First eco-toxicological evidence of ivabradine effect on the marine bacterium Vibrio fischeri: A chiral view.

Ivabradine (S-ivabradine) is a contemporary antihypertensive drug designed and commercialized for cardiovascular diseases treatment over the world. In this work the enantiomer-specific stability and acute toxicity of ivabradine to the marine bacterium Vibrio fischeri as well as the potential mechanism of action were investigated for the first time. With this aim, real concentrations of ivabradine enantiomers under abiotic and biotic conditions were determined by Capillary Electrophoresis (CE) with cyclodextrins (CDs) as chiral selectors. A moderate chiral stability without enantiomeric interconversion was observed for ivabradine. The bioluminescence inhibition method revealed an enantioselective toxicity of ivabradine to marine bacterium. The order of ecotoxicity was R-ivabradine < racemic ivabradine < S-ivabradine with EC50 (t = 5 min) values about 75.98, 11.11 and 7.93 mg/L, respectively. Confocal Live/Dead stained images showed that bacterial envelops cells were seriously damaged after exposure to S-ivabradine. S-ivabradine also disturbed the esterase activity and significantly increased the ROS level compared with the control. Thus, oxidative stress originating membrane cells damage and enzymatic activity changes was shown to be the primary mechanism of S-ivabradine toxicity to marine bacterium. Our results highlight the need for more eco-toxicological evaluations of the cardiovascular drug S-ivabradine on other aquatic organisms to establish the risk on the environment.