Up-regulated inflammatory factors endothelin, NFκB, TNFα and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats

Abstract

The exaggerated cardiac arrhythmias in cardiomyopathy induced by l-thyroxine treatment are related to ion channelopathies and to an abnormal endothelin (ET) pathway. It was hypothesized that an increased incidence of ventricular fibrillation (VF) could be mediated by inflammatory factors including the ET pathway, nuclear factor kappa B (NFκB), tumor necrosis factor-α (TNFα) and inducible nitric oxide synthase (iNOS). Abnormal expression of NFκB, TNFα, iNOS and enhanced VF are linked with the activated ET pathway and a significant reversion could be achieved by the selective endothelin A receptor antagonist darusentan. Cardiomyopathy in rats was produced by l-thyroxine treatment (0.3 mg kg − 1 d − 1 , sc) for 10 days. The mRNA expression of the ET pathway, NFκB, TNFα, iNOS and the activity of the redox system were assayed in association with the incidence of VF produced by coronary ligation/reperfusion. Darusentan was administered on days 6–10 of l-thyroxine treatment. The VF incidence, which was higher in the l-thyroxine cardiomyopathy group, was suppressed by darusentan. The mRNA levels of preproET-1, endothelin converting enzyme, endothelin receptor A (ET AR), endothelin receptor B (ET BR), NFκB, TNFα and iNOS in left ventricle were up-regulated in the cardiomyopathic heart. There was significant oxidative stress in this cardiomyopathy model. Darusentan suppressed the up-regulated mRNA levels of ET AR, ET BR, NFκB, TNFα, and iNOS. These results indicate that the high incidence of VF which is related to up-regulation of inflammatory factors in the cardiomyopathic myocardium is significantly suppressed by selective ET AR blockade.