Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein.
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 (IK(V)) and an A-type current (IK(A)) could be identified. Proadifen (10 microM), clotrimazole (30 microM) and 17-ODYA (5 microM) each inhibited IK(V) but had little effect on IK(A). 3. When cells were held at -10 mV to inactivate the time-dependent K-currents, IK(V) and IK(A), levcromakalim (3 microM) induced a time-independent outward K-current (IK(ATP)) which was totally inhibited by clotrimazole (30 microM) and almost fully inhibited by proadifen (10 microM). 17-ODYA (5 microM) had no effect on IK(ATP) and exerted only a minor inhibitory action on this current at 20 microM. 4. 17-ODYA (5 microM) potentiated current flow through the large conductance, Ca-sensitive K-channel (BKCa). In contrast, proadifen (10 microM) had no effect on IBK(Ca) whereas clotrimazole (30 microM) exerted a small but significant inhibitory action. 5. Proadifen (10 microM) and clotrimazole (30 microM) each inhibited the magnitude but increased the frequency of spontaneous contractions in whole portal veins. 17-ODYA (5 microM) had no effect on spontaneous contractions but these were inhibited when the concentration of 17-ODYA was increased to 50 microM. 6. The spasmolytic effect of levcromakalim on spontaneous contractions was antagonized by proadifen (10-30 microM) in a concentration-dependent manner but 17-ODYA (up to 50 microM) 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.
School of Biological Sciences, University of Manchester.
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G
Edwards
P M
PM
Zygmunt
E D
ED
Högestätt
A H
AH
Weston
D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011188:Potassium / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; C047008:17-octadecynoic acid; D011335:Proadifen; D003022:Clotrimazole; D011188:Potassium