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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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.
Conflict of interest
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