MODULATION OF THE INWARDLY RECTIFYING K-ADRENERGIC STIMULATION( CHANNEL IN ISOLATED HUMAN ATRIAL MYOCYTES BY ALPHA(1))

We have examined the alpha(1)-adrenergic modulation of the inwardly-re ctifying K+ channel (I-K1) in isolated human atrial myocytes using the patch clamp technique. alpha(1)-Adrenergic agonist methoxamine produc ed action potential prolongation and a depolarization of the resting m embrane potential. Under whole-cell voltage-clamp conditions, bath app lication of methoxamine can inhibit macroscopic I-K1. The methoxamine- induced inhibition was reversible and concentration dependent, with th e concentration for half-maximal inhibition being 18 mu M, The methoxa mine-induced inhibition of I-K1 was prevented by bath application of a lpha(1)-adrenergic blocker prazosin. The current was similarly inhibit ed by phorbol ester (PMA), an activator of protein kinase C (PKC). In contrast, methoxamine failed to inhibit the current in the presence of a specific PKC inhibitor H-9, suggesting that PKC is involved in the methoxamine-induced inhibition of I-K1. In single channel recording fr om cell-attached patches, bath-applied methoxamine could suppress I-K1 channels by decreasing the frequency and duration of bursting without affecting unitary amplitude. Direct application of purified PKC to ex cised inside-out patches inhibited channel activity similar to methoxa mine in cell-attached patches, The PKC selective inhibitor, PKC19-36, prevented the PKC-induced inhibition of the channel. We conclude that human atrial I-K1 can be inhibited by alpha(1)-adrenergic stimulation via PKC-dependent pathways.