Mild irritant prevents ethanol-induced gastric mucosal microcirculatory disturbances through actions of calcitonin gene-related peptide and PGI₂in rats

Abstract

Pretreatment with a mild irritant such as 1 M NaCl prevented ethanol-induced mucosal injury, which was abolished by indomethacin, suggesting involvement of endogenous PGs. With the use of intravital microscopy, we investigated the mechanism in microcirculation whereby a mild irritant prevents ethanol-induced mucosal injury. Microcirculation of the basal part of gastric mucosa in anesthetized rats was observed through a window with transillumination. Diameters of arterioles, collecting venules, and venules were measured with an electric microscaler. One molar NaCl alone caused dilation of arterioles and constrictions of collecting venules and venules, which were inhibited by indomethacin. Ethanol (50%) applied to mucosa constricted collecting venules and venules but dilated arterioles. Constriction of collecting venules resulted in mucosal congestion. Pretreatment with 1 M NaCl inhibited ethanol-induced constrictions of collecting venules and venules, and administration of indomethacin or a calcitonin gene-related peptide (CGRP) antagonist, CGRP-(8-37), abolished elimination of constrictions. Topical application (1 nM-10 microM) of PGE2 or beraprost sodium (a PGI2 analog) to microvasculature markedly and dose-dependently dilated arterioles, whereas that of PGE2, but not beraprost, slightly constricted collecting venules. Pretreatment of microvasculature with a nonvasoactive concentration of PGE2 (100 nM) or beraprost (1 nM) completely inhibited ethanol-induced constriction of collecting venules. The inhibitory effect of beraprost but not of PGE2 was abolished by CGRP-(8-37). Present results suggest that the mechanism whereby 1 M NaCl prevents ethanol-induced injury is elimination of constrictions of collecting venules and venules by CGRP whose release may be enhanced by PGI2 but not by PGE2.

Calcitonin gene-related peptide facilitates revascularization during hindlimb ischemia in mice

“…Endogenous CGRP has been shown to protect the heart (16) against ischemic injury and damage. We have reported that CGRP plays critical roles in the maintenance of gastric mucosal integrity (4,5,28). Maintenance of gastric mucosal integrity is highly dependent on the alarm systems that can rapidly sense the harmful chemical or mechanical stimuli to which the mucosa is exposed.…”

“…The gastrointestinal tract is known to be rich in neuronal systems, among which afferent neurons of extrinsic origin are reported to operate as an emergency protective system (15). The functions of these afferents sensitive to chemicals are reported to be mediated by CGRP released in the gastric mucosa (28).…”

Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide

“…The gastrointestinal tract is known to be rich in neuronal systems, among which afferent neurons of extrinsic origin are reported to operate as an emergency protective system (16). The functions of these afferents sensitive to chemicals are reported to be mediated by CGRP released in the gastric mucosa (16,17). It was reported that a neuropeptide, substance P, had a proangiogenic activity (18), although the details of the mechanism of this proangiogenic activity were not studied precisely.…”

Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying

“…PGE 2 and PGI 2 are the major PGs generated in the stomach (4). We had reported previously that PGs could protect gastric mucosa from ethanol through the inhibition of microcirculatory dysfunctions (37). When gastric mucosa was exposed to capsaicin or highosmolarity solution, such as 1 M NaCl, both of which can increase PGE 2 and PGI 2 in the stomach, PGI 2 -PGI receptor (IP) signaling exhibits protective actions through the release of a protective neuropeptide, calcitonin gene-related peptide (CGRP) (4,2).…”

“…When gastric mucosa was exposed to capsaicin or highosmolarity solution, such as 1 M NaCl, both of which can increase PGE 2 and PGI 2 in the stomach, PGI 2 -PGI receptor (IP) signaling exhibits protective actions through the release of a protective neuropeptide, calcitonin gene-related peptide (CGRP) (4,2). However, the protective action of PGE 2 was CGRP-independent (4,37).…”