Fingolimod, a sphingosine 1-phosphate (S1P) receptor subtype 1, 3, 4 and 5 
modulator, has been used for the treatment of patients with relapsing forms of 
multiple sclerosis, but atrioventricular conduction block and/or QT-interval 
prolongation have been reported in some patients after the first dose. In this 
study, we directly compared the electropharmacological profiles of fingolimod 
with those of siponimod, a modulator of sphingosine 1-phosphate receptor subtype 
1 and 5, using in vivo guinea-pig model and in vitro human ether-a-go-go-related 
gene (hERG) assay to better understand the onset mechanisms of the clinically 
observed adverse events. Fingolimod (0.01 and 0.1mg/kg) or siponimod (0.001 and 
0.01mg/kg) was intravenously infused over 10min to the halothane-anaesthetized 
guinea pigs (n=4), whereas the effects of fingolimod (1μmol/L) and siponimod 
(1μmol/L) on hERG current were examined (n=3). The high doses of fingolimod and 
siponimod induced atrioventricular conduction block, whereas the low dose of 
siponimod prolonged PR interval, which was not observed by that of fingolimod. 
The high dose of fingolimod prolonged QT interval, which was not observed by 
either dose of siponimod. Meanwhile, fingolimod significantly inhibited hERG 
current, which was not observed by siponimod. These results suggest that S1P 
receptor subtype 1 in the heart could be one of the candidates for fingolimod- 
and siponimod-induced atrioventricular conduction block since S1P receptor 
subtype 5 is localized at the brain, and that direct IKr inhibition may play a 
key role in fingolimod-induced QT-interval prolongation.