Inhibition of PGI2 signaling by miconazole in vascular smooth muscle cells

Wei Zhou, Tong D Lu, Arthur A. Spector, Hon Chi Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Miconazole is widely used clinically as an anti-fungal agent and experimentally as a cytochrome P450 (CYP) inhibitor. In rat coronary arteries that produce PGI2 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 (1 μM) stimulated cAMP production by 22-fold (183 ± 29 pmol/mg at baseline, 4062 ± 212 pmol/mg with carbacyclin, n = 3, p < 0.001). The carbacyclin effect was significantly attenuated by treatment with miconazole (1542 ± 201 pmol/mg, n = 3, p < 0.001 versus carbacyclin alone), but not by SKF525A (3460 ± 406 pmol/mg, n = 3, p = NS versus carbacyclin alone). These results indicate that in addition to its CYP inhibition properties, miconazole inhibits PGI2 signaling. Hence, experiments using miconazole as a CYP inhibitor should be interpreted with caution.

Original languageEnglish (US)
Pages (from-to)28-34
Number of pages7
JournalProstaglandins and Other Lipid Mediators
Volume80
Issue number1-2
DOIs
StatePublished - Jul 2006

Fingerprint

Miconazole
Epoprostenol
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Cells
Cytochrome P-450 Enzyme System
Large-Conductance Calcium-Activated Potassium Channels
montirelin
Chemical activation
Arachidonic Acid
Dilatation
Antifungal agents
Iloprost
Mesenteric Arteries
Phosphodiesterase Inhibitors
Metabolites
carboprostacyclin
Vasodilation
Rats

Keywords

  • Arachidonic acid
  • Carbacyclin
  • Cytochrome P450
  • Miconazole
  • PGI
  • Smooth muscle cells

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Inhibition of PGI2 signaling by miconazole in vascular smooth muscle cells. / Zhou, Wei; Lu, Tong D; Spector, Arthur A.; Lee, Hon Chi.

In: Prostaglandins and Other Lipid Mediators, Vol. 80, No. 1-2, 07.2006, p. 28-34.

Research output: Contribution to journalArticle

@article{44e7ea76b8e84d82800b72a7026a085f,
title = "Inhibition of PGI2 signaling by miconazole in vascular smooth muscle cells",
abstract = "Miconazole is widely used clinically as an anti-fungal agent and experimentally as a cytochrome P450 (CYP) inhibitor. In rat coronary arteries that produce PGI2 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 (1 μM) stimulated cAMP production by 22-fold (183 ± 29 pmol/mg at baseline, 4062 ± 212 pmol/mg with carbacyclin, n = 3, p < 0.001). The carbacyclin effect was significantly attenuated by treatment with miconazole (1542 ± 201 pmol/mg, n = 3, p < 0.001 versus carbacyclin alone), but not by SKF525A (3460 ± 406 pmol/mg, n = 3, p = NS versus carbacyclin alone). These results indicate that in addition to its CYP inhibition properties, miconazole inhibits PGI2 signaling. Hence, experiments using miconazole as a CYP inhibitor should be interpreted with caution.",
keywords = "Arachidonic acid, Carbacyclin, Cytochrome P450, Miconazole, PGI, Smooth muscle cells",
author = "Wei Zhou and Lu, {Tong D} and Spector, {Arthur A.} and Lee, {Hon Chi}",
year = "2006",
month = "7",
doi = "10.1016/j.prostaglandins.2006.03.005",
language = "English (US)",
volume = "80",
pages = "28--34",
journal = "Prostaglandins",
issn = "1098-8823",
publisher = "Elsevier Inc.",
number = "1-2",

}

TY - JOUR

T1 - Inhibition of PGI2 signaling by miconazole in vascular smooth muscle cells

AU - Zhou, Wei

AU - Lu, Tong D

AU - Spector, Arthur A.

AU - Lee, Hon Chi

PY - 2006/7

Y1 - 2006/7

N2 - Miconazole is widely used clinically as an anti-fungal agent and experimentally as a cytochrome P450 (CYP) inhibitor. In rat coronary arteries that produce PGI2 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 (1 μM) stimulated cAMP production by 22-fold (183 ± 29 pmol/mg at baseline, 4062 ± 212 pmol/mg with carbacyclin, n = 3, p < 0.001). The carbacyclin effect was significantly attenuated by treatment with miconazole (1542 ± 201 pmol/mg, n = 3, p < 0.001 versus carbacyclin alone), but not by SKF525A (3460 ± 406 pmol/mg, n = 3, p = NS versus carbacyclin alone). These results indicate that in addition to its CYP inhibition properties, miconazole inhibits PGI2 signaling. Hence, experiments using miconazole as a CYP inhibitor should be interpreted with caution.

AB - Miconazole is widely used clinically as an anti-fungal agent and experimentally as a cytochrome P450 (CYP) inhibitor. In rat coronary arteries that produce PGI2 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 (1 μM) stimulated cAMP production by 22-fold (183 ± 29 pmol/mg at baseline, 4062 ± 212 pmol/mg with carbacyclin, n = 3, p < 0.001). The carbacyclin effect was significantly attenuated by treatment with miconazole (1542 ± 201 pmol/mg, n = 3, p < 0.001 versus carbacyclin alone), but not by SKF525A (3460 ± 406 pmol/mg, n = 3, p = NS versus carbacyclin alone). These results indicate that in addition to its CYP inhibition properties, miconazole inhibits PGI2 signaling. Hence, experiments using miconazole as a CYP inhibitor should be interpreted with caution.

KW - Arachidonic acid

KW - Carbacyclin

KW - Cytochrome P450

KW - Miconazole

KW - PGI

KW - Smooth muscle cells

UR - http://www.scopus.com/inward/record.url?scp=33745806593&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745806593&partnerID=8YFLogxK

U2 - 10.1016/j.prostaglandins.2006.03.005

DO - 10.1016/j.prostaglandins.2006.03.005

M3 - Article

VL - 80

SP - 28

EP - 34

JO - Prostaglandins

JF - Prostaglandins

SN - 1098-8823

IS - 1-2

ER -