Rapid component I Kr of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by α 1-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways

Abstract

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 α 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 α 1-adrenoceptors using phenylephrine (0.1 nM–100 μM) reduced I kr current in a dose-dependent manner at 37 °C. Phenylephrine (0.1 μM) reduced I kr current to 66.83 ± 3.16%. Chelerythrine (1 μM), a specific inhibitor of protein kinase C (PKC) completely inhibited the changes in I kr trigged by 0.1 μM phenylephrine. KT5720 (2.5 μM), a specific inhibitor of protein kinase A (PKA) partially inhibited the current decrease induced by 0.1 μM phenylephrine. Both chelerythrine and KT5720 drastically reduced the phenylephrine-induced effects, indicating possible involvement of PKC and PKA in the α 1-adrenergic inhibition of I kr. Our data suggest a link between I kr and the α 1-adrenoceptor, involving activation of PKC and PKA in arrhythmogenesis.