Inhibition of maxi-K currents in ferret portal vein smooth muscle cells by the antifungal clotrimazole.
The antifungal agent clotrimazole (CLT) is a potent small-molecule inhibitor of Ca-activated K (KCa) currents of intermediate conductance in murine erythroleukemia cells. This study demonstrates that CLT also inhibits large-conductance KCa currents (maxi-K currents) in acutely dissociated vascular smooth muscle (VSM) cells of ferret portal vein. The magnitude of block of a component of the whole cell K current by CLT was sensitive to test potential. CLT inhibited unitary maxi-K currents in outside-out patches, apparently by decreasing the mean open time. A metabolite of CLT lacking an imidazole ring also inhibited K currents. In contrast, the antifungal drug ketoconazole increased these same currents. Thus the inhibitory action of CLT appears to be due to a direct interaction with the channel protein rather than to imidazole block of cytochrome P-450 activity. Consistent with inhibition of maxi-K currents by CLT, superfusion of strips of portal vein VSM with CLT enhanced isometric tension and spontaneous rate of contraction, suggesting that CLT modulation of maxi-K currents may alter vasomotor functioning.
Rittenhouse
A R
AR
Molecular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
Parker
C
C
Brugnara
C
C
Morgan
K G
KG
Alper
S L
SL
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018999:Charybdotoxin / Q000494:pharmacology; D003022:Clotrimazole / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004553:Electric Conductivity; D005289:Ferrets; D005905:Glyburide / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014118:Toxins, Biological / Q000494:pharmacology
D000935:Antifungal Agents; D010455:Peptides; D026902:Potassium Channel Blockers; D013757:Tetraethylammonium Compounds; D014118:Toxins, Biological; D018999:Charybdotoxin; D019789:Tetraethylammonium; C064719:iberiotoxin; D003577:Cytochrome P-450 Enzyme System; D015761:4-Aminopyridine; D003022:Clotrimazole; D005905:Glyburide