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Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein
Author(s) -
Edwards Gillian,
Zygmunt Peter M.,
Högestätt Edward D.,
Weston Arthur H.
Publication year - 1996
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.1476-5381.1996.tb15728.x
Subject(s) - clotrimazole , chemistry , potassium channel , pharmacology , enzyme inhibitor , biophysics , biochemistry , in vitro , biology , antifungal , microbiology and biotechnology
1 The effects of the cytochrome P450 inhibitors, proadifen, clotrimazole and 17‐octadecynoic acid (17‐ODYA) on K‐currents in freshly‐isolated single cells derived from rat portal vein and on mechanical activity in whole veins were studied. 2 When cells were stepped from −90 mV to a series of test potentials (from −80 to +50 mV), a delayed rectifier current ( I K(V) ) and an A‐type current ( I K(A) ) could be identified. Proadifen (10 μ m ), clotrimazole (30 μ m ) and 17‐ODYA (5 μ m ) each inhibited I K(A) but had little effect on I K(A) . 3 When cells were held at −10 mV to inactivate the time‐dependent K‐currents, I K(V) and I K(A) , levcromakalim (3 μ m ) induced a time‐independent outward K‐current ( I K(ATP) ) which was totally inhibited by clotrimazole (30 μ m ) and almost fully inhibited by proadifen (10 μ m ). 17‐ODYA (5 μ m ) had no effect on I K(ATP) and exerted only a minor inhibitory action on this current at 20 μ m . 4 17‐ODYA (5 μ m ) potentiated current flow through the large conductance, Ca‐sensitive K‐channel (BK Ca ). In contrast, proadifen (10 μ m ) had no effect on I BK(Ca) whereas clotrimazole (30 μ m ) exerted a small but significant inhibitory action. 5 Proadifen (10 μ m ) and clotrimazole (30 μ m ) each inhibited the magnitude but increased the frequency of spontaneous contractions in whole portal veins. 17‐ODYA (5 μ m ) had no effect on spontaneous contractions but these were inhibited when the concentration of 17‐ODYA was increased to 50 μ m . 6 The spasmolytic effect of levcromakalim on spontaneous contractions was antagonized by proadifen (10–30 μ m ) in a concentration‐dependent manner but 17‐ODYA (up to 50 μ m ) was without effect. 7 These results in portal vein show that cytochrome P450 inhibitors exert profound effects on a variety of K‐channel subtypes. This suggests that enzymes dependent on this cofactor may be important regulators of K‐channel activity in smooth muscle. The relevance of these findings for the identification of the pathway involved in the synthesis of the endothelium‐derived hyperpolarizing factor is discussed.