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.