EFFECTS OF CYTOCHROME-P450 INHIBITORS ON POTASSIUM CURRENTS AND MECHANICAL-ACTIVITY IN RAT PORTAL-VEIN

1 The effects of the cytochrome P450 inhibitors, proadifen, clotrimazo le and 17-octadecynoic acid (17-ODYA) on K-currents in freshly-isolate d 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 K-type current (I-K(A)) could be identified. Proadifen (10 mu M), clotrimazole (30 mu M) and 17-ODYA (5 mu M) each inhibited I-K(V) but had little effect on I-K(A). 3 When cells were he ld at -10 mV to inactivate the time-dependent K-currents, I-K(V) and I -K(A), levcromakalim (3 mu M) induced a time-independent outward K-cur rent (I-K(ATP)) which was totally inhibited by clotrimazole (30 mu M) and almost fully inhibited by proadifen (10 mu M). 17-ODYA (5 mu M) ha d no effect on I-K(ATP) and exerted only a minor inhibitory action on this current at 20 mu M. 4 17-ODYA (5 mu M) potentiated current flow t hrough the large conductance, Ca-sensitive K-channel (BKCa). In contra st, proadifen (10 mu M) had no effect on I-BK(Ca) whereas clotrimazole (30 mu M) exerted a small but significant inhibitory action. 5 Proadi fen (10 mu M) and clotrimazole (30 mu M) each inhibited the magnitude but increased the frequency of spontaneous contractions in whole porta l veins. 17-ODYA (5 mu M) had no effect on spontaneous contractions bu t these were inhibited when the concentration of 17-ODYA was increased to 50 mu M 6 The spasmolytic effect of levcromakalim on spontaneous c ontractions was antagonized by proadifen (10-30 mu M) in a concentrati on-dependent manner but 17-ODYA (up to 50 mu M) was without effect. 7 These results in portal vein show that cytochrome P450 inhibitors exer t profound effects on a variety of K-channel subtypes. This suggests t hat enzymes dependent on this cofactor may be important regulators of K-channel activity in smooth muscle. The relevance of these findings f or the identification of the pathway involved in the synthesis of the endothelium-derived hyperpolarizing factor is discussed.