Rapid component IKr of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by α1-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways

Ventricular tachyarrhythmias are often precipitated by physical or emotional stress, indicating a link between increased adrenergic stimulation and cardiac ion channel activity. Human ether-a-go-go related gene (hERG) potassium channels conduct the rapid component of delayed rectifier potassium current, I-kr, a crucial component for action potential repolarization. To evaluate the correlation between increased alpha(1)-adrenergic activity and the rapid component of cardiac I-kr, whole-cell patch-clamp recording was performed in isolated guinea-pig ventricular myocytes. Stimulation of alpha(1)-adrenoceptors using phenylephrine (0.1 nM-100 mu M) reduced I-kr, current in a dose-dependent manner at 37 degrees C. Phenylephrine (0.1 mu M) reduced I-kr current to 66.83 +/- 3.16%. Chelerythrine (1 mu M), a specific inhibitor of protein kinase C (PKC) completely inhibited the changes in I-kr trigged by 0.1 mu M phenylephrine. KT5720 (2.5 mu M), a specific inhibitor of protein kinase A (PKA) partially inhibited the current decrease induced by 0.1 mu M phenylephrine. Both chelerythrine and KT5720 drastically reduced the phenylephrine-induced effects, indicating possible involvement of PKC and PKA in the alpha(1)-adrenergic inhibition of I-kr, Our data suggest a link between I-kr and the alpha(1)-adrenoceptor, involving activation of PKC and PKA in arrhythmogenesis. (c) 2009 Elsevier B.V. All rights reserved.