Adrenergic modulation of ultrarapid delayed rectifier K+ current in human atrial myocytes

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 proteins kinase A and C, suggesting possible modulation by adrenergic stimulation. The present study was designed to assess the adrenergic regulation of I(km) in human atrial myocytes. Isoproterenol increased I(km) in human atrial myocytes. Isoproterenol increased 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 1 (kur) when the protein kinase A inhibit 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 β-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 β adrenergic stimulation enhances, whereas α-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(km) by adrenergic influences is a potentially novel control mechanism for human atrial repolarization and arrhythmias.link_to_subscribed_fulltex