Document Detail


FTY720 (fingolimod) increases vascular tone and blood pressure in spontaneously hypertensive rats via inhibition of sphingosine kinase.
MedLine Citation:
PMID:  22251137     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 BP. We previously showed that inhibition of sphingosine kinase increases vascular tone and BP in hypertensive, but not normotensive rats. Since FTY720 is reported to have inhibitory effects on sphingosine kinase, we investigated whether FTY720 increases vascular tone and BP only in hypertensive rats via this mechanism.
EXPERIMENTAL APPROACH: The contractile and BP 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 (SHRs).
KEY RESULTS: Oral administration of FTY720 induced an increase in mean arterial pressure in SHR, whereas a decrease in BP was observed in WKY rats, as measured 24 h after administration. Similar to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced large contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions were inhibited by endothelium denudation, COX and thromboxane synthase inhibitors, and by thromboxane receptor antagonism, indicating that (like DMS-induced contractions) they were endothelium-dependent and mediated by thromboxane A₂.
CONCLUSIONS AND IMPLICATIONS: These data demonstrate that FTY720 increases vascular tone and BP only in hypertensive rats, most likely as a result of its inhibitory effect on sphingosine kinase.
Authors:
Léon J A Spijkers; Astrid E Alewijnse; Stephan L M Peters
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  British journal of pharmacology     Volume:  166     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-18     Completed Date:  2012-10-09     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1411-8     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Affiliation:
Department of Pharmacology & Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure / drug effects
Carotid Arteries / cytology,  drug effects,  metabolism*,  pathology
Cyclooxygenase Inhibitors / pharmacology
Endothelium, Vascular / cytology,  drug effects,  metabolism*,  pathology
Enzyme Inhibitors / adverse effects,  chemistry,  pharmacology
Hypertension / chemically induced,  metabolism*,  pathology,  physiopathology
Immunosuppressive Agents / adverse effects,  chemistry,  pharmacology
Isoenzymes / antagonists & inhibitors,  metabolism
Male
Muscle, Smooth, Vascular / cytology,  drug effects,  metabolism*,  pathology
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors,  metabolism*
Propylene Glycols / adverse effects,  chemistry,  pharmacology
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Sphingosine / adverse effects,  analogs & derivatives,  chemistry,  pharmacology
Thromboxane A2 / antagonists & inhibitors,  metabolism
Vascular Resistance* / drug effects
Vasoconstrictor Agents / adverse effects,  chemistry,  pharmacology
Chemical
Reg. No./Substance:
0/Cyclooxygenase Inhibitors; 0/Enzyme Inhibitors; 0/Immunosuppressive Agents; 0/Isoenzymes; 0/Propylene Glycols; 0/Vasoconstrictor Agents; 123-78-4/Sphingosine; 3QN8BYN5QF/fingolimod; 57576-52-0/Thromboxane A2; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase
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