title: Intrarenal dopamine attenuates deoxycorticosterone acetate/high salt-induced blood pressure elevation in part through activation of a medullary cyclooxygenase 2 pathway.
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 micromol/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 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.
authors.affiliation: Nashville Veterans' Administration Hospital and Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001795:Blood Pressure Determination; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000009:adverse effects / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011336:Probability; D011897:Random Allocation; D017673:Sodium Chloride, Dietary / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D001552:Benzazepines; C534628:SCH 23390; D017673:Sodium Chloride, Dietary; D003900:Desoxycorticosterone; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D004298:Dopamine