Signaling mechanisms involved in the intestinal pro-secretory actions of hydrogen sulfide

Abstract

Background H 2 S actions in the gut involve neural activation. This study aimed to reveal the signaling mechanisms responsible for the pro-secretory effect of H 2 S by using TRPV1 and unselective TRP blockers and inhibitors of other signaling cascades hitherto described to be targeted by H 2 S elsewhere. Methods Ussing chamber voltage clamp technique was used to study actions of the H 2 S donor NaHS on secretion in guinea-pig and human colon. NaHS effects on guinea-pig primary afferents were also evaluated. Key Results NaHS evoked secretion was significantly reduced in guinea-pig and human tissue by the selective TRPV1 blockers capsazepine, AMG9801, SB705498, BCTC; LY294002 (Phosphatidylinositol-3 kinase (PI3K) inhibitor), SKF96365 (store operated calcium channel blocker), 2-APB (inositol triphosphate blocker), and atropine but not by HC030031 (TRPA1 blocker) or L-and T-type calcium channel antagonists. Actions of TRPV1 antagonists suggested non-competitive inhibition at multiple sites. In guinea-pig colon, Gd 3+ and La 3+ (unselective TRP blockers) had no effects while ruthenium red reduced NaHS effects; in human colon Gd 3+ attenuated NaHS response. NaHS response was inhibited by neurokinin-1 and -3 receptor blockers in guinea-pig and neurokinin-1 and -2 receptor blockade in human tissue. There was cross-desensitization between NaHS and capsaicin responses. NaHS induced capsazepine and LY294002 sensitive afferent discharge. Conclusions & Inferences H 2 S evokes mucosal secretion by targeting TRPV1 expressing afferent nerves which activate cholinergic secretomotor neurons via release of substance P acting in a species dependent manner on neurokinin-1, -2 or -3 receptors. Besides TRPV1 signaling H 2 S may target intracellular calcium dependent pathways and PI3K.

H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO–TRPA1–CGRP signalling pathway

“…Furthermore, previous studies have also linked H 2 S to TRPA1 and microvascular blood flow mediated by CGRP53 and H 2 S and TRPA1/TRPV1 intestinal pro-secretory actions54. However, only very high concentrations of H 2 S activated TRPA1 (as we also observed, Supplementary Fig.…”

Inhibition of cystathionine β-synthetase suppresses sodium channel activities of dorsal root ganglion neurons of rats with lumbar disc herniation

“…Of note is that recent studies showed that sodium channels are not the sole target of H 2 S-induced pain hypersensitivity. T-type calcium channels2324, TRPV12526, TRPA120 and NMDA receptors27 have been indicated to play a crucial role in nociception. Conversely, H 2 S has been reported to mediate an anti-nociceptive effect by opening K(ATP) channels2829 and to prevent the development of opioid withdrawal-induced hyperalgesia by suppressing spinal calcitonin gene-related peptide expression30.…”

Hydrogen Sulfide Selectively Potentiates Central Preganglionic Fast Nicotinic Synaptic Input in Mouse Superior Mesenteric Ganglion

“…In the CNS, H 2 S enhances NMDA receptormediated responses during tetanic nerve stimulation in the hippocampus (Abe and Kimura, 1996;Tan et al, 2010;Austgen et al, 2011), reversibly inhibits synaptic responses in dorsal raphe serotonergic neurons (Kombian et al, 1993), and augments synaptic neurotransmission in the rat nucleus tractus solitarius (Austgen et al, 2011). In the peripheral nervous system, H 2 S induces contraction of the bladder wall (Patacchini et al, 2004) and acts on enteric neurons in the human and guinea pig colon to increase chloride secretion (Schicho et al, 2006;Krueger et al, 2010).…”