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J Physiol Pharmacol. 2012 Feb;63(1):61-8.

Hydrogen sulfide-induced colonic mucosal cytoprotection involves T-type calcium channel-dependent neuronal excitation in rats.

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Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, Japan.


Hydrogen sulfide (H(2)S) is generated from L-cysteine by certain enzymes including cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), and causes excitation of nociceptors mainly via activation of Ca(v)3.2 T-type Ca(2+) channels in the peripheral tissue, facilitating somatic and colonic pain. Here, we investigated whether sensory nerves and Ca(v)3.2 are involved in the H(2)S-induced mucosal cytoprotection against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Colitis was evaluated 3 days after intracolonic (i.c.) TNBS in the rat. Phosphorylation of ERK in the spinal dorsal horn was detected by immunohistochemistry. Protein expression of Ca(v)3.2 in the dorsal root ganglia (DRG) and of CSE and CBS in the colon was determined by Western blotting. Repeated i.c. NaHS significantly suppressed the TNBS-induced colitis in rats, an effect prevented by ablation of sensory nerves with repeated administration of capsaicin. Repeated pretreatment with T-type Ca(2+) channel blockers including ethosuximide significantly reduced the protective effects of repeated i.c. NaHS in the rats with TNBS-induced colitis. A single i.c. administration of NaHS induced ethosuximide-sensitive prompt phosphorylation of ERK in the spinal dorsal horn at T13 and L6-S1 levesl in the rats 1 day or 3 days after TNBS treatment, but not in naive rats. Ca(v)3.2 protein was upregulated in DRG 1 day after i.c. TNBS in rats, while CSE, but not CBS, protein was downregulated in the colon. Our findings suggest that luminal H(2)S causes excitation of sensory nerves most probably by activating Ca(v)3.2 T-type Ca(2+) channels that are upregulated in the early stage of colitis, leading to colonic mucosal cytoprotection in rats.

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