Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice

Ines Armando, Laureano D. Asico, Xiaoyan Wang, John E. Jones, Maria Paula Serrão, Santiago Cuevas, David Grandy, Patricio Soares-da-Silva, Pedro A. Jose

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)1-10
    Number of pages10
    JournalHypertension Research
    DOIs
    StateAccepted/In press - Apr 13 2018

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    ASJC Scopus subject areas

    • Internal Medicine
    • Physiology
    • Cardiology and Cardiovascular Medicine

    Cite this

    Armando, I., Asico, L. D., Wang, X., Jones, J. E., Serrão, M. P., Cuevas, S., Grandy, D., Soares-da-Silva, P., & Jose, P. A. (Accepted/In press). Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice. Hypertension Research, 1-10. https://doi.org/10.1038/s41440-018-0041-5