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

The exaggerated cardiac arrhythmias in cardiomyopathy induced by L-thyroxine treatment are related to ion charmelopathies 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 (NF kappa B), tumor necrosis factor-alpha (TNF alpha) and inducible nitric oxide synthase (NOS). Abnormal expression of NF kappa B, TNF alpha, NOS 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, NF kappa B, TNF alpha, NOS 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-tbyroxine 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 (ETAR), endothelin receptor B (ETBR), NF kappa B, TNFa and NOS 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 ETAR, ETBR, NF kappa B, TNF alpha, and NOS. 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 ETAR blockade. (c) 2006 Elsevier Inc. All rights reserved.