Inhibition of PGI2 signaling by miconazole in vascular smooth muscle cells.
Miconazole is widely used clinically as an anti-fungal agent and experimentally as a cytochrome P450 (CYP) inhibitor. In rat coronary arteries that produce PGI(2) as the major arachidonic acid (AA) metabolite, activation of the large-conductance K(+) (BK) channels in coronary arterial smooth muscle cells by AA was inhibited by miconazole but not by the CYP inhibitor SKF525A. Activation of BK currents in coronary smooth muscle cells by carbacyclin or iloprost also was inhibited by miconazole but not by SKF525A, suggesting that miconazole might have properties other than those of CYP inhibition. In addition, carbacyclin-induced dilation of isolated mesenteric arteries was inhibited by treatment with miconazole (51.9+/-4.2% dilation in control, n=7 versus 30.1+/-4.0% with miconazole, n=4, p<0.005) but not SKF525A (52.8+/-3.6%, n=8). In contrast, miconazole did not affect BK channel activation and vasodilation produced by the phosphodiesterase inhibitor RO-201724. In cultured coronary smooth muscle cells, carbacyclin (1microM) stimulated cAMP production by 22-fold (183+/-29pmol/mg at baseline, 4062+/-212pmol/mg with carbacyclin, n=3, p<0.001). The carbacyclin effect was significantly attenuated by treatment with miconazole (1542+/-201pmol/mg, n=3, p<0.001 versus carbacyclin alone), but not by SKF525A (3460+/-406pmol/mg, n=3, p=NS versus carbacyclin alone). These results indicate that in addition to its CYP inhibition properties, miconazole inhibits PGI(2) signaling. Hence, experiments using miconazole as a CYP inhibitor should be interpreted with caution.
Zhou
Wei
W
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States.
Lu
Tong
T
Spector
Arthur A
AA
Lee
Hon-Chi
HC
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008825:Miconazole / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D051036:Large-Conductance Calcium-Activated Potassium Channels; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C026678:carboprostacyclin; D008825:Miconazole; D011335:Proadifen; D011464:Epoprostenol; D000242:Cyclic AMP