[Cardioprotective effect of the selective sigma-1 receptor agonist, SA4503].

Abstract

We previously reported that the sigma-1 receptor is down-regulated in cardiomyocytes following heart failure in transverse aortic constriction (TAC) mice. In this review, we summarized the anti-hypertrophic action of selective sigma-1 receptor agonist, SA4503 in the hypertrophied cultured cardiomyocytes and discussed its possible mechanism of cardioprotection. Treatment with SA4503 (0.1-1 μM) dose-dependently inhibited hypertrophy in cultured cardiomyocytes induced by angiotensin II (Ang II). We also found that α1 receptor stimulation by phenylephrine (PE) promotes ATP production through IP3 receptor-mediated Ca(2+) mobilization into mitochondria in cultured cardiomyocytes. Interestingly, the PE-induced ATP production was impaired after Ang II-induced hypertrophy and SA4503 treatment largely restored PE-induced ATP production. The impaired PE-induced ATP production was associated with reduced mitochondrial size. The SA4503 treatment completely restored mitochondrial size concomitant with restored ATP production. These effects were blocked by sigma-1 receptor antagonist, NE-100 and sigma-1 receptor siRNA. We also confirmed that chronic SA4503 administration also significantly attenuates myocardial hypertrophy and restores ATP production in transverse aortic constriction mice. Taken together, sigma-1 receptor stimulation with selective agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca(2+) mobilization and ATP production via sigma-1 receptor stimulation. Sigma-1 receptor stimulation represents a new therapeutic strategy to rescue heart from hypertrophic dysfunction in heart failure.

• Authors: Kohga Hirano, Hideaki Tagashira, Kohji Fukunaga
• Journal: Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi) Vol. 134 Issue 6 Pg. 707-13 ( 2014) ISSN: 1347-5231 [Electronic] Japan
• PMID: 24882645 (Publication Type: Journal Article, Review)

Chemical References

• Piperazines
• Receptors, sigma
• sigma-1 receptor
• SA 4503
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cardiomegaly (drug therapy, physiopathology)
• Humans
• Mitochondria (drug effects, metabolism)
• Myocytes, Cardiac (drug effects)
• Piperazines (chemistry, pharmacology)
• Receptors, sigma (agonists)