Role of endothelin in the effects of isoprenaline on potassium currents and calsequestrin 2 expression in the heart.

1. Activation of beta-receptors may modulate potassium channels and calcium handling proteins and serve as a basis for arrhythmogenesis. We determined whether an endothelin (ET) receptor antagonist CPU0213 could relieve the isoprenaline-(ISO) induced changes in I(Kr) and I(Ks) and calsequestrin 2 (CASQ2) in the heart. 2. In isolated ventricular myocytes, the I(Kr) and I(Ks) currents and expression for CASQ2, FKBP12.6, SERCA2a and ET(A)R were measured in the presence of ISO and either propranolol or CPU0213. 3. In the presence of ISO, I(Kr) and I(Ks) currents were significantly exaggerated and FKBP12.6, SERCA2a and CASQ2 were downregulated together with upregulation of ET(A)R in the myocardium. Interestingly, endothelin-1 was also effective in downregulating the expression of CASQ2. These changes were partially relieved by either CPU0213 or propranolol. 4. I(Kr) and I(Ks) currents can be separated into exaggerated/induced and basic components in the presence of ISO. The former, induced by ISO, is pathological and sensitive to either CPU0213 or propranolol. 5. Exaggerated I(Kr) and I(Ks) and downregulated CASQ2 by ISO are relevant to stress-related events in which the ET pathway is actively involved. By suppressing the ISO-exaggerated I(Kr) and I(Ks) and normalizing the expression of CASQ2, endothelin receptor antagonism is likely promising in dealing with stress-related cardiac arrhythmias.