| Abstrakt: |
We have examined the a1-adrenergic modulation of the inwardly-rectifying K+ channel (IK1) in isolated human atrial myocytes using the patch clamp technique. a1-Adrenergic agonist methoxamine produced action potential prolongation and a depolarization of the resting membrane potential. Under whole-cell voltage clamp conditions, bath application of methoxamine can inhibit macroscopic IK1. The methoxamine-induced inhibition was reversible and concentration dependent, with the concentration for half-maximal inhibition being 18 µm. The methoxamine-induced inhibition of IK1 was prevented by bath application of a1-adrenergic blocker prazosin. The current was similarly inhibited 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 IK1. In single channel recording from cell attached patches, bath-applied methoxamine could suppress IK1 channels by decreasing the frequency and duration of bursting without affecting unitary amplitude. Direct application of purified PKC to excised inside-out patches inhibited channel activity similar to methoxamine in cell-attached patches. The PKC selective inhibitor, PKC19-36, prevented the PKC-induced inhibition of the channel. We conclude that human atrial IK1 can be inhibited by a1-adrenergic stimulation via PKC-dependent pathways. |
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