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Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice.


ABSTRACT: Abnormalities of the D2R gene (DRD2) play a role in the pathogenesis of human essential hypertension; variants of the DRD2 have been reported to be associated with hypertension. Disruption of Drd2 (D2-/-) in mice increases blood pressure. The hypertension of D2-/- mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D2-/- mice the effect of etamicastat, a reversible peripheral inhibitor of dopamine-?-hydroxylase that reduces the biosynthesis of norepinephrine from dopamine and decreases sympathetic nerve activity. Blood pressure was measured in anesthetized D2-/- mice treated with etamicastat by gavage, (10?mg/kg), conscious D2-/- mice, and D2+/+ littermates, and mice with the D2R selectively silenced in the kidney, treated with etamicastat in the drinking water (10?mg/kg per day). Tissue and urinary catecholamines and renal expression of selected G protein-coupled receptors, enzymes related to the production of reactive oxygen species, and sodium transporters were also measured. Etamicastat decreased blood pressure both in anesthetized and conscious D2-/- mice and mice with renal-selective silencing of D2R to levels similar or close to those measured in D2+/+ littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D2-/- mice. It also normalized the increased renal protein expressions of ETBR, NADPH oxidase isoenzymes, and urinary 8-isoprostane, as well as renal NHE3 and NCC, and increased the renal expression of D1R but not D5R in D2-/- mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D2-/- mice.

SUBMITTER: Armando I 

PROVIDER: S-EPMC6503839 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice.

Armando Ines I   Asico Laureano D LD   Wang Xiaoyan X   Jones John E JE   Serrão Maria Paula MP   Cuevas Santiago S   Grandy David K DK   Soares-da-Silva Patricio P   Jose Pedro A PA  

Hypertension research : official journal of the Japanese Society of Hypertension 20180413 7


Abnormalities of the D<sub>2</sub>R gene (DRD2) play a role in the pathogenesis of human essential hypertension; variants of the DRD2 have been reported to be associated with hypertension. Disruption of Drd2 (D<sub>2</sub><sup>-/-</sup>) in mice increases blood pressure. The hypertension of D<sub>2</sub><sup>-/-</sup> mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D<sub>2</sub><sup>-/-</su  ...[more]

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