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Br J Pharmacol. 2011 Oct;164(3):946-57. doi: 10.1111/j.1476-5381.2011.01355.x.

Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt.

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  • 1Centre Hospitalier de L'Université de Montréal Research Center, Québec, Canada.

Abstract

BACKGROUND AND PURPOSE:

Regression of left ventricular hypertrophy by moxonidine, a centrally acting sympatholytic imidazoline compound, results from a sustained reduction of DNA synthesis and transient stimulation of DNA fragmentation. Because apoptosis of cardiomyocytes may lead to contractile dysfunction, we investigated in spontaneously hypertensive rats (SHR), time- and dose-dependent effects of in vivo moxonidine treatment on cardiac structure and function as well as on the inflammatory process and signalling proteins involved in cardiac cell survival/death.

EXPERIMENTAL APPROACH:

12 week old SHR received moxonidine at 0, 100 and 400 µg·kg(-1)·h(-1) , s.c., for 1 and 4 weeks. Cardiac function was evaluated by echocardiography; plasma cytokines were measured by elisa and hearts were collected for histological assessment of fibrosis and measurement of cardiac proteins by Western blotting. Direct effects of moxonidine on cardiac cell death and underlying mechanisms were investigated in vitro by flow cytometry and Western blotting.

KEY RESULTS:

After 4 weeks, the sub-hypotensive dose of moxonidine (100 µg) reduced heart rate and improved global cardiac performance, reduced collagen deposition, regressed left ventricular hypertrophy, inhibited Akt and p38 MAPK phosphorylation, and attenuated circulating and cardiac cytokines. The 400 µg dose resulted in similar effects but of a greater magnitude, associated with blood pressure reduction. In vitro, moxonidine inhibited norepinephrine-induced neonatal cardiomyocyte mortality but increased fibroblast mortality, through I(1)-receptor activation and differential effects on downstream Akt and p38 MAPK.

CONCLUSIONS AND IMPLICATIONS:

While the antihypertensive action of centrally acting imidazoline compounds is appreciated, new cardiac-selective I(1)-receptor agonists may confer additional benefit.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

PMID:
21426316
[PubMed - indexed for MEDLINE]
PMCID:
PMC3195917
Free PMC Article
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