Intrarenal Dopamine Attenuates Deoxycorticosterone Acetate/High Salt–Induced Blood Pressure Elevation in Part Through Activation of a Medullary Cyclooxygenase 2 Pathway
- 1 November 2009
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 54 (5), 1077-1083
- https://doi.org/10.1161/HYPERTENSIONAHA.109.137174
Abstract
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 −/− 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 E 2 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 E 2 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.Keywords
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