The Heart Rate Decrease Caused by Acute FTY720 Administration Is Mediated by the G Protein-Gated Potassium Channel IKACh

Abstract

Sphingosine-1-phosphate (S1P) is an endogenous agonist for a family of five G protein-coupled receptors (S1P 1-5 ) involved in cell proliferation, cardiovascular development and lymphocyte trafficking. The sphingolipid drug FTY720 displays structural similarity to S1P and efficacy as an immunosuppressant in models of autoimmune disease and in solid organ transplantation. While FTY720 is well-tolerated in humans, it produces a transient reduction of heart rate (HR). As S1P activates the cardiac G protein-gated potassium channel I KACh , we speculated that the FTY720-induced HR reduction reflects I KACh activation. We examined FTY720 effects on atrial myocytes from wild-type and I KACh -deficient mice. In wild-type myocytes, the active phosphate metabolite of FTY720 (FTY720-P) induced single channel activity with conductance, open time, GTP sensitivity and rectification identical to that of I KACh . In whole-cell recordings, FTY720-P evoked an inwardly rectifying potassium current in ∼90% of myocytes responding to acetylcholine. Comparable channel activity was never observed in myocytes from I KAChdeficient mice. In wild-type mice, acute FTY720 administration produced a dose-dependent, robust HR reduction. In contrast, the HR reduction induced by FTY720 in I KACh -deficient mice was blunted. We conclude that the effect of acute FTY720 administration on HR is mediated primarily by I KACh activation.

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists

“…13 Bradycardia is also observed in humans, but it is now thought to arise through activation of S1P 1 rather than S1P 3 , 10,14 which is consistent with the finding that S1P 3 -sparing agonists have been shown to cause a reduction in heart rate in human trials. 10,15 More recently, S1P 3 has been found to be associated with pro-fibrotic properties.…”

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

“…It is now understood that in humans at least, this cardiovascular event more likely results from S1P 1 -dependent G protein gated inwardly rectifying potassium (GIRK) channel activation on human atrial myocytes. 13,14 Regardless, S1P 3 -sparing agonists may still be desirable, as nonselective S1P 1 agonists are associated with pro-fibrotic responses via S1P 2 -and S1P 3 -dependent signaling. 15,16 Identification of new agents with reduced elimination half-life has been sought after, as full lymphocyte recovery following fingolimod treatment requires >5 weeks and could be a complicating factor in the event of opportunistic infection.…”

FTY720/Cyclosporine Regimens in De Novo Renal Transplantation: A 1-Year Dose-Finding Study

“…This finding supports other clinical trials with FTY720 in maintenance renal transplant recipients, which suggest that FTY720 elicits a mild pharmacodynamic effect on reducing heart rate (8,9,13). The reduction in heart rate observed following FTY720 is thought to be mediated by I KACh (a cardiac potassium channel) activation, and the transient nature of the effect may be due to agonist-induced homologous desensitization involving S1P-R internalization (14)(15)(16). As noted in the current study, no other cardiac events have been associated with FTY720 administration in renal transplant patients (8,9,13).…”