A Long-Term Study Evaluating the Effects of Nicorandil Treatment on Duchenne Muscular Dystrophy-Associated Cardiomyopathy in mdx Mice

J Cardiovasc Pharmacol Ther. 2022 Jan-Dec;27:10742484221088655. doi: 10.1177/10742484221088655.

Abstract

Background: Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by dystrophin gene mutations affecting striated muscle. Due to advances in skeletal muscle treatment, cardiomyopathy has emerged as a leading cause of death. Previously, nicorandil, a drug with antioxidant and nitrate-like properties, ameliorated cardiac damage and improved cardiac function in young, injured mdx mice. Nicorandil mitigated damage by stimulating antioxidant activity and limiting pro-oxidant expression. Here, we examined whether nicorandil was similarly cardioprotective in aged mdx mice.

Methods and results: Nicorandil (6 mg/kg) was given over 15 months. Echocardiography of mdx mice showed some functional defects at 12 months compared to wild-type (WT) mice, but not at 15 months. Disease manifestation was evident in mdx mice via treadmill assays and survival, but not open field and grip strength assays. Cardiac levels of SOD2 and NOX4 were decreased in mdx vs. WT. Nicorandil increased survival in mdx but did not alter cardiac function, fibrosis, diaphragm function or muscle fatigue.

Conclusions: In contrast to our prior work in young, injured mdx mice, nicorandil did not exert cardioprotective effects in 15 month aged mdx mice. Discordant findings may be explained by the lack of cardiac disease manifestation in aged mdx mice compared to WT, whereas significant cardiac dysfunction was previously seen with the sub-acute injury in young mice. Therefore, we are not able to conclude any cardioprotective effects with long-term nicorandil treatment in aging mdx mice.

Keywords: Duchenne muscular dystrophy; cardiomyopathy; mdx; nicorandil; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiomyopathies* / drug therapy
  • Cardiomyopathies* / etiology
  • Cardiomyopathies* / prevention & control
  • Heart
  • Mice
  • Mice, Inbred mdx
  • Muscular Dystrophy, Duchenne* / complications
  • Muscular Dystrophy, Duchenne* / drug therapy
  • Muscular Dystrophy, Duchenne* / genetics
  • Nicorandil / pharmacology

Substances

  • Nicorandil