Potential role of the gaseous mediator hydrogen sulphide (H2S) in inhibition of human colonic contractility

Background: Hydrogen sulphide (H2S) is an endogenous signalling molecule that might play a physiologically relevant role in gastrointestinal motility. Cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) are two enzymes responsible for H2S production. D,L-Propargylglycine (PAG) is a CSE inhibitor whereas both aminooxyacetic acid (AOAA) and hydroxylamine (HA) are CBS inhibitors. The characterization of H2S responses and its mechanism of action are crucial to define H2S function. Methods: Human colonic strips were used to investigate the role of H2S on contractility (muscle bath) and smooth muscle electrophysiology (microelectrodes). NaHS was used as a H2S donor. Results: Combination of PAG and AOAA depolarized the smooth muscle (5-6 mV, n=4) and elicited a transient increase in tone (260.5 +/- 92.8 mg, n=12). No effect was observed on neural mediated inhibitory junction potential or relaxation. In the presence of tetrodotoxin 1 mu M, NaHS concentration-dependently inhibited spontaneous contractions (EC50=329.2 mu M, n=18). This effect was partially reduced by the guanylyl cyclase inhibitor ODQ 10 mu M (EC50 n=12) and by L-NNA 1 mM (EC50 = 1.4 mM, n=8). NaHS reversibly blocked neural mediated cholinergic (EC50=2 mM) and tachykinergic (EC50 = 5.7 mM) contractions. NaHS concentration-dependently reduced the increase in spontaneous mechanical activity (AUC) induced by carbachol (EC50=1.9 mM) and NKA (EC50=1.7 mM AUC). Conclusions: H2S might be an endogenous gasomediator regulating human colonic contractility. Its inhibitory effect is observed at high concentrations and could be mediated by a direct effect on smooth muscle with a possible synergistic effect with NO, as well as by an interaction with the cholinergic and tachykinergic neural mediated pathways. (C) 2015 Elsevier Ltd. All rights reserved.