| FTY720 (Fingolimod) increases vascular tone and blood pressure in spontaneously hypertensive rats via inhibition of sphingosine kinase. | |
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MedLine Citation:
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PMID: 22251137 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background and purpose. FTY720 (Fingolimod) is a recently approved orally administered drug for the treatment of multiple sclerosis. Phase II and III clinical trials have demonstrated that this drug modestly increases blood pressure. We have previously shown that inhibition of sphingosine kinase increases vascular tone and blood pressure in hypertensive, but not normotensive rats. Since FTY720 is reported to have sphingosine kinase inhibitory effects, we investigated whether FTY720 increases vascular tone and blood pressure only in hypertensive rats via this mechanism. Experimental approach. The contractile and blood pressure modulating effects of FTY720 were studied in vivo and ex vivo (wire myography) in age-matched normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Key results. Oral administration of FTY720 induced an increase in mean arterial pressure in SHR, whereas a decrease in blood pressure was observed in WKY rats, as measured 24 hours after administration. In analogy to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced major contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 (FTY720-P) did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions (like DMS-induced contractions) proved to be endothelium-dependent and to be mediated by thromboxane A(2) , since these contractions could be inhibited by endothelium denudation, cyclooxygenase and thromboxane synthase inhibitors and by thromboxane receptor antagonism. Conclusions and Implications. These data demonstrate that FTY720 increases vascular tone and blood pressure only in hypertensive rats, most likely due to its sphingosine kinase inhibitory effect. |
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Authors:
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Léon J A Spijkers; Astrid E Alewijnse; Stephan L M Peters |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-17 |
Journal Detail:
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Title: British journal of pharmacology Volume: - ISSN: 1476-5381 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society. |
Affiliation:
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Department of Pharmacology & Pharmacotherapy, Academic Medical Center, Amsterdam, the Netherlands. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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