EFFECTS OF CYTOCHROME-P-450 INHIBITORS ON IONIC CURRENTS IN ISOLATED RAT TYPE-I CAROTID-BODY CELLS

Hypoxic chemoreception in the carotid body involves selective inhibiti on of K+ channels in type I cells. We have investigated whether cytoch rome P-450 may act as an O-2 sensor coupling hypoxia to K+ channel inh ibition, by investigating the actions of P-450 inhibitors to modulate channel activity (recorded using patch-clamp techniques) in type I cel ls isolated from 8- to 12-day-old rat pups. The imidazole antimycotic P-450 inhibitors miconazole and clotrimazole (1-10 mu M) inhibited the Ca2+-activated (K-Ca) and voltage-gated K+ (K-v) currents in isolated type I cells. Single-channel recordings indicated that the K-Ca chann els could be inhibited directly by miconazole. Miconazole also irrever sibly inhibited Ca2+ channel currents. By contrast, acute application of the suicide substrate P-450 inhibitor, 1-aminobenzotriazole (1-ABT; 3 mM) was without effect on K+ or Ca2+ currents. Hypoxia (16-23 mmHg) reversibly inhibited K+ currents and prevented the inhibitory actions of miconazole. Furthermore, the inhibitory actions of miconazole coul d be partially reversed by hypoxia. Pretreatment of cells for 60 min w ith 3 mM 1-ABT substantially reduced the inhibitory actions of hypoxia on K+ currents. Our results indicate that imidazole antimycotic P-450 inhibitors can directly and nonselectively inhibit ionic channels in type I cells but, more importantly, provide evidence to suggest that h ypoxic inhibition of K+ currents in type I cells is mediated in part a t least by cytochrome P-450.