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

    Fingerprint

    Antihypertensive Agents
    Kidney
    Endothelin B Receptors
    Blood Pressure
    Dopamine
    8-epi-prostaglandin F2alpha
    Norepinephrine
    etamicastat
    mouse DRD2 protein
    Hypertension
    NADPH Oxidase
    G-Protein-Coupled Receptors
    Mixed Function Oxygenases
    Drinking Water
    Isoenzymes
    Catecholamines
    Reactive Oxygen Species
    Oxidative Stress
    Sodium
    Enzymes

    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., ... 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

    Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice. / Armando, Ines; Asico, Laureano D.; Wang, Xiaoyan; Jones, John E.; Serrão, Maria Paula; Cuevas, Santiago; Grandy, David; Soares-da-Silva, Patricio; Jose, Pedro A.

    In: Hypertension Research, 13.04.2018, p. 1-10.

    Research output: Contribution to journalArticle

    Armando, I, Asico, LD, Wang, X, Jones, JE, Serrão, MP, Cuevas, S, Grandy, D, Soares-da-Silva, P & Jose, PA 2018, 'Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice', Hypertension Research, pp. 1-10. https://doi.org/10.1038/s41440-018-0041-5
    Armando, Ines ; Asico, Laureano D. ; Wang, Xiaoyan ; Jones, John E. ; Serrão, Maria Paula ; Cuevas, Santiago ; Grandy, David ; Soares-da-Silva, Patricio ; Jose, Pedro A. / Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice. In: Hypertension Research. 2018 ; pp. 1-10.
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    AU - Wang, Xiaoyan

    AU - Jones, John E.

    AU - Serrão, Maria Paula

    AU - Cuevas, Santiago

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