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(Circulation Research. 1996;78:903-915.)
© 1996 American Heart Association, Inc.

Articles

Adrenergic Modulation of Ultrarapid Delayed Rectifier K⁺ Current in Human Atrial Myocytes

Gui-Rong Li, Jianlin Feng, Zhiguo Wang, Bernard Fermini, Stanley Nattel

From the Montreal Heart Institute Research Centre (Canada).

Correspondence to Stanley Nattel, MD, Montreal Heart Institute Research Centre, 5000 Belanger St, Montreal, Quebec, H1T 1C8, Canada.

Abstract The ultrarapid delayed rectifier K⁺ current (I_Kur) in human atrial cells appears to correspond to Kv1.5 cloned channels and to play an important role in human atrial repolarization. Kv1.5 channels have consensus sites for phosphorylation by protein kinase A and C, suggesting possible modulation by adrenergic stimulation. The present study was designed to assess the adrenergic regulation of I_Kur in human atrial myocytes. Isoproterenol increased I_Kur in a concentration-dependent manner, with significant effects at concentrations as low as 10 nmol/L. The effects of isoproterenol were reversible by washout or by the addition of propranolol (1 µmol/L). Isoproterenol's effects were mimicked by the direct adenylate cyclase stimulator, forskolin, and by the membrane-permeable form of cAMP, 8-bromo cAMP. Isoproterenol had no effect on I_Kur when the protein kinase A inhibitor peptide, PKI(6-22)amide, was included in the pipette solution; in a separate set of experiments in which isoproterenol alone increased I_Kur by 45±9% relative to control, subsequent superfusion with isoproterenol in the presence of the protein kinase inhibitor H-7 failed to alter I_Kur. In contrast to isoproterenol, phenylephrine (in the presence of propranolol to block ß-adrenergic effects) induced a concentration-dependent inhibition of I_Kur, with significant effects observed at concentrations as low as 10 µmol/L. The inhibitory actions of phenylephrine were reversed by the addition of prazosin and prevented by coadministration with a highly selective inhibitor of protein kinase C, bisindolylmaleimide. These results indicate that ß-adrenergic stimulation enhances, whereas -adrenergic stimulation inhibits, I_Kur and suggest that these actions are mediated by protein kinase A and protein kinase C, respectively. The modulation of I_Kur by adrenergic influences is a potentially novel control mechanism for human atrial repolarization and arrhythmias.

Key Words: ion channels • cardiac arrhythmias • isoproterenol • phenylephrine • heart repolarization

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