P47 Exogenous and endogenous hydrogen sulfide (H2S) in gastroprotection against ischemia/reperfusion lesions progressing into chronic ulcers. Role of endogenous prostaglandins, sensory neuropeptides and vanilloid receptors

Abstract

H 2 S is an endogenous gasotransmitter which exerts vasodilatatory, neuromodulatory and anti-inflammatory activities but little is known whether this gaseous mediator affects ischemia–reperfusion (I/R)-induced gastric erosions. We studied the effect of H 2 S precursor, l -cysteine and H 2 S-donor, NaHS on I/R lesions induced by 30 min of I followed by 3 h of R and their progression into chronic gastric ulcers at 12–72 h after the end of I. Rats exposed to I/R received once daily (1) l -cysteine (2–40 mg/kg) and (2) NaHS (0.1–10 mg/kg i.g.) combined or not with the inhibitor of CSE, d , l -propargylglycine (PAG 30 mg/kg i.g.); (3) the non-selective (indomethacin; 5 mg/kg i.p.) or selective COX-1 (SC-560, 5 mg/kg i.p.) and COX-2 inhibitors (celecoxib 30 mg/kg i.g.); (4) blockade of sensory nerves by capsaicin (125 mg/kg s.c.) and the inhibition of vanilloid receptor (VR-1) by capsazepine (10 mg/kg i.g.). The number of gastric lesions was measured by planimetry, the gastric blood flow (GBF) determined by H 2 -gas clearance technique, the mucosal concentration of H 2 S was determined spectrophotometrically, the plasma IL-1beta and TNF-alpha were determined by ELISA and mRNA expressions for CSE, COX-1-, COX-2-, CGRP, IL-1beta-, and TNF-alpha were assessed by RT-PCR. I/R-induced gastric mucosal lesions progressed into gastric ulcers at 72 h following the end of I. The significant fall in the H 2 S concentration and GBF were observed in gastric mucosa of I/R and these effects persisted up to 72 h upon standard I/R. NaHS (5 mg/kg i.g.) and l -cysteine (20 mg/kg i.g.) which significantly increased H 2 S content in the gastric mucosa and GBF, significantly reduced I/R-induced gastric lesions area at 24 h and 72 h following end of I. Capsaicin denervation, capsazepine and treatment with COXs inhibitors exacerbated I/R injury and significantly reduced the GBF and these effects were reversed by co-treatment with CGRP (10 μg/kg s.c.) or dimethyl PGE 2 (5 μg/kg i.g.) in the presence of NaHS and cysteine in capsaicin-denervated or COX-1- and COX-2-inhibited animals. The mRNA expression for CSE and CBS was increased in I/R gastric mucosa and this was inhibited by NaHS and cysteine. We conclude that (1) pathogenesis of I/R injury involves the fall in the generation of H 2 S and (2) NaHS and cysteine protect the gastric mucosa against I/R lesions and accelerate the healing of these lesions progressing into gastric ulcers via an increase in GBF mediated by endogenous H 2 S, PG pathway and CGRP.