has been reported in essential hypertension and experimental hypertension models. Using catechol-O-methyl-transferase knockout (COMT^–/–) mice, which have increased renal dopamine because of deletion of the major renal dopamine-metabolizing enzyme, we investigated the effect of intrarenal dopamine on the development of hypertension in the deoxycorticosterone acetate/high-salt (DOCA/HS) model. DOCA/HS led to significant increases in systolic blood pressure in wild-type mice (from 115±2 to 153±4 mm Hg), which was significantly attenuated in COMT^–/– mice (from 114±2 to 135±3 mm Hg). In DOCA/HS COMT^–/– mice, the D1-like receptor antagonist SCH-23390 increased systolic blood pressure (156±2 mm Hg). DOCA/HS COMT^–/– mice also exhibited more urinary sodium excretion (COMT^–/– versus wild-type: 3038±430 versus 659±102 µmol/L per 24 hours; P<0.01). Furthermore, DOCA/HS-induced renal oxidative stress was significantly attenuated in COMT^–/– mice. COX-2–derived prostaglandins in the renal medulla promote sodium excretion, and dopamine stimulates medullary prostaglandin production. Renal medullary COX-2 expression and urinary prostaglandin E₂ excretion were significantly higher in COMT^–/– than in wild-type mice after DOCA/HS treatment. In DOCA/HS-treated COMT^–/– mice, the COX-2 inhibitor SC-58236 reduced urinary sodium and prostaglandin E₂ excretion and increased systolic blood pressure (153±2 mm Hg). These studies indicate that an activated renal dopaminergic system attenuates the development of hypertension, at least in large part through activating medullary COX-2 expression/activity, and also decreases oxidative stress resulting from DOCA/HS.

Key Words: dopamine • hypertension • cyclooxygenase 2 • prostaglandin E₂ • oxidative stress • kidney