Effects of cytochrome p-450 inhibitors on ionic currents in isolated rat type i carotid body cells, and modulation of such effects by hypoxia. Hatton, C. J., and C. Peers. Institute for Cardiovascular Research, Leeds University, Leeds LS2 9JT, U.K.
APStracts 3:0019C, 1996.
Hypoxic chemoreception in the carotid body involves selective inhibition of K+ channels in type I cells. We have investigated whether cytochrome P-450 may act as an oxygen sensor coupling hypoxia to K+ channel inhibition, by investigating the actions of P-450 inhibitors to modulate channel activity (recorded using patch-clamp techniques) in type I cells isolated from 8-12 day-old rat pups. The imidazole antimycotic P-450 inhibitors miconazole and clotrimazole (1-10[mu]M) inhibited the Ca2+-activated (KCa) and voltage gated K+ (Kv) currents in isolated type I cells. Single channel recordings indicated that the KCa channels could be inhibited directly by miconazole. Miconazole also irreversibly inhibited Ca2+ channel currents. By contrast, acute application of the suicide-substrate P -450 inhibitor, 1-aminobenzotriazole (1-ABT; 3mM) was without effect on K+ or Ca2+ currents. Hypoxia (16-23mmHg) reversibly inhibited K+ currents, and prevented the inhibitory actions of miconazole. Furthermore, the inhibitory actions of miconazole could be partially reversed by hypoxia. Pretreatment of cells for 60min with 3mM 1-ABT substantially reduced the inhibitory actions of hypoxia on K+ currents. Our results indicate that imidazole antimycotic P-450 inhibitors can directly and non-selectively inhibit ionic channels in type I cells but, more importantly, provide evidence to suggest that hypoxic inhibition of K+ currents in type I cells is mediated in part at least by cytochrome P-450. 

Received 10 July 1995; accepted in final form 3 January 1996.
APS Manuscript Number C415-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 25 January 96