title: The effect of the sphingosine-1-phosphate analogue FTY720 on atrioventricular nodal tissue.
abstract: The sphingosine-1-phosphate (S1P) receptor modulator, fingolimod (FTY720), has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular (AV) conduction block have been reported in some patients after the first dose. The underlying mechanism of this AV node conduction blockade is still not well-understood. In this study, we hypothesize that expression of this particular arrhythmia might be related to a direct effect of FTY720 on AV node rather than a parasympathetic mimetic action. We, therefore, investigated the effect of FTY720 on AV nodal, using in vitro rat model preparation, under both basal as well as ischaemia/reperfusion conditions. We first look at the expression pattern of S1P receptors on the AV node using real-time PCR. Although all three S1P receptor isoforms were expressed in AVN tissues, S1P1 receptor isoform expression level was higher than S1P2 and S1P3. The effect of 25 nM FTY720 on cycle length (CL) was subsequently studied via extracellular potentials recordings. FTY720 caused a mild to moderate prolongation in CL by an average 9% in AVN (n = 10, P < 0.05) preparations. We also show that FTY720 attenuated both ischaemia and reperfusion induced AVN rhythmic disturbance. To our knowledge, these remarkable findings have not been previously reported in the literature, and stress the importance for extensive monitoring period in certain cases, especially in patients taking concurrently AV node blocker agents.
authors: Egom Clinical and Translational Research Services, Halifax, NS, Canada.
authors: Emmanuel E
authors: EE
authors: Egom
authors: Department of Cardiovascular Diseases, International Clinical Research Center, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic.
authors: Peter
authors: P
authors: Kruzliak
authors: Department of Cardiovascular Diseases, International Clinical Research Center, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic.|Department of Medical Physics and Biophysics, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovak Republic.
authors: Vladimir
authors: V
authors: Rotrekl
authors: Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.|Department of Pharmacology, University of Oxford, Oxford & Institute of Cardiovascular Sciences, UK.
authors: Ming
authors: M
authors: Lei
mesh_terms: D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects* / Q000503:physiopathology; D004210:Dissection; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008246:Lysophospholipids / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: atrioventricular node; fingolimod; sphingosine-1-phosphate