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Ischemic preconditioning is considered as the most powerful gastroprotective intervention against mucosal lesions and ulcerations but the mechanism of this phenomenon has been little examined. In this study we tested the effects of inactivation of sensory nerves in new rat model combining acute gastric erosions with subsequent ulcers induced by ischemia-reperfusion (I/R). I/R lesions were produced in rats by clamping the celiac artery for 0.5 h followed by 3 h ofreperfusion in rats with intact or inactivated sensory nerves by pretreatment with capsaicin for two weeks before the I/R. The animals were killed at 0 and 3 h and 3 days after I/R and the area of gastric lesions was determined planimetrically, the gastric blood flow (GBF) by H2-gas clearance technique and the plasma levels of gastrin by RIA. Gastric mucosal content of calcitonin gene related peptide (CGRP) was assessed by RIA. Following I/R, gastric erosive lesions occurred after 3 h and these erosive lesions then progressed into gastric ulcers within 3 days in all rats. Sensory-inactivation with capsaicin caused several fold increase in the area of early (at 3 h) acute lesions and later (at 3 d) gastric ulcers induced by I/R. This enhancement of acute and then chronic gastric lesions was accompanied by a significant fall in GBF, an elevation of plasma gastrin and a decrease in mucosal expression of CGRP. Ischemic preconditioning markedly reduced acute lesions and chronic ulcerations induced by I/R and attenuated the changes in plasma gastrin and mucosal CGRP contents but these effects were significantly more pronounced in rats with intact sensory nerves but less in capsaicin-inactivated animals. We conclude that: 1) The I/R resulted in the formation of early acute gastric lesions followed 3 days later by chronic gastric ulcers and this gastric injury was accompanied by an impairment of gastric microcirculation, hypergastrinemia and suppression the gastric mucosal CGRP; 2) Gastric ischemic-preconditioning significantly attenuated both acute mucosal damage and chronic ulcers induced by I/R and this was accompanied by a rise in gastric blood flow; 3) The inactivation of sensory nerves with capsaicin enhanced the formation of I/R-induced acute and chronic gastric lesions and strongly attenuated the gastroprotection afforded by I/R possibly due to the decline in mucosal blood flow and the fall in expression of integrity peptides such as CGRP and 4) The excessive release of gastrin may limit the extent of mucosal lesions observed during progression of gastric erosions into ulcers induced by I/R.
Pharmacological analysis of C-terminal fragment of Calcitonin Gene-related Peptide [Tyr0]CGRP(28-37) (Ct-CGRP) in isolated pig uterine artery (UA) collected on days 17-18 of the oestrous cycle were studied. It was found that inhibition of a-adrenergic receptor activity (with phentolamine, 10-3 mol/1) inhibited the vasocontractile reaction of Ct-CGRP (10-8 mol/1), while ß-adrenergic receptors blockade (propranolol, 10-6 mol/1) did not affect the influence of this peptide on isolated UA. Methoxamine (ai-adrenomimetic, 10-5 mol/1) caused an increase (P < 0.01) in UA tension and subsequent Ct-CGRP treatment intensified (P < 0.01) this reaction in the UA examined, while prazosin (aradrenolytic, 10-6 mol/1) prevented the Ct-CGRP action. Clonidine (a2-adrenomimetic, 10-5 mol/1) did not elevate the UA tension and inhibited the Ct-CGRP action. Rauwolscin (a2-adrenolytic, 10-6 mol/1) caused an insignificant influence on UA tension but did not inhibit the Ct-CGRP action in the vessel examined. Moreover, the studies showed that Ct-CGRP intensified the action of desipramine (10-5 mol/1), while the nifedipine (10-5 mol/1) pretreatment prevented the action of this peptide. On the basis of the results obtained we conclude that the action of the rat C-terminal [Tyr0]CGRP(28-37) is related to the stimulation of neuronal release of noradrenaline (NA) as well as to the inhibition of the process of NA uptake in the adrenergic synapses in U A and/or to the stimulation of Ca2++ transport into the smooth muscle cells of UA.
The presence of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), galanin (GAL), substance P (SP) and calcitonin gene-related peptide (CGRP) was studied in neurons and nerve fibers of the porcine otic ganglion. ChAT-positive neurons were very numerous while VAChT-positive nerve cells were moderate in number. The number of neurons containing NPY and VIP was lower and those containing SOM, GAL, SP or CGRP were observed as scarce, or single nerve cells. The above mentioned substances (except SOM) were present in nerve fibers of the ganglion. ChAT- and VAChT-positive nerve fibers were numerous, while the number of nerve terminals containing NPY, VIP and SP was lower. GAL- and CGRP-positive nerve fibers were scarce.
Previous immunocytochemical studies provided conflicting data concerning occurrence of the CGRP-immunoreactive neuronal cell bodies in the porcine spinal cord. In the present study, we have investigated expression of the CGRP and its possible coexpression with ChAT in the gray matter of the thoracic, lumbar and sacral spinal cord of the pig. Our study revealed a large number of CGRP-immunoreactive cells in the motor nucleus of the ventral horn, and less and singe perikarya intermediolateral and intermediomedial nuclei, respectively. Double staining immunocytochemistry, depending on the cross-section level, disclosed the highest ChAT/CGRP colocalization subsequently in the motor nucleus of the ventral horn, then in the intermediolateral and intermediomedial nucleus. Our data provide morphological evidence confirming expression of CGRP in the porcine spinal nuclei while its coexpression in cholinergic neurons suggests that CGRP may play a role in modulation of the spinal cholinergic transmission.
Leptin, a product of ob gene controlling food intake, has recently been detected in the stomach and shown to be released by CCK and implicated in gastroprotection against various noxious agents but it is unknown whether centrally applied leptin influences ischemia-reperfusion (I/R)-induced gastric erosions that progress into deeper gastric ulcerations. In this study we compared the effects of leptin and CCK-8 applied intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) on gastric mucosal lesions induced by I/R and topical application of 75% ethanol. Several major series of Wistar rats were used to examine the effects of leptin and CCK applied centrally on gastroprotection against I/R and ethanol in rats with A) vagotomy by cutting of vagal nerves, B) suppression of NO-synthase with L-NNA (20 mg/kg i.p.), C) inactivation of sensory nerves by capsaicin (125 mg/kg s.c.) and D) inhibition of CGRP receptors with CGRP8-37 (100 µg/kg i.p.) applied with or without the i.c.v. pretreatment with leptin or CCK-8. Rats were anesthetized 1 h after ethanol administration or at 3 h and 3 days upon the end of ischemia to measure the gastric blood flow (GBF) and then to determine the area of gastric lesions by planimetry. Blood was withdrawn for the measurement of plasma leptin and gastrin levels by radioimmunoassay (RIA). Leptin (0.1—20 µg/kg i.p.) dose-dependently attenuated gastric lesions induced by 75% ethanol and I/R; the dose reducing these lesions by 50% (ED50) was 8 µg/kg and 6 µg/kg, respectively and this protective effect was similar to that obtained with CCK-8 applied in a standard dose of 10 µg/kg i.p. This protective effect of leptin was accompanied by a significant increase in GBF and plasma gastrin levels whereas CCK-8 increased plasma leptin levels but failed to affect plasma gastrin levels. Leptin and CCK-8 applied i.c.v. in a dose of 625 ng/rat reduced significantly the area of I/R induced gastric lesions and raised the GBF and plasma leptin levels with the extent similar to those achieved with peripheral administration of leptin or CCK-8 (10 µg/kg i.p.). The protective and hyperemic effects of centrally administered leptin or CCK-8 (625 ng/rat i.c.v.) were completely abolished by vagotomy and significantly attenuated by sensory denervation with capsaicin or by CGRP antagonist, CGRP8-37. The pretreatment with L-NNA to inhibit NO-synthase activity attenuated significantly the protective and hyperemic effects of CCK but not those of leptin while capsaicin denervation counteracted leptin-- induced protection and rise in the GBF but attenuated significantly those of CCK. We conclude that: 1) central leptin exerts a potent gastroprotective activity against I/R-induced gastric erosions that progress into deeper gastric lesions and this protection depends upon vagal activity and sensory nerves and involves hyperemia probably mediated by NO and 2) leptin mimics the gastroprotective effect of CCK and may be implicated in the protective and hyperemic actions of this peptide against mucosal damage evoked by I/R.
Limitation of the damage to the organs such as heart, liver, intestine, stomach and brain by an earlier brief complete occlusion of their arteries is defined as ischemic preconditioning (IP). No study so for has been undertaken to check whether brain-gut axis is involved in the gastroprotection exhibited by gastric IP or in that induced by repeated brief episodes of ischemia of remote organs such as heart and liver. This study was designed to determine the possible involvement of vagal and sensory afferent nerves, in the mechanism of gastric and remote organ IP on the gastric mucosa in rats exposed to prolonged ischemia-reperfusion with or without functional ablation of sensory nerves by capsaicin or in those with removed vagal innervation by vagotomy. This gastric IP was induced by short ischemia episodes (occlusion of celiac artery 1-5 times for 5 min) applied 30 min before subsequent ischemia followed by 3 h of reperfusion (I/R) and compared with remote IP induced by occlusion of left descending coronary artery or hepatic artery plus portal vein. The area of gastric lesions was determined by planimetry, gastric blood flow (GBF) was measured by H2-gas clearance method and mucosal biopsy samples were taken for the assessment of calcitonin gene-related peptide (CGRP) by RIA. Exposure of gastric mucosa to standard 3 h of I/R produced numerous gastric lesions and significant fall in the GBF and mucosal CGRP content. Two 5 min short ischemic episodes by occlusion of coronary or hepatic arteries, significantly reduced gastric damage induced by I/R with the extent similar to that exhibited by two short (5 min) episodes of gastric ischemia. These protective effects of gastric and remote IPs were accompanied by a restoration of the fall in the CGRP content caused by I/R alone. Protection and hyperemia induced by gastric IP were significantly attenuated in capsaicin-denervated or vagotomized animals and completely removed in those exposed to the combination of vagotomy and capsaicin-denervation. The IP-induced protection and hyperemia were restored by the administration of exogenous CGRP to gastric IP in capsaicin-treated animals. Gastroprotective and hyperemic actions of remote IP were markedly diminished in capsaicin-denervated rats and in those subjected to vagotomy. We conclude that brief ischemia in remote organs such as heart and liver protects gastric mucosa against gastric injury induced by I/R as effectively as gastric IP via mechanism involving both vagal and sensory nerves releasing vasodilatatory mediators such as CGRP.
The majority of research for the calcitonin gene-related peptide (CGRP) in the stomach in the hypertension has been devoted to the submucosal blood flow, and no attention has been paid to its quantitative distribution in the gastric neuroendocrine cells. The aim of the present study was to examine the number and distribution of CGRP-containing cells in the pylorus of “two kidney, one clip” (2K1C) renovascular hypertension model in rats. The studies were carried out on the stomach of rats. After 6 week period of the renal artery clipping procedure, eight 2K1C rats developed stable hypertension. The hypertension significantly increased the number of endocrine cells pylorus immunoreactive to calcitonin gene-related peptide (CGRP) antisera. The differences between the hypertensive rats and the control group concerned not only the number of endocrine cells but also their distribution. CGRP participates in the regulation of cardiovascular functions both in normal state and in the pathophysiology of hypertension through interactions with the prohypertensive systems. The changes induced by hypertension in the neuroendocrine cells containing CGRP of the rats are discussed.
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