Abstract
Heart failure is known for alteration of cardiac catecholamine responsiveness involving adrenergic receptor (AR) down-regulation. Trimetazidine, a metabolically active anti-ischemic drug, accelerates the turnover of phospholipids. The present study evaluated the consequences of trimetazidine treatment (supposed to increase phospholipid synthesis) on AR in heart failure in rats. In control rats, trimetazidine (7.5 mg/day supplied in the diet) induced after 8 weeks a significant increase in both β- (+54%) and α-AR (+30%) density, although after 12 weeks, the receptor density was normalized. Heart failure was obtained by ascending aortic banding. These heart failure rats developed a severe cardiac hypertrophy, mainly affecting the left ventricle, which was significantly reduced in the trimetazidine-treated group. The plasma level of brain natriuretic peptide (BNP), a marker of heart failure severity, was significantly increased in the heart failure group as compared with the sham group (900 and 1200% after 8 and 12 weeks, respectively). In the trimetazidine-treated group, the plasma BNP increase was significantly lower. The development of heart failure was associated with a decrease in β- and α-AR sites (−23 and −36% versus sham, respectively) after 8 weeks and continued to decrease after 12 weeks (−37 and −48% versus sham, respectively). This down-regulation was prevented by trimetazidine without alteration in affinity. These results suggest that trimetazidine prevents AR desensitization and cardiac hypertrophy, in a pressure-overload model of heart failure. This cytoprotection suggests that membrane homeostasis preservation may be considered as a therapeutic target in the treatment of heart failure.
Footnotes
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DOI: 10.1124/jpet.102.042143
- Abbreviations:
- AR
- adrenergic receptor
- AS
- aortic stenosis
- Sh
- sham
- BNP
- brain natriuretic peptide
- TMZ
- trimetazidine
- Ct
- control
- CGP-12177
- 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one
- ICI 118.551
- (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride
- RIA
- radioimmunoassay
- LV
- left ventricle
- PI
- phosphatidylinositol
- PIP2
- phosphatidylinositol bisphosphate
- Received July 23, 2002.
- Accepted November 7, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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