Abstract
Hydrogen sulfide (H2S) is an endogenous mediator, synthesized from l-cysteine by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) or 3-mercaptopyruvate sulfurtransferase (3-MST). The mechanism(s) involved in H2S-gastroprotection against ischemia/reperfusion (I/R) lesions and their time-dependent progression into deeper gastric ulcerations have been little studied. We determined the effect of l-cysteine, H2S-releasing NaHS or slow H2S releasing compound GYY4137 on gastric blood flow (GBF) and gastric lesions induced by 30 min of I followed by 3, 6, 24 and 48 h of R. Role of endogenous prostaglandins (PGs), afferent sensory nerves releasing calcitonin gene-related peptide (CGRP), the gastric expression of hypoxia inducible factor (HIF)-1α and anti-oxidative enzymes were examined. Rats with or without capsaicin deactivation of sensory nerves were pretreated i.g. with vehicle, NaHS (18–180 μmol/kg) GYY4137 (90 μmol/kg) or l-cysteine (0.8–80 μmol/kg) alone or in combination with (1) indomethacin (14 μmol/kg i.p.), SC-560 (14 μmol/kg), celecoxib (26 μmol/kg); (2) capsazepine (13 μmol/kg i.p.); and (3) CGRP (2.5 nmol/kg i.p.). The area of I/R-induced gastric lesions and GBF were measured by planimetry and H2-gas clearance, respectively. Expression of mRNA for CSE, CBS, 3-MST, HIF-1α, glutathione peroxidase (GPx)-1, superoxide dismutase (SOD)-2 and sulfide production in gastric mucosa compromised by I/R were determined by real-time PCR and methylene blue method, respectively. NaHS and l-cysteine dose-dependently attenuated I/R-induced lesions while increasing the GBF, similarly to GYY4137 (90 μmol/kg). Capsaicin denervation and capsazepine but not COX-1 and COX-2 inhibitors reduced NaHS- and l-cysteine-induced protection and hyperemia. NaHS increased mRNA expression for SOD-2 and GPx-1 but not that for HIF-1α. NaHS which increased gastric mucosal sulfide release, prevented further progression of acute I/R injury into deeper gastric ulcers at 6, 24 and 48 h of R. We conclude that H2S-induced gastroprotection against I/R-injury is due to increase in gastric microcirculation, anti-oxidative properties and afferent sensory nerves activity but independent on endogenous prostaglandins.
Highlights
Hydrogen sulfide (H2 S) plays an important role as intracellular gaseous transmitter and contributes to many physiological and pathological processes [1,2]
Endogenous H2 S is synthesized from L-cysteine by the activity of two main pirydoxal-5-phosphate (P5P, vitamin B6 ) dependent enzymes: cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) [8,9] or by 3-mercaptopyruvate sulfurtransferase (3-MST) in co-activity with cysteine aminotransferase [10]
Exposure to I followed by 3 h of R caused the extensive hemorrhagic erosions in gastric mucosa of rats pretreated with vehicle-control (Figure 1A)
Summary
Hydrogen sulfide (H2 S) plays an important role as intracellular gaseous transmitter and contributes to many physiological and pathological processes [1,2]. This molecule exerts vasoactive activity to nitric oxide (NO) and carbon monoxide (CO), all three considered to act as endogenous gaseous mediators [3,4,5,6]. H2 S plays an important role in the regulation of the physiological functions of gastrointestinal (GI) tract and the mechanism of GI-integrity maintenance [11].
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