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-β-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.

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Acknowledgements

BIAL - Portela & Cª, S.A. supported this study. BIAL had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Ines Armando.

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P.S.S. is an employee of BIAL - Portela & Cª, S.A. (the sponsor of the study). The remaining authors declare that they have no conflict of interest.

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Armando, I., Asico, L.D., Wang, X. et al. Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice. Hypertens Res 41, 489–498 (2018). https://doi.org/10.1038/s41440-018-0041-5

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