title: The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁) and hypertension (S1P₃) in rat.
abstract: Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P₁,₅ agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation.
authors.affiliation: Department of Cardiometabolic Disease Research, Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States of America. ryan.fryer@boehringer-ingelheim.com
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Akalushi
authors.initials: A
authors.lastname: Muthukumarana
authors.forename: Paul C
authors.initials: PC
authors.lastname: Harrison
authors.forename: Suzanne
authors.initials: S
authors.lastname: Nodop Mazurek
authors.forename: Rong Rhonda
authors.initials: RR
authors.lastname: Chen
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Harrington
authors.forename: Roger M
authors.initials: RM
authors.lastname: Dinallo
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Horan
authors.forename: Lori
authors.initials: L
authors.lastname: Patnaude
authors.forename: Louise K
authors.initials: LK
authors.lastname: Modis
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
mesh_terms: D000818:Animals; D001384:Azetidines / Q000009:adverse effects* / Q000494:pharmacology; D001593:Benzyl Compounds / Q000009:adverse effects* / Q000494:pharmacology; D001919:Bradycardia / Q000139:chemically induced* / Q000473:pathology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D000068876:Fingolimod Hydrochloride; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D011409:Propylene Glycols / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000145:classification; D013110:Sphingosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; C578989:siponimod