Transient prevention of ethanol-induced gastric lesion by capsaicin due to release of endogenous calcitonin gene-related peptide in rats

Pre-exposure of the rat gastric mucosa to capsaicin reduced the mucosal lesion by 50% ethanol to 1/4. Treatment with an antagonist of calcitonin gene-related peptide (CGRP), CGRP (8-37), nullified the effect of capsaicin. During constant perfusion of the gastric lumen with physiological saline + pepstatin, the CGRP level was not increased by 50% ethanol, but it showed a peak (802.5 +/- 145.7 pg/2 min) after 1.6 mM capsaicin. Four minutes after capsaicin, the CGRP level was kept at a high level and the gastric lesion was markedly reduced by re-exposure of the mucosa to 50% ethanol. At 20-30 min after capsaicin, the CGRP levels returned to the resting level and the reddened area by 50% ethanol was not reduced. It was concluded that capsaicin transiently prevented the mucosal lesion through CGRP release.     

L-carnitine inhibits ethanol-induced gastric mucosal injury in rats

L-carnitine is a quaternary amine that is essential for the normal oxidation of long-chain fatty acids by mitochondria. It is known that L-carnitine and its derivatives prevent the formation of reactive oxygen species, scavenge free radicals and protect cells from peroxidative stress. Oxygen-derived free radicals and lipid peroxidation products play a critical role in the pathogenesis of ethanol-induced gastric mucosal injury. The aim of the present study was to determine the effect of L-carnitine on lipid peroxidation induced by ethanol in the rat stomach. In our study, gastric mucosal injury was induced by the intragastric administration of 1 ml of absolute ethanol. Test compounds were given to rats by gavage 30 min before the ethanol administration. The animals were killed 60 min after the administration of ethanol. The stomach of each animal was removed. Mucosal damage was evaluated by macroscopic examination, histological analysis and by measurement of lipid peroxidation and glutathione activity. The intragastric administration of ethanol induced hyperemia and hemorrhagic erosions in the rat stomachs. L-carnitine significantly prevented gastric ulcerogenesis induced by ethanol and decreased the ulcer index. Plasma and gastric lipid peroxidation that was increased significantly by ethanol was decreased after treatment with L-carnitine. Ethanol treatment decreased significantly the gastric glutathione levels, and pretreatment with L-carnitine increased them significantly. Based on these data, the beneficial effects of L-carnitine on ethanol-induced gastric mucosal injury may be attributed to its antiperoxidative effects.     

Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury.

Alleviative effects of histidine and carnosine in mice against ethanol-induced oxidative and inflammatory was examined. After chronic alcoholic liver injury was induced, histidine and carnosine at 0.5, 1, 2g/L were added to the drinking water for 3 weeks. Results showed that the post-intake of histidine or carnosine markedly decreased alanine aminotransferase and aspartate aminotransferase activities (P<0.05). Ethanol treatment increased malondialdehyde (MDA) level, decreased glutathione (GSH) content and catalase and glutathione peroxidase (GPX) activities, and increased cytochrome P450 2E1 (CYP2E1) activity in liver (P<0.05). The post-intake of histidine and carnosine significantly decreased MDA formations, increased GSH content, enhanced catalase and GPX activities, and suppressed CYP2E1 activity (P<0.05), in which the effects on catalase and CYP2E1 activities were dose-dependent (P<0.05). Ethanol treatment elevated hepatic levels of c-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) (P<0.05), the post-intake of histidine and carnosine significantly and dose-dependently diminished the release of CRP, IL-6, and TNF-alpha (P<0.05). Ethanol treatment caused down-regulation in both catalase and GPX mRNA expression, and up-regulated both IL-6 and TNF-alpha mRNA expression (P<0.05). Histidine and carnosine post-treatments significantly and dose-dependently upregulated catalase mRNA, and down-regulated mRNA expression of IL-6 and TNF-alpha (P<0.05). Based on the observed anti-oxidative and anti-inflammatory effects, the supplement of histidine or carnosine might be helpful for the treatment of chronic alcoholic liver injury.     

Protective effect of Matricaria chamomilla on ethanol-induced acute gastric mucosal injury in rats

The antiulcerogenic and antioxidant properties of Matricaria chamomilla L. (Compositae) hydroalcoholic extract (MCE) on ethanol-induced gastric mucosal injury were investigated in rats. After the induction of gastric mucosal injury, all groups were sacrificed; the gastric ulcer index was calculated, and malondialdehyde (MDA) and reduced glutathione (GSH) in whole blood and gastric tissue, and serum ascorbic acid, retinol, and β-carotene levels were measured in all groups. Pretreatment with MCE at some doses significantly reduced gastric lesions. Again, some doses of MCE significantly reduced the MDA, and significantly increased GSH levels in gastric tissue or whole blood. Serum β-carotene and retinol levels were significantly higher in the 200?mg/kg MCE-administered group with respect to control. As a result, MCE clearly has a protective effect against ethanol-induced gastric mucosal lesions, and this effect, at least in part, depends upon the reduction in lipid peroxidation and augmentation in antioxidant activity.     

Beneficial effects of apricot-feeding on myocardial ischemia-reperfusion injury in rats

The present study was undertaken to evaluate the cardio-protective potential of apricot-feeding in the ischemia-reperfusion (I/R) model of rats in vivo. Rats were divided into three groups of 12 rats each. Group 1 was fed with a standard rat chow, groups 2 and 3 were fed with a standard rat chow supplemented with 10% or 20% dried apricot during 3 months before the beginning of I/R studies. To produce I/R, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats.     

The cardioprotective effects of nitroglycerin-induced preconditioning are mediated by calcitonin gene-related peptide

Previous investigations have shown that endogenous calcitonin gene-related peptide (CGRP) may play an important role in the mediation of ischemic preconditioning and that nitroglycerin evokes the release of CGRP. In the present study, we examined whether nitroglycerin provides a preconditioning stimulus, and whether the cardioprotective effects of nitroglycerin-induced preconditioning involve endogenous CGRP. Thirty minutes of global ischemia and 30 min of reperfusion caused a significant impairment of cardiac contractile function and an increased release of creatine kinase. Pretreatment with nitroglycerin at the concentration of 3x10(-7) or 10(-6) M for 5 min produced a significant improvement of cardiac function and a decrease in the release of creatine kinase. The content of CGRP-like immunoreactivity in coronary effluent was increased during nitroglycerin perfusion. However, the cardioprotection afforded by nitroglycerin was abolished by CGRP-(8-37) (10(-7) M), a selective CGRP receptor antagonist. Pretreatment with capsaicin (50 mg/kg, s.c.), which specifically depletes the transmitter content of sensory nerves, also abolished the protective effects of nitroglycerin and markedly reduced the release of CGRP from the heart during nitroglycerin perfusion. These findings suggest that nitroglycerin-induced preconditioning is related to stimulation of CGRP release in rat hearts.     

Dual effects of zinc sulphate on ethanol-induced gastric injury in rats: possibly mediated by an action on mucosal blood flow

The present study examines the protective effect of zinc sulphate against ethanol-induced gastric mucosal ulcers in rats. Absolute ethanol decreased the gastric mucosal blood flow and produced haemorrhagic lesions in the glandular mucosa. Zinc sulphate preincubation in an ex-vivo stomach chamber preparation prevented the formation of ethanol-induced lesions and attenuated the decrease of blood flow produced by ethanol. Subcutaneous injection of the same doses of the drug at 15 and 30 min before ethanol exposure, markedly reduced the blood flow and also aggravated ethanol-induced gastric injury; however, when injected at 23 and 24 h before ethanol administration, zinc sulphate protected against lesion formation but had no effect on the vascular changes induced by ethanol in the gastric glandular mucosa. These findings show that the antiulcer effect of zinc sulphate occurs only when the drug is given orally, or injected s.c. 23 and 24 h before ethanol challenge. Furthermore, this protective action is probably not entirely mediated by preservation of the gastric mucosal blood flow.     

Paracetamol confers resistance to ethanol-induced gastric mucosal damage in rats

Paracetamol given orally or subcutaneously did not produce any observable gastric mucosal damage, nor did it change the acidity of the residual secretion in rat stomachs. However, it delayed the gastric emptying rate and increased the residual volume of gastric secretion. Pretreatment with paracetamol 250 mg kg-1 significantly prevented ethanol-induced gastric ulceration. Although it did not influence ethanol-stimulated acid secretion, it increased the mucosal mucus content in the ethanol-treated animals. The findings suggest that the protective mechanism of paracetamol against ethanol-induced damage is likely to be due to improved gastric mucosal integrity, through an increase in the adherent mucosal mucus which protects the underlying delicate cellular structures.     

The depressor and vasodilator effects of rutaecarpine are mediated by calcitonin gene-related peptide

Previous studies have shown that rutaecarpine has depressor and vasodilator effects, and activates vanilloid receptors to evoke calcitonin gene-related peptide (CGRP) release. In the present study, we examined whether the depressor and vasodilator effects of rutaecarpine are related to the stimulation of endogenous CGRP release via activation of vanilloid receptors in rats. Rutaecarpine (30, 100, or 300 microg/kg, i. v.) caused a depressor effect concomitantly with an increase in the plasma concentrations of CGRP in a dose-dependent manner, and the effects of rutaecarpine were abolished by pretreatment with capsaicin (50 mg/kg, s. c.) which depletes neurotransmitters in sensory nerves. In aortic and superior mesenteric arterial rings, rutaecarpine (10 (-7)-10(-5) M) or capsaicin (3 x 10(-9)-3 x 10(-6) M) caused a concentration-dependent vasodilator response, which was significantly attenuated by capsazepine (10(-5) M), a competitive vanilloid receptor antagonist, or by CGRP-(8-37) (10(-6) M), a selective CGRP receptor antagonist. After pretreatment with capsaicin (10(-5) M) for 20 min, vasodilator responses to rutaecarpine were also markedly attenuated. Similarly, pretreatment with rutaecarpine (10(-5) M) for 20 min also attenuated vasodilator responses to capsaicin. These results suggest that the depressor and vasodilator effects of rutaecarpine are related to stimulation of endogenous CGRP release via activation of vanilloid receptors in rats.     

Anti-ulcer activity of calcitonin gene-related peptide in rats

Calcitonin gene-related peptide (CGRP, 5-10 micrograms/kg s.c.). reduced both incidence and degree of indomethacin- or acetylsalicylic acid (ASA) plus HCl-induced gastric as well as cysteamine-induced duodenal ulcers in rats. CGRP had no effect on ethanol-induced gastric lesions. The anti-ulcer activity of CGRP is most likely ascribable to its potent antisecretory properties.     

葛根素干预对糖尿病肾病大鼠降钙素基因相关肽的影响研究

目的研究葛根素对糖尿病肾病（DN）大鼠降钙素基因相关肽（CGRP）的影响。方法链脉佐菌素（STZ）诱导糖尿病大鼠模型,随机分为糖尿病组（D组）、葛根素治疗组（S组）,同时另设正常对照组（CN组）,给药干预14周后,测定空腹血糖（FBG）、尿微量白蛋白（U—mAIb）、血浆内皮素（ET）和CGRP含量。结果糖尿病大鼠UAER增加,ET升高,CGRP下降,给予葛根素治疗14周后,S组DN大鼠U—mAIb较D组显著降低,ET显著下降,CGRP明显升高。结论葛根素对糖尿病大鼠肾脏病变有一定的保护作用,其部分机制可能是通过上调CGRP含量而实现的。     

高压氧对颅脑损伤鼠内皮素及降钙素基因相关肽的影响

目的观察高压氧(HBO)治疗急性颅脑损伤大鼠血浆和损伤皮层内皮素(ET)和降钙素基因相关肽(CGRP)含量的变化。方法32只SD大鼠,随机为分正常组,急性颅脑损伤组(分颅脑损伤后6、24、48h组),高压氧治疗组(分颅脑损伤后6、24、48h组),常氧高氮处理组(分颅脑损伤后6、24、48h组)。每组各8只大鼠。各组动物出舱后按时间要求尽量在安静状态下快速断头取血及损伤皮层,采用放免法测定血浆及损伤皮层ET及CGRP含量。结果SD大鼠急性颅脑损伤后,其血浆和损伤皮层组织ET含量有不同程度的升高,而CGRP含量有不同程度的降低;高压氧治疗后,各组血浆及损伤皮层组织ET含量均有不同程度地降低,而血浆及损伤皮层CGRP含量亦有不同程度升高。结论急性颅脑损伤的发生发展与血浆和损伤皮层组织ET含量升高和CGRP含量降低有关;高压氧治疗可能通过降低ET含量和升高CGRP含量,从而起到治疗急性颅脑损伤的作用     

Duodenal ulcers are associated with a depletion of duodenal calcitonin gene-related peptide-like immunoreactivity in rats

Calcitonin gene-related peptide-like immunoreactivity (CGRP-li) was decreased in duodenal samples from animals treated with ulcerogens such as dulcerozine, cysteamine or mepirizole. The degree of these experimental ulcers was inversely correlated with the levels of duodenal CGRP-li. These findings show that endogenous CGRP may play an important role in duodenal ulcerogenesis.     

Involvement of calcitonin gene-related peptide in the depressor effects of losartan and perindopril in rats

Previous investigations have indicated that calcitonin gene-related peptide (CGRP) plays an important role in the regulation of cardiovascular function, and that the development of hypertension may be related to the reduction of sensory vasodilator nerve actions. In the present study, we examined the effect of perindopril, an angiotensin-converting enzyme inhibitor, and losartan, an angiotensin II receptor antagonist, on the plasma level and synthesis of CGRP in 2 kidneys, 1-clip hypertensive rats (2K1C, Goldblatt). In the hypertension group, systolic blood pressure and mean artery pressure were raised, and the level of CGRP in plasma was slightly raised compared with control groups. Chronic treatment with losartan or perindopril significantly increased the plasma concentration of CGRP and the expression of CGRP mRNA in dorsal root ganglia in the 2K1C, Goldblatt hypertensive rats. These results suggest that the 2K1C, Goldblatt hypertensive model has a compensatory increase of sensory nerve actions, and that the depressor effects of perindopril or losartan may be related to stimulation of the synthesis and release of CGRP in the 2K1C, Goldblatt hypertensive rats.     

Effects of calcitonin gene-related peptide on [3H]norepinephrine release in medulla oblongata of spontaneously hypertensive rats

We now describe the effects of calcitonin gene-related peptide (CGRP) on [3H]norepinephrine (NE) release in medulla oblongata of spontaneously hypertensive rats (SHR). CGRP inhibited stimulation-evoked [3H]NE release in a dose-dependent manner in Sprague-Dawley rats, although the basal release of [3H]NE was not affected by the peptide. In SHR, the inhibitory effect of CGRP on stimulation-evoked [3H]NE release was significantly attenuated compared with Wistar Kyoto rats. These results suggest that CGRP might be involved in the regulation of central sympathetic nervous activity in hypertension.     

Effects of non-steroidal anti-inflammatory drugs on rat gastric mucosal leukotriene C4 and prostanoid release: relation to ethanol-induced injury.

1. The effects of oral and subcutaneous administration of the non-steroidal anti-inflammatory drugs sodium salicylate, aspirin and indomethacin on ex vivo gastric mucosal release of leukotriene C4 (LTC4) prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2) were investigated in rats under basal conditions as well as after challenge with ethanol. 2. Basal release of PGE2, 6-oxo-PGF1 alpha and TXB2 was inhibited by oral administration of aspirin (0.6-400 mgkg-1) and indomethacin (4 or 20 mgkg-1), but not by sodium salicylate (up to 400 mgkg-1), in a dose-dependent manner. Oral administration of aspirin in the dose range 3.2-400 mgkg-1 and of indomethacin (20 mgkg-1) additionally inhibited release of LTC4, while sodium salicylate (up to 400 mgkg-1) had no effect. Indomethacin (20 mgkg-1) and aspirin (400 mgkg-1) administered subcutaneously inhibited generation of cyclo-oxygenase products of arachidonate metabolism, but did not significantly affect LTC4 synthesis. 3. Oral instillation of ethanol caused gastric mucosal damage and simultaneously induced a selective increase in the ex vivo release of LTC4 from rat gastric mucosa, while release of cyclo-oxygenase products of arachidonate metabolism was not significantly affected. Oral pretreatment of rats with sodium salicylate protected the gastric mucosa and simultaneously inhibited the ethanol-stimulated gastric mucosal LTC4 release in a dose-dependent manner. Sodium salicylate had no effects on the release of PGE2 and TXB2, while that of 6-oxo-PGF1 alpha was slightly increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective effects of calcitonin gene-related peptide on guinea-pig cardiac anaphylaxis

Anaphylactic events occurring in cardiac tissues can result in cardiac dysfunction via vasoconstriction and arrhythmias. Calcitonin gene-related peptide (CGRP) is the most potent vasodilator and possesses anti-arrhythmic action. We examined the influence of CGRP on cardiac anaphylaxis in guinea-pigs. In the Langendorff-perfused heart of passively sensitized guinea-pigs, antigen challenge evoked a decrease in coronary flow, left ventricular pressure and its maximum first derivatives (+/-dP/dtmax) and an increased heart rate. Antigen challenge also induced atrioventricular conduction block. Treatment with CGRP (1 or 3 nM) significantly improved the recovery of cardiac function and reduced the incidence and duration of atrioventricular block without influencing the increased heart rate. Pretreatment with capsaicin caused effects similar to those of CGRP and markedly elevated the content of CGRP in coronary effluent. Ischaemic preconditioning, induced by two cycles each of 5 min global ischaemia and 5 min reperfusion, also improved cardiac function and raised the level of CGRP in coronary effluent. The protective effects of ischaemic preconditioning were abolished in the presence of the CGRP receptor antagonist CGRP8-37. Histamine release did not differ significantly during any of the interventions. The findings of the present study indicate that, in guinea-pig hearts, CGRP protects against cardiac anaphylaxis and that the cardioprotection by CGRP is independent of histamine release.     

不同程度创伤性脑损伤大鼠降钙素基因相关肽表达变化及其意义

目的建立液压创伤性脑损伤(TBI)模型,探讨创伤性脑损伤大鼠降钙素基因相关肽(CGRP)表达变化及其意义。方法健康雄性Wistar大鼠168只,体质量250～300g,随机分为损伤轻度、中度、重度及对照组各42只。各组分别再随机分为0.5、2、6、12、24、48、72h各7个亚组每组6只。采用液压颅脑损伤仪,对轻度、中度、重度组分别给予0.5～1.0atm(1atm=101.3kPa)、1.5～2.0atm、2.5～3.0atm液压冲击力,制成轻、中、重3型液压颅脑损伤模型。分别于致伤后相应时间点对各组大鼠断头取脑。采用苏木素-伊红(HE)染色观察TBI中组织病理改变,免疫组织化学检测创伤区大脑皮层CGRP表达。结果①光镜观察显示:创伤后12～48h时脑组织损伤最严重。②不同程度TBI中创伤区大脑皮层CGRP神经元表达的阳性单位呈现规律性变化,损伤程度越重,CGRP表达的阳性单位变化幅度越大。不同程度TBI组及对照组之间创伤区大脑皮层中CGRP神经元表达的阳性单位不同,差异有统计学意义;重度组明显低于轻度、中度及对照组,差异有统计学意义;轻度、中度及对照组之间,差异无统计学意义。TBI中损伤程度和时间对于创伤区大脑皮层中CGRP神经元表达的阳性单位有交互效应,中度2h时最高,重度24h时最低。结论不同程度TBI中创伤区大脑皮层CGRP神经元表达的阳性单位量与损伤程度及损伤后时间有关。     

Beneficial effects of methionine and histidine in aspirin solutions on gastric mucosal damage in rats.

Amino acids methionine and histidine, which are soluble in propylene glycol, were investigated for their purported beneficial effects on aspirin-induced gastric mucosal damage in the rat. The pathognomonic changes observed microscopically in the fundic region of the stomach of animals administered daily doses (100 mg/kg), for up to 15 days, of aspirin solutions (0.36 M) in propylene glycol incorporated with the amino acids were compared with those of animals given equivalent quantities of aspirin in an aqueous suspension combined with an aluminum hydroxide antacid. A "delayed" onset of aspirin-induced cellular damage due to the presence of amino acids, analogous to that associated with the use of antacids, was found as determined partly by differences in the staining ability of injured cells with hematoxylin and eosin.