ArticlePloS one2012
The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁) and hypertension (S1P₃) in rat.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 79 citations in OpenAlex.
- Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial.Journal of neurology, neurosurgery, and psychiatry · 2014Trial
- Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.Nature communications · 2024Article
- Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis.International journal of molecular sciences · 2022Article
- Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease.Nature reviews. Gastroenterology & hepatology · 2022Review
- Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases.Nature reviews. Rheumatology · 2022Review
- Sphingolipid metabolism and signaling in cardiovascular diseases.Frontiers in cardiovascular medicine · 2022Review
- Sphingolipid Metabolism and Signaling in Endothelial Cell Functions.Advances in experimental medicine and biology · 2022Review
- Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod.Frontiers in pharmacology · 2022Review
- A Human Retinal Pigment Epithelium-Based Screening Platform Reveals Inducers of Photoreceptor Outer Segments Phagocytosis.Stem cell reports · 2020Article
- The role of sphingosine 1-phosphate and its receptors in cardiovascular diseases.Journal of cellular and molecular medicine · 2020Review
- Sphingosine-1-Phosphate: Its Pharmacological Regulation and the Treatment of Multiple Sclerosis: A Review Article.Biomedicines · 2020Review
- A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models.Acta pharmaceutica Sinica. B · 2020Article
- A Sphingosine-1-Phosphate Receptor Modulator Attenuated Secondary Brain Injury and Improved Neurological Functions of Mice after ICH.Oxidative medicine and cellular longevity · 2020Article
- Sphingolipids in the Heart: From Cradle to Grave.Frontiers in endocrinology · 2020Review
- Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway.Journal of cellular and molecular medicine · 2020Article
- FTY720 controls disease severity and attenuates sciatic nerve damage in chronic experimental autoimmune neuritis.Journal of neuroinflammation · 2019Article
- An update on sphingosine-1-phosphate receptor 1 modulators.Bioorganic & medicinal chemistry letters · 2018Review
- S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure.Hypertension (Dallas, Tex. : 1979) · 2017Article
- Sphingolipids in obesity and related complications.Frontiers in bioscience (Landmark edition) · 2017Review
- Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery.Biomolecules & therapeutics · 2017Review
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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