FTY720 (fingolimod) increases vascular tone and blood pressure in spontaneously hypertensive rats via inhibition of sphingosine kinase

• Published in: British journal of pharmacology Vol. 166; no. 4; pp. 1411 - 1418
• Main Authors: Spijkers, Léon JA, Alewijnse, Astrid E, Peters, Stephan LM
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-06-2012; Nature Publishing Group
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Carotid Arteries - cytology; Carotid Arteries - drug effects; Carotid Arteries - metabolism; Carotid Arteries - pathology; Cyclooxygenase Inhibitors - pharmacology; EDCF; Endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fingolimod; Fingolimod Hydrochloride; FTY720; hypertension; Hypertension - chemically induced; Hypertension - metabolism; Hypertension - pathology; Hypertension - physiopathology; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - pharmacology; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Kinases; Male; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Pharmacology. Drug treatments; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Propylene Glycols - adverse effects; Propylene Glycols - chemistry; Propylene Glycols - pharmacology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Research Papers; Rodents; sphingolipids; Sphingosine - adverse effects; Sphingosine - analogs & derivatives; Sphingosine - chemistry; Sphingosine - pharmacology; sphingosine kinase; Thromboxane A2 - antagonists & inhibitors; Thromboxane A2 - metabolism; Vascular Resistance - drug effects; vasoconstriction; Vasoconstrictor Agents - adverse effects; Vasoconstrictor Agents - chemistry; Vasoconstrictor Agents - pharmacology; Rat; sphingolipids; sphingosine kinase; Cardiovascular disease; Vasomotricity; Sphingosine; Arterial pressure; Blood pressure; Hypertension; EDCF; Fingolimod; Enzyme; Transferases; Rodentia; Vasoconstriction; Sphingolipid; Endothelium; Immunomodulator; Vertebrata; Mammalia; Kinase; Animal; FTY720; Hemodynamics; Immunosuppressive agent
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.01865.x

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.