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Nitric Oxide. 2015 Apr 30;46:131-44. doi: 10.1016/j.niox.2014.12.012. Epub 2014 Dec 30.

Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.

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Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia; Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia.
Institute of Normal and Pathological Physiology, SAS, Bratislava, Slovakia.
Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia; Center for Molecular Medicine, SAS, Bratislava, Slovakia.
LOX Technologies, Bratislava, Slovakia.
Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
University of Exeter Medical School, Exeter, UK. Electronic address:


H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium derivatised dithiolethione (AP39), in the presence and absence of reduced nitric oxide bioavailability and (ii) to determine the effects of AP39 on myocardial membrane channels; CaV3, RyR2 and Cl(-). Normotensive, L-NAME- or phenylephrine-treated rats were administered Na2S, AP39 or control compounds (AP219 and ADT-OH) (0.25-1 µmol kg(-1)i.v.) and haemodynamic parameters measured. The involvement of membrane channels T-type Ca(2+) channels CaV3.1, CaV3.2 and CaV3.3 as well as Ca(2+) ryanodine (RyR2) and Cl(-) single channels derived from rat heart sarcoplasmic reticulum were also investigated. In anaesthetised Wistar rats, AP39 (0.25-1 µmol kg(-1) i.v) transiently decreased blood pressure, heart rate and pulse wave velocity, whereas AP219 and ADT-OH and Na2S had no significant effect. In L-NAME treated rats, AP39 significantly lowered systolic blood pressure for a prolonged period, decreased heart rate and arterial stiffness. In electrophysiological studies, AP39 significantly inhibited Ca(2+) current through all three CaV3 channels. AP39 decreased RyR2 channels activity and increased conductance and mean open time of Cl(-) channels. This study suggests that AP39 may offer a novel therapeutic opportunity in conditions whereby (•)NO and H2S bioavailability are deficient such as hypertension, and that CaV3, RyR2 and Cl(-) cardiac membrane channels might be involved in its biological actions.


AP39; Blood pressure; H(2)S; Nitric oxide deficiency; Pulse wave velocity

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