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

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

    Research output: Contribution to journalArticle

    Abstract

    Abnormalities of the D 2 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 2 -/- ) in mice increases blood pressure. The hypertension of D 2 -/- mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D 2 -/- 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 D 2 -/- mice treated with etamicastat by gavage, (10 mg/kg), conscious D 2 -/- mice, and D 2 +/+ littermates, and mice with the D 2 R 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 D 2 -/- mice and mice with renal-selective silencing of D 2 R to levels similar or close to those measured in D 2 +/+ littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D 2 -/- 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 D 1 R but not D 5 R in D 2 -/- mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D 2 -/- mice.

    Original languageEnglish (US)
    Pages (from-to)489-498
    Number of pages10
    JournalHypertension Research
    Volume41
    Issue number7
    DOIs
    StatePublished - Jul 1 2018

    ASJC Scopus subject areas

    • Internal Medicine
    • Physiology
    • Cardiology and Cardiovascular Medicine

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  • Cite this

    Armando, I., Asico, L. D., Wang, X., Jones, J. E., Serraõ, M. P., Cuevas, S., Grandy, D. K., Soares-Da-Silva, P., & Jose, P. A. (2018). Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice article. Hypertension Research, 41(7), 489-498. https://doi.org/10.1038/s41440-018-0041-5