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

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

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anethole Trithione / chemistry
  • Anethole Trithione / metabolism
  • Anethole Trithione / pharmacology*
  • Animals
  • Blood Pressure / drug effects*
  • Caveolin 3 / drug effects*
  • Hydrogen Sulfide / chemistry
  • Hydrogen Sulfide / metabolism
  • Hydrogen Sulfide / pharmacology*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / metabolism
  • Organophosphorus Compounds / pharmacology*
  • Phenylephrine / pharmacology
  • Pulse Wave Analysis
  • Rats
  • Rats, Wistar
  • Ryanodine Receptor Calcium Release Channel / drug effects*

Substances

  • Cav3 protein, rat
  • Caveolin 3
  • Organophosphorus Compounds
  • Ryanodine Receptor Calcium Release Channel
  • Phenylephrine
  • Anethole Trithione
  • NG-Nitroarginine Methyl Ester
  • Hydrogen Sulfide