Effect of Differentially Selective S1P Receptor Agonists on Cardiovascular Function after Acute and Long‐Term Administration in Rat Suggestive of Subtype‐Specific Bradycardia (S1P₁) and Hypertension (S1P₃)

Abstract

Sphingosine‐1‐Phospate (S1P) and S1P receptor agonists elicit mechanism‐based effects on cardiovascular function in vivo. Indeed, FTY‐720 (subtype non‐selective S1PX agonist) produces mild hypertension in patients (2–3 mmHg in a 1‐yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, possibly dependent upon the CV effect in question (e.g. bradycardia/hypertension), and perhaps even species‐dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, the cardiovascular effects of FTY‐720 after acute i.v. infusion in anesthetized rats, and after oral administration for up to 15‐d in telemetry‐instrumented conscious rats, was tested. The more selective S1P1,5 agonist, BAF‐312, was tested in the same models. We demonstrate that acute i.v. infusion (0.1, 0.3, 1.0 mg/kg/20min) of both FTY‐720 and BAF‐312 elicits bradycardia in rat, results suggestive of an S1P1 mediated mechanism. However, while FTY‐720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose‐dependent hypertension after multiple days of oral administration in rat (mean MAP=102, 107, 109 mmHg vs. 97 mmHg in vehicle controls), BAF‐312 (0.3, 3.0, 30.0 mg/kg/d) had no effect on blood pressure suggesting that hypertension produced by FTY‐720 is mediated by a non‐S1P1 subtype, likely S1P3. Moreover, hypertension in the presence of FTY‐720 may imply that FTY‐720 affects renal sodium handling in rats. In summary, results in anesthetized and conscious rats administered FTY‐720 or BAF‐312 suggest that S1P1 receptors mediate bradycardia while hypertension is mediated by S1P3 receptor activation.