Phenylephrine (10 microM), added in the bathing solution, stimulated the cardiac muscarinic K+ channel (IK.ACh) in the cell-attached patch. The pipette solution contained 10 microM atropine and 100 microM theophylline to block the muscarinic acetylcholine and adenosine receptors, respectively. The channel activation induced by phenylephrine was blocked by prazosin, an alpha 1-antagonist, indicating that alpha 1-adrenergic receptor mediates the response. Phenylephrine-induced activation was prevented by nordihydroguaiaretic acid, a lipoxygenase inhibitor, and AA-861, a 5-lipoxygenase inhibitor, but was not affected by indomethacin, a cyclooxygenase inhibitor. These observations suggest that 5-lipoxygenase metabolites of arachidonic acid may be involved in the alpha-adrenergic activation of IK.ACh.