Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein
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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 ((IK(A))) could be identified. Proadifen (10 μM), clotrimazole (30 μM) and 17-ODYA (5 μM) each inhibited I(K(V)) 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 μM) induced a time-independent outward K-current ((I(K(ATP))) which was totally inhibited by clotrimazole (30 μM) and almost fully inhibited by proadifen (10 μM). 17-ODYA (5 μM) had no effect on I(K(ATP)) and exerted only a minor inhibitory action on this current at 20 μM. 4. 17-ODYA (5 μM) potentiated current flow through the large conductance, Ca-sensitive K-channel (BK(Ca)). In contrast, proadifen (10 μM) had no effect on I(BK(Ca)) whereas clotrimazole (30 μM) exerted a small but significant inhibitory action. 5. Proadifen (10 μM) and clotrimazole (30 μM) each inhibited the magnitude but increased the frequency of spontaneous contractions in whole portal veins. 17-ODYA (5 μM) had no effect on spontaneous contractions but these were inhibited when the concentration of 17-ODYA was increased to 50 μM. 6. The spasmolytic effect of levcromakalim on spontaneous contractions was antagonized by proadifen (10-30 μM) in a concentration-dependent manner but 17-ODYA (up to 50 μM) 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.
Ämnesklassifikation (UKÄ) – OBLIGATORISK
|Tidskrift||British Journal of Pharmacology|
|Status||Published - 1996 jan 1|
|Peer review utförd||Ja|