title: Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.
abstract: 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.
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia; Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors.forename: Lenka
authors.initials: L
authors.lastname: Tomasova
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Pavlovicova
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia.
authors.forename: Lubica
authors.initials: L
authors.lastname: Malekova
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia.
authors.forename: Anton
authors.initials: A
authors.lastname: Misak
authors.affiliation: Institute of Normal and Pathological Physiology, SAS, Bratislava, Slovakia.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Kristek
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia; Center for Molecular Medicine, SAS, Bratislava, Slovakia.
authors.forename: Marian
authors.initials: M
authors.lastname: Grman
authors.affiliation: Institute of Normal and Pathological Physiology, SAS, Bratislava, Slovakia.
authors.forename: Sona
authors.initials: S
authors.lastname: Cacanyiova
authors.affiliation: LOX Technologies, Bratislava, Slovakia.
authors.forename: Milan
authors.initials: M
authors.lastname: Tomasek
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tomaskova
authors.affiliation: Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
authors.forename: Alexis
authors.initials: A
authors.lastname: Perry
authors.affiliation: Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia.
authors.forename: Lubica
authors.initials: L
authors.lastname: Lacinova
authors.affiliation: Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia.
authors.forename: Karol
authors.initials: K
authors.lastname: Ondrias
authors.affiliation: University of Exeter Medical School, Exeter, UK. Electronic address: m.whiteman@exeter.ac.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
mesh_terms: D000781:Anethole Trithione / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D051244:Caveolin 3 / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D063177:Pulse Wave Analysis; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*
chemical_list: C495549:Cav3 protein, rat; D051244:Caveolin 3; D009943:Organophosphorus Compounds; D019837:Ryanodine Receptor Calcium Release Channel; D010656:Phenylephrine; D000781:Anethole Trithione; D019331:NG-Nitroarginine Methyl Ester; D006862:Hydrogen Sulfide
keywords: AP39; Blood pressure; H(2)S; Nitric oxide deficiency; Pulse wave velocity