Cilostazol prevents endothelin-induced smooth muscle constriction and proliferation

Cilostazol is a phosphodiesterase inhibitor that has been shown to inhibit platelet activation. Endothelin is known to be the most potent endogenous growth promoting and vasoactive peptide. In patients and animal models with stroke, the level of circulating endothelin increases and complicates the r...

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Bibliographic Details
Published in:PloS one 2012-09, Vol.7 (9), p.e44476
Main Authors: Kawanabe, Yoshifumi, Takahashi, Maki, Jin, Xingjian, Abdul-Majeed, Shakila, Nauli, Andromeda M, Sari, Youssef, Nauli, Surya M
Format: Article
Language:English
Subjects:
Analysis
Animal models
Animals
Biology
Blocking
Calcium
Calcium (extracellular)
Calcium - metabolism
Calcium influx
Cell culture
Cell growth
Cell Proliferation
Cerebral Arteries - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Cytosol - metabolism
Dose-Response Relationship, Drug
Endothelin
Endothelins
Endothelins - metabolism
Femoral artery
Femur
Flow cytometry
Flow Cytometry - methods
Heart failure
Immunohistochemistry - methods
Inhibition
Inhibitors
Kinases
Medicine
Mice
Microscopy, Fluorescence - methods
Muscle, Smooth - pathology
Muscles
Pathology
Pharmacology
Phosphodiesterase
Phosphodiesterase inhibitors
Phosphodiesterase Inhibitors - pharmacology
Piperazines - pharmacology
Protein kinase A
Purines - pharmacology
Rodents
Sildenafil
Sildenafil Citrate
Smooth muscle
Stroke
Sulfones - pharmacology
Tetrazoles - pharmacology
Vasoactive agents
Vasoconstriction
Vasodilator Agents - pharmacology
Veins & arteries
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Summary:Cilostazol is a phosphodiesterase inhibitor that has been shown to inhibit platelet activation. Endothelin is known to be the most potent endogenous growth promoting and vasoactive peptide. In patients and animal models with stroke, the level of circulating endothelin increases and complicates the recovery progress contributed by vascular constriction (an immediate pathology) and vascular proliferation (a long-term pathology). However, the effects of cilostazol on endothelin have not been explored. To demonstrate the dual-antagonizing effects of cilostazol on vasoconstriction and cell proliferation induced by endothelin, we used primary culture of mouse vascular smooth muscle cells in vitro, mouse femoral artery ex vivo, and intracranial basilar artery ex vivo. We show that the dual-inhibition effects of cilostazol are mediated by blocking endothelin-induced extracellular calcium influx. Although cilostazol does not inhibit endothelin-induced intraorganellar calcium release, blockade of extracellular calcium influx is sufficient to blunt endothelin-induced vasoconstriction. We also show that cilostazol inhibits endothelin-induced cellular proliferation by blocking extracellular calcium influx. Inhibition of cAMP-dependent protein kinase (PKA) can block anti-proliferation activity of cilostazol, confirming the downstream role of PKA in cellular proliferation. To further demonstrate the selectivity of the dual-antagonizing effects of cilostazol, we used a different phosphodiesterase inhibitor. Interestingly, sildenafil inhibits endothelin-induced vasoconstriction but not cellular proliferation in smooth muscle cells. For the first time, we show selective dual-antagonizing effects of cilostazol on endothelin. We propose that cilostazol is an excellent candidate to treat endothelin-associated diseases, such as stroke.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0044476