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 inhibition of K+ channels in type I cells. We have investigated whether cytochrome P-450 may act as an O2 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-to 12-day-old rat pups. The imidazole antimycotic P-450 inhibitors miconazole and clotrimazole (1-10 microM) inhibited the Ca(2+)-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; 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 could be partially reversed by hypoxia. Pretreatment of cells for 60 min with 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 hypoxic inhibition of K+ currents in type I cells is mediated in part at least by cytochrome P-450.
Hatton
C J
CJ
Institute for Cardiovascular Research, Leeds University, United Kingdom.
Peers
C
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D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002344:Carotid Body / Q000166:cytology / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D003022:Clotrimazole / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004553:Electric Conductivity; D000860:Hypoxia / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007477:Ions; D008825:Miconazole / Q000494:pharmacology; D026902:Potassium Channel Blockers; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D014230:Triazoles / Q000494:pharmacology
D000935:Antifungal Agents; D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D007477:Ions; D026902:Potassium Channel Blockers; D014230:Triazoles; C033020:1-aminobenzotriazole; C029899:imidazole; D008825:Miconazole; D003022:Clotrimazole