ADRENERGIC MODULATION OF ULTRARAPID DELAYED RECTIFIER K+ CURRENT IN HUMAN ATRIAL MYOCYTES

The ultrarapid delayed rectifier K+ current (I-Kur) in human trial cel ls appears to correspond to Kv1.5 cloned channels and to play an impor tant role in human atrial repolarization. Kv1.5 channels have consensu s sites for phosphorylation by protein kinase A and C, suggesting poss ible modulation by adrenergic stimulation. The present study was desig ned to assess the adrenergic regulation of I-Kur in human atrial myocy tes. 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 mu mol/L). Isoproterenol's effects were mimicked by the direct adenylate cyclase stimulator, forskolin, and by the membra ne-permeable form of cAMP, 8-bromo cAMP. Isoproterenol had no effect o n I-Kur when the protein kinase A inhibitor peptide, PKI(6-22)amide, w as included in the pipette solution; in a separate set of experiments in which isoproterenol alone increased I-Kur by 45+/-9% relative to co ntrol, subsequent superfusion with isoproterenol in the presence of th e protein kinase inhibitor H-7 failed to alter I-Kur. In contrast to i soproterenol, phenylephrine (in the presence of propranolol to block b eta-adrenergic effects) induced a concentration-dependent inhibition o f I-Kur with significant effects observed at concentrations as low as 10 mu mol/L. The inhibitory actions of phenylephrine were reversed by the addition of prazosin and prevented by coadministration with a high ly selective inhibitor of protein kinase C, bisindolylmaleimide. These results indicate that beta-adrenergic stimulation enhances, whereas a lpha-adrenergic stimulation inhibits, I-Kur and suggest that these act ions are mediated by protein kinase A and protein kinase C, respective ly. The modulation of I-Kur by adrenergic influences is a potentially novel control mechanism for human atrial repolarization and arrhythmia s.