A potential repositioning of Trimetazidine for the treatment of bladder dysfunction: effects on mouse detrusor contractility and cytoprotection


Engin S. , Kaya Yaşar Y. , Barut E. N. , Duman M. , Kerimoğlu G. , Sezen F. S.

4th WG meeting, MuTaLig COST Action, İzmir, Türkiye, 5 - 06 Mart 2020, ss.27

  • Basıldığı Şehir: İzmir
  • Basıldığı Ülke: Türkiye
  • Sayfa Sayıları: ss.27

Özet

Trimetazidine (TMZ) is a novel anti-ischemic agent. This effect is mediated via inhibition of fatty acid oxidation and improvement of myocardial energy metabolism (1). Both metabolic and cytoprotective effects of TMZ in cardiac tissue has been extensively studied, however, its effects on other muscle tissue and potential therapeutic utility is unknown (2). The aim of our project is to critically evaluate the actions of TMZ on mouse bladder contractility and mouse model of cyclophosphamide (CP) - induced inflammation. To investigate the effect of TMZ on contractility, detrusor smooth muscle strips were obtained from male Balb/c mice (25-35 grams), and changes in isometric tension was recorded. TMZ pretreatment (300-1000 µM) attenuated carbachol- and KCI- induced contractions (p<0.05). TMZ (10-1000 µM) induced a concentration-dependent relaxation in KCl-pre-contracted strips (Emax=66.50±3.48). Incubation of detrusor strips with BaCl2 (Kir channel blocker) significantly decreased TMZ-induced relaxation whereas incubation of tetraethylammonium, glibenclamide, and 4-aminopyridine had no effect. TMZ pretreatment (300-1000 µM) significantly inhibited CaCl2-induced contraction in Ca2+ -free Krebs solution, also reduced the contractile response to carbachol in the presence of nifedipine. To investigate the cytoprotective effects of TMZ, hemorrhagic cystitis was induced with CP (300 mg/kg, ip) and TMZ (10 and 20 mg/kg/day, ip; treatment) or vehicle (control) was applied for 3 consecutive days before CP. TMZ (20 mg/kg) prevented CP-induced histopathologic alterations. Collectively, our results demonstrate that TMZ inhibits detrusor contractility via affecting intracellular calcium release and by inhibiting Kir channels. Non-vascular smooth muscle relaxation and cytoprotective effect of TMZ suggest that this novel molecule has a potential for repurposing/repositioning for bladder dysfunction and diseases.