Antagonism of levcromakalim by imidazoline‐ and guanidine‐derivatives in rat portal vein: involvement of the delayed rectifier

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Abstract
In rat whole portal veins, guanabenz (100 nm to 10 μm) and antazoline (100 nm to 100 μm) each increased the amplitude, frequency and duration of spontaneous contractions. In addition, guanabenz (30 μm) and antazoline (30 μm) each antagonized the ability of levcromakalim (3 nm to 10 μm) to inhibit the spontaneous contractions of this tissue. Whole‐cell voltage‐clamp recordings were made from freshly‐isolated rat portal vein cells dispersed by a collagenase/pronase enzyme treatment. The ability of several agents (antazoline, cirazoline, clonidine, guanabenz and phentolamine, each containing an imidazoline or guanidine moiety), to modulate potassium (K) currents and to inhibit the actions of levcromakalim was investigated. Antazoline, cirazoline, clonidine, guanabenz and phentolamine (each at a concentration of 30 μm) had little effect on control non‐inactivating currents but inhibited the delayed‐rectifier current, IK(V). Levcromakalim (1 μm) induced a non‐inactivating current, IK(ATP), and also inhibited the delayed rectifier current, IK(V). Glibenclamide (1 μm) had no effect on control delayed rectifier or non‐inactivating currents, but it inhibited the simultaneous induction of IK(ATP) and reduction of IK(V) produced by levcromakalim (1 μm). Antazoline, cirazoline, clonidine and guanabenz (each at a concentration of 30 μm) prevented the induction of IK(ATP) by levcromakalim (1 μm). Phentolamine (30 μm) and clonidine (30 μm) each inhibited the IK(ATP) generated by levcromakalim (1 μm). It is concluded that a variety of agents which possess either an imidazoline (antazoline, cirazoline, clonidine and phentolamine) or a guanidine (guanabenz) moiety within their structure inhibit the delayed rectifier current, IK(V). This action may thus be mediated via a so‐called non‐adrenoceptor imidazoline binding site. Furthermore, the ability of these ligands to inhibit IK(V) and to antagonize both the induction of IK(ATP) and the vasorelaxation produced by levcromakalim is consistent with the view that the channel (KATP) which underlies IK(ATP) is a voltage‐insensitive state of the delayed rectifier K‐channel (KV).