Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Armando, I (Author) Other; Asico, LD (Author) Other; Wang, XY (Author) Other; Jones, JE (Author) Other; Maria Paula Serrão (Author) FMUP; Cuevas, S (Author) Other; Grandy, DK (Author) Other; Soares da Silva, P (Author) Other; Jose, PA (Author) Other

Journal

Title: Hypertension Research

Vol. 41

Pages: 489-498

ISSN: 0916-9636

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-00N-VQ4

DOI: 10.1038/s41440-018-0041-5

Abstract (EN): 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 (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-beta-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 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 D-2(-/-) mice and mice with renal-selective silencing of D2R 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 D1R but not D5R 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.

Language: English

Type (Professor's evaluation): Dissemination

No. of pages: 10