Parenteral Na2S, a fast-releasing H2S donor, but not GYY4137, a slow-releasing H2S donor, lowers blood pressure in rats

Abstract

Hydrogen sulfide (H₂S) is involved in blood pressure regulation. We evaluated hemodynamic effects of Na₂S and morpholin-4-ium (4-methoxyphenyl)(morpholino)phosphinodithioate (GYY4137), H₂S donors. GYY4137 is the most widely studied slow-releasing H₂S donor, however, its ability to release H₂S under physiological conditions is unclear. Hemodynamics were recorded in anaesthetized Wistar-Kyoto rats at baseline and after intravenous (IV) or intraperitoneal (IP) administration of either a vehicle (20% dimethyl sulfoxide), GYY4137 or Na₂S. The stability of GYY4137 in buffers and in plasma was evaluated with nuclear magnetic resonance. The vehicle, as well as GYY4137, given IV did not affect mean arterial blood pressure (MABP), whereas Na₂S produced a significant decrease in MABP. Similarly, IP given Na₂S, but not GYY4137, lowered MABP. In the buffers at pH of 7.4 and 5.5 and in rat plasma no reaction of GYY4137 was found during 18 hours of observation. In contrast, rapid decomposition of GYY4137 occurred in buffers at pH 2.0. In conclusion, parenteral GYY4137 does not exert a hemodynamic effect in Wistar-Kyoto rats. This seems to be due to the high stability of GYY4137 at physiological pH. Therefore, it is likely that widely reported biological effects of GYY4137 are not H₂S-dependent but may depend on GYY4137 itself. However, the H₂S-dependent biological effects of GYY4137 may be expected in tissues characterized by low pH.

Keywords: GYY4137; H2S-donor; blood pressure; gaseous transmitter; hydrogen sulfide; sodium sulfide.