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Antagonism of levcromakalim by imidazoline‐ and guanidine‐derivatives in rat portal vein: involvement of the delayed rectifier
Author(s) -
Ibbotson Timothy,
Edwards Gillian,
Weston Arthur H.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb14001.x
Subject(s) - chemistry , imidazoline receptor , phentolamine , glibenclamide , guanabenz , pharmacology , clonidine , endocrinology , biochemistry , agonist , medicine , receptor , diabetes mellitus
1 In rat whole portal veins, guanabenz (100 n m to 10 μ m ) and antazoline (100 n m to 100 μ m ) each increased the amplitude, frequency and duration of spontaneous contractions. In addition, guanabenz (30 μ m ) and antazoline (30 μ m ) each antagonized the ability of levcromakalim (3 n m to 10 μ m ) to inhibit the spontaneous contractions of this tissue. 2 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. 3 Antazoline, cirazoline, clonidine, guanabenz and phentolamine (each at a concentration of 30 μ m ) had little effect on control non‐inactivating currents but inhibited the delayed‐rectifier current, I K(V) . 4 Levcromakalim (1 μ m ) induced a non‐inactivating current, I K(ATP) , and also inhibited the delayed rectifier current, I K(V) . 5 Glibenclamide (1 μ m ) had no effect on control delayed rectifier or non‐inactivating currents, but it inhibited the simultaneous induction of I K(ATP) and reduction of I K(V) produced by levcromakalim (1 μ m ). 6 Antazoline, cirazoline, clonidine and guanabenz (each at a concentration of 30 μ m ) prevented the induction of I K(ATP) by levcromakalim (1 μ m ). Phentolamine (30 μ m ) and clonidine (30 μ m ) each inhibited the I K(ATP) generated by levcromakalim (1 μ m ). 7 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, I K(V) . This action may thus be mediated via a so‐called non‐adrenoceptor imidazoline binding site. Furthermore, the ability of these ligands to inhibit I K(V) and to antagonize both the induction of I K(ATP) and the vasorelaxation produced by levcromakalim is consistent with the view that the channel (K ATP ) which underlies I K(ATP) is a voltage‐insensitive state of the delayed rectifier K‐channel (K V ).