Abstract
Carbon monoxide (CO) has been reported to contribute to the maintenance of gastric mucosal integrity, gastroprotection, and ulcer healing. However, involvement of transient receptor potential vanilloid receptor type 1 (TRPV1) located on afferent sensory fibers endings and sensory neuropeptide calcitonin gene-related peptide (CGRP) in CO-mediated gastroprotection against ethanol-induced gastric damage has not been explored. Male Wistar rats with and without denervation of afferent sensory neurons induced by capsaicin (total dose 125 mg/kg within 3 days) were pretreated with vehicle, CO donor tricarbonyldichlororuthenium (II) dimer (CORM-2, 5 mg/kg i.g.), administered alone or with CGRP-α (10 μg/kg i.p.) or TRPV1 antagonist capsazepine (5 mg/kg i.g.), followed 30 min later by intragastric (i.g.) administration of 75% ethanol. The area of gastric damage and gastric blood flow (GBF) were assessed planimetrically and by laser flowmetry, respectively. Microscopic evaluation of ethanol-induced gastric lesions was performed after haematoxylin/eosin (H&E) or alcian blue/periodic acid-Schiff/alcian blue (AB/PAS) staining. Gastric mucosal mRNA fold change for heme oxygenase (HMOX)-1, HMOX-2, CGRP-α, CGRP-β, inducible nitric oxide synthase (iNOS), endothelial (e)NOS, neuronal (n)NOS, cyclooxygenase (COX)-1, COX-2, and protein expression for HMOX-1 and TRPV1 was determined by real-time PCR or Western blot, respectively. Pretreatment with CORM-2 combined or not with CGRP reduced ethanol-induced gastric lesions and elevated GBF. Capsaicin-denervation or co-treatment with capsazepine or CGRP and CORM-2 in capsaicin-denervated animals failed to affect these beneficial effects of CO donor. In rats with intact sensory nerves, CORM-2 increased gastric mRNA level for HMOX-1 and CGRP-α. In capsaicin-denervated rats, CORM-2 increased eNOS mRNA fold change and TRPV1 protein expression while capsaicin denervation itself decreased HMOX-1 protein expression and eNOS mRNA level. We conclude that CO prevents gastric mucosa from ethanol-induced lesions due to activation of TRPV1/CGRP-α system and accompanying increase in gastric microcirculation but independently on afferent sensory nerve activity despite the stimulation of TRPV1 protein and CGRP-α mRNA expression.
Highlights
Gastric mucosal integrity is maintained by the activity of various physiological factors such as endogenous prostaglandins, nitric oxide (NO), hydrogen sulfide (H2S), and mechanisms such as mucus producing and bicarbonates secreting epithelial cells, gastric microcirculation, and expression and activity of scavengers of reactive oxygen species (ROS) [1,2,3]
Necrotizing agents i.e., ethyl alcohol, drugs such as non-steroid anti-inflammatory drugs (NSAIDs) or stress are considered as the major factors responsible for the disruption of gastric mucosal barrier causing a fall in the gastric blood flow (GBF) and an impairment of protective lines of mucosal defense system [4,5]
To our best knowledge we provided for the first time the experimental evidence that mechanism of gastroprotective effect of carbon monoxide (CO) released from its pharmacological donor, CORM-2 against necrotic ethanol-induced gastric damage involves the upregulation of TRPV1 protein expression in gastric mucosa
Summary
Gastric mucosal integrity is maintained by the activity of various physiological factors such as endogenous prostaglandins, nitric oxide (NO), hydrogen sulfide (H2S), and mechanisms such as mucus producing and bicarbonates secreting epithelial cells, gastric microcirculation, and expression and activity of scavengers of reactive oxygen species (ROS) [1,2,3]. Gastric microcirculation is regulated by the activity of afferent sensory neurons, known to release the vasoactive mediator calcitonin gene-related peptide (CGRP) through the activation of transient receptor potential vanilloid receptor type 1 (TRPV1) at the site of inflammation [6,7,8]. Besides NO and H2S, carbon monoxide (CO) has recently been reported to play an essential role in the maintenance of gastric mucosal integrity due to its anti-inflammatory and vasoactive properties involved in the regulation of GBF [9,10,11]. Our group reported that gaseous mediators NO, H2S, and CO, exhibited gastroprotective activity but in contrast to NO and H2S, the CO-induced protection was found to be independent on the activity of afferent sensory neurons [8,11]. The contribution of TRPV1 and CGRP to CO-mediated gastroprotection against ethanol-induced gastric lesions has not been fully investigated and needs further evaluation
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