Abstract

Summary1. Activation of β‐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 IKr and IKs and calsequestrin 2 (CASQ2) in the heart.2. In isolated ventricular myocytes, the IKr and IKs currents and expression for CASQ2, FKBP12.6, SERCA2a and ETAR were measured in the presence of ISO and either propranolol or CPU0213.3. In the presence of ISO, IKr and IKs currents were significantly exaggerated and FKBP12.6, SERCA2a and CASQ2 were downregulated together with upregulation of ETAR 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. IKr and IKs 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 IKr and IKs and downregulated CASQ2 by ISO are relevant to stress‐related events in which the ET pathway is actively involved. By suppressing the ISO‐exaggerated IKr and IKs and normalizing the expression of CASQ2, endothelin receptor antagonism is likely promising in dealing with stress‐related cardiac arrhythmias.

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