Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein
Edwards, Gillian ; Zygmunt, Peter M. LU
; Högestätt, Edward D.
LU
and Weston, Arthur H.
(1996)
In British Journal of Pharmacology
119(4).
p.691-701
- Abstract
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... (More)
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.
(Less)
- author
- Edwards, Gillian
; Zygmunt, Peter M.
LU
; Högestätt, Edward D.
LU
and Weston, Arthur H.
- publishing date
- 1996-01-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 17-ODYA, BK(Ca), Clotrimazole, Cytochrome P450, EDHF, K(ATP), K-currents, Proadifen, Rat portal vein, Whole-cell voltage clamp
- in
- British Journal of Pharmacology
- volume
- 119
- issue
- 4
- pages
- 11 pages
- publisher
- Wiley
- external identifiers
-
- scopus:0029907118
- pmid:8904643
- ISSN
- 0007-1188
- DOI
- 10.1111/j.1476-5381.1996.tb15728.x
- language
- English
- LU publication?
- no
- id
- 19c18434-b48a-4caf-b5e3-7475679195fd
- date added to LUP
- 2019-05-31 21:40:16
- date last changed
- 2024-03-03 12:47:15
@article{19c18434-b48a-4caf-b5e3-7475679195fd,
abstract = {{<p>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.</p>}},
author = {{Edwards, Gillian and Zygmunt, Peter M. and Högestätt, Edward D. and Weston, Arthur H.}},
issn = {{0007-1188}},
keywords = {{17-ODYA; BK(Ca); Clotrimazole; Cytochrome P450; EDHF; K(ATP); K-currents; Proadifen; Rat portal vein; Whole-cell voltage clamp}},
language = {{eng}},
month = {{01}},
number = {{4}},
pages = {{691--701}},
publisher = {{Wiley}},
series = {{British Journal of Pharmacology}},
title = {{Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein}},
url = {{http://dx.doi.org/10.1111/j.1476-5381.1996.tb15728.x}},
doi = {{10.1111/j.1476-5381.1996.tb15728.x}},
volume = {{119}},
year = {{1996}},
}