Nicorandil Ameliorates Doxorubicin-Induced Cardiotoxicity in Rats, as Evaluated by 7 T Cardiovascular Magnetic Resonance Imaging

Abstract

Purpose Doxorubicin-induced cardiotoxicity (DIC) is a common side effect of doxorubicin chemotherapy, and a major mechanism of DIC is inflammation. However, no effective method exists to prevent DIC. In the present study, we investigated the cardioprotective effects of nicorandil against DIC using multiparametric cardiac magnetic resonance (CMR) imaging and elucidated the anti-inflammatory properties of nicorandil in rat models. Methods Male Sprague-Dawley rats received four weekly intraperitoneal doxorubicin doses (4 mg/kg/injection) to establish the DIC model. After treatment with or without nicorandil (3 mg/kg/day) or diazoxide (10 mg/kg/day) orally, all the groups underwent weekly CMR examinations, including cardiac function and strain assessment and T2 mapping, for 6 weeks. Additionally, blood samples and hearts were collected to examine inflammation and histopathology. Results According to our results, the earliest DIC CMR parameter in the doxorubicin group was T2 mapping time prolongation compared with the DIC rats treated with nicorandil (doxorubicin+nicorandil group) at week 2. Subsequently, the left ventricular ejection fraction (LVEF) and global peak systolic myocardial strain in the doxorubicin group were significantly reduced, and nicorandil effectively inhibited these effects at week 6. Our results were confirmed by histopathological evaluations. Furthermore, nicorandil treatment had a protective effect against the doxorubicin-induced inflammatory response. Interestingly, similar protective results were obtained using the KATP channel opener diazoxide. Conclusion Collectively, our findings indicate that nicorandil application ameliorates DIC in rats with significantly higher cardiac function and myocardial strain and less fibrosis, apoptosis and inflammatory cytokine production. Nicorandil prevents T2 abnormalities in the early stages of DIC, showing a high clinical value for early nicorandil treatment in chemotherapy patients.

Development of a green, concise synthesis of nicotinamide derivatives catalysed by Novozym® 435 from Candida antarctica in sustainable continuous-flow microreactors

“…The resulting stream was connected to a sample vial to collect the nal mixture. The main products were separated by silica gel chromatography and were conrmed by 1 H NMR, 13 C NMR.…”

“…9 Along with an increasing focus on the utilization of natural resources in organic synthesis, nicotinamide derivatives are gaining more and more interest. Numerous nicotinamide derivatives with various substituents have been applied to medicine and agrochemistry, such as AAT-008 (EP4 receptor antagonists), 10 boscalid and diflufenican (broad-spectrum fungicide), 11 nicorandil (cardiovascular medicines), 12,13 coramine (respiratory stimulant), apatinib (anti-cancer) 14,15 ( Fig. 1 ).…”

KATP channels are regulators of programmed cell death and targets for the creation of novel drugs against ischemia/reperfusion cardiac injury

“…Diazoxide inhibited creatine kinase and LDH release from H9c2 cells, mitochondrial permeability transition pore (MPT pore) opening, Ca 2+ overload, ROS generation, and apoptosis [126]. It was found that nicorandil and diazoxide prevented doxorubicin‐induced cardiofibrosis and apoptosis in rats [99].…”