title: Endothelin receptor antagonist CPU0213 suppresses ventricular fibrillation in L-thyroxin induced cardiomyopathy.
abstract: Arrhythmias correlate with disorders of either K(2+) channels in sarcolemma or calcium modulating system in sarcoplasmic reticulum which handles Ca(2+) intracellularly. We hypothesized that an activated endothelin (ET) signaling pathway, which may be associated with an alteration of K(+) channels and Ca(2+) uptake activity in the myocardium, participated in the exaggerated ventricular fibrillation (VF) incidence in cardiomyopathy (CM) induced by L-thyroxin. We intended to test if a dual endothelin receptor antagonist CPU0213 is effective to suppress VF correlating with a reversal of abnormalities in expression of the ion channels in sarcolemma and sarcoplasmic reticulum. The CM was induced by L-thyroxin administration for 10 days, and the altered expression of ion channels and the ET system was examined and the susceptibility to VF was evaluated by 10-min ischemia followed by reperfusion (I/R). Rats were treated with either propranolol or CPU0213 from day 6-10 of L-thyroxin medication. An increased VF incidence on I/R episode in the CMwas found relative to control. An elevated myocardial ET-1 and preproET-1 expression were associated with abnormal mRNAlevel of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a), phospholamban (PLB), and ERG, MinK, and Kv4.2 in sarcolemma. Propranolol and CPU0213 were equally effective in reversing the alterations of gene phenotype and exaggerated VF in CM hearts. In conclusion, an activated ET receptor signaling plays a role in the progression of augmented VF in association with abnormal expression of ion channels in both sarcolemma and sarcoplasmic reticulum in the CM.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, 210009 Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Tao
authors.initials: T
authors.lastname: Na
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000150:complications*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis / Q000235:genetics; D008297:Male; D018384:Oxidative Stress; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics; D051672:Shal Potassium Channels / Q000235:genetics; D013974:Thyroxine / Q000633:toxicity; D014693:Ventricular Fibrillation / Q000188:drug therapy*
chemical_list: C513821:CPU0213; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011720:Pyrazoles; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013974:Thyroxine; D002118:Calcium