angiotensin-i and Stomach-Ulcer

The inhibition of angiotensin-converting enzyme (ACE) or the blockade of angiotensin (Ang) AT-1 receptors affords protection against acute gastric mucosal injury, but whether the major metabolite of renin-angiotensin system (RAS), Ang-(1-7), accelerates the healing process of preexisting gastric ulcers remains unknown. Previous studies documented that Ang-(1-7) acting via its own Mas receptor exerts vascular responses opposing those of Ang II. We studied the effects of the Ang-(1-7)/Mas receptor axis on the healing rate of acetic-acid-induced gastric ulcers with or without the blockade of Mas receptors by A 779 and compared it with the effects of activation and blockade of the AT-1 receptor by the treatment with Ang II and losartan, respectively, the inhibition of ACE by lisinopril, the NO/cNOS inhibition by L-NAME and inhibition of prostaglandin/COX system by indomethacin in the presence of Ang-(1-7). Additionally, ex vivo metabolism of Ang I in gastric tissue was assessed by LC/MS method. At day 9 after ulcer induction, the area of these ulcers and the accompanying changes in total gastric blood flow (GBF) were determined as were gastric mucosal blood flow (GMBF) at ulcer margin and gastric oxygen uptake (GVO2). The gastric mucosal expression of mRNAs for constitutive nitric oxide synthase (cNOS), superoxide dismutase (SOD), and pro-inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) and plasma level of both cytokines were determined by RT-PCR and ELISA. The 9 days treatment with Ang II dose-dependently increased the area of gastric ulcers and this effect was accompanied by a significant fall in the GBF, GVO2 and GMBF at ulcer margin. In contrast, treatment with Ang-(1-7) which produced a significant rise in the luminal content of NO significantly reduced the area of gastric ulcer and significantly increased the GBF, GVO2 and the GMBF at ulcer margin. Similar GMBF changes and significant reduction the area of gastric ulcer was observed in rats with gastric ulcers treated with the agonist of Mas receptor, AVE 0991. These effects of Ang-(1-7) and AVE 0991 were eliminated by blockade of the Mas receptor with A779. Similarly to Ang-(1-7), treatment with losartan or lisinopril significantly reduced the area of gastric ulcers and the accompanying increase in the GMBF at ulcer margin and these effects were significantly attenuated by a concomitant administration of L-NAME and indomethacin. The rate of healing of ulcers was ass

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Cytokines; Enzyme Inhibitors; Gastric Mucosa; Imidazoles; Indomethacin; Interleukin-1beta; Lisinopril; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Prostaglandins; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Stomach Ulcer; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects in various organisms, including gastroprotection. ACE II is responsible for converting Ang II into an active peptide, Ang-(1-7), which in turn binds the Mas receptor. Recent studies have shown that diminazene aceturate (Dize) a trypanocidal used in animals, activates ACE II. Thus, in this study, we aimed to evaluate the gastroprotective effects of Dize via the ACE II/Ang-(1-7)/Mas receptor pathway against gastric lesions induced by ethanol and acetic acid in mice. The results showed that Dize could promote gastric protection via several mechanisms, including increased levels of antioxidants and anti-inflammatory factors (e.g., decreasing tumor necrosis factor and interleukin-6 expression and reducing myeloperoxidase activity), maturation of collagen fibers, and promotion of re-epithelialization and regeneration of gastric tissue in different injury models. Thus, Dize represents a novel potential gastroprotective agent.

Topics: Acetic Acid; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Disease Models, Animal; Ethanol; Female; Gastric Mucosa; Male; Mice; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Stomach Ulcer

To assess the gastro-protective potential of the angiotensin (Ang-) (1-7) on the gastric secretion and ulceration induced by cold restraint stress (CRS) in adult male rats and the possible contribution of nitric oxide and prostaglandin E2. Rats were pylorically ligated and divided randomly into the following groups (8 rats each): control, cold-restraint stressed (CRS), stressed Ang-(1-7) treated, stressed L-NNA-Ang-(1-7) treated, stressed Indo-Ang-(1-7) treated groups. Our results revealed that Ang-(1-7) pre-treatment proved to be protective against development of ulcerative lesions in CRS model as evidenced by histological examination and the reduction of the ulcer index and this could be mediated through reduction of free and total acidity and pepsin concentration of gastric secretion with significantly decreased lipid peroxidation and increased the gastric protective nitric oxide and prostaglandin E2 levels. Furthermore, Ang-(1-7) pre-treatment has anti-apoptotic effect, evident by its down-regulation of the CRS induced over-expression of the gastric caspase 3. In addition, the gastro-protective effects of Ang-(1-7) were significantly attenuated by co-administration with L-NNA or indomethacin. In conclusion, Ang-(1-7) can be considered a potential therapeutic agent to protect against the major clinical challenge of gastric injury resulting from stress. Nitric oxide and prostaglandin E2 seem to contribute to the Ang-(1-7)'s gastro-protective effect (Tab. 2, Fig. 5, Ref. 35).

Topics: Angiotensin I; Animals; Anti-Ulcer Agents; Dinoprostone; Gastric Juice; Gastric Mucosa; Indomethacin; Male; Nitric Oxide; Peptide Fragments; Prostaglandins; Protective Agents; Random Allocation; Rats; Rats, Wistar; Stomach Ulcer; Stress, Psychological

Stress ulcers can develop with severe physiological stress, and have been proposed as being brain-driven events. New findings continue to suggest that stress ulcers can be more effectively managed through central manipulation rather than by simply altering local gastric factors. Angiotensin (1-7) (Ang (1-7)) is present as an endogenous constituent of the brain and stomach. The beneficial effects of Ang (1-7) have been confirmed in the vessels, brain, heart, kidney, liver and lungs, but not in the stomach. Given the accumulating evidence suggesting the anti-stress activities of Ang (1-7), its potential gastroprotective effect in the context of stress requires further investigation. In the present study, rat gastric mucosal lesions were induced by 2h of cold-restraint stress. We observed that these lesions were significantly attenuated after 1 week of intracerebroventricular treatment with Ang (1-7). This gastroprotective effect was associated with attenuated oxidative stress and suppressed acid secretion. Brain Ang (1-7) administration profoundly modified responses to stress, indicated by altered levels of several stress hormones, including Ang II, glucocorticoid, norepinephrine, serotonin, and dopamine, in blood or stress-related brain regions. These findings indicate that Ang (1-7) exerts anti-stress activities by restoring the gastric microenvironment and modulating the stress pathways. Ang (1-7) may be a promising agent for stress ulcer prophylaxis and therapy, administered through brain-permeable mimics or carriers.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Cold Temperature; Corticosterone; H(+)-K(+)-Exchanging ATPase; Infusions, Intraventricular; Male; Norepinephrine; Peptide Fragments; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stomach Ulcer; Stress, Physiological

Angiotensin-(1-7) [Ang-(1-7)] is a major vasoactive metabolite of angiotensin I (Ang I), both being important components of the renin-angiotensin system (RAS). Ang-(1-7) acting via Mas receptor was documented in kidneys, heart, brain, and gastrointestinal (GI)-tract. We studied the gastroprotective activity of exogenous Ang-(1-7) in rats exposed to water immersion and restraint stress (WRS) without or with A-779 [d-Ala7-Ang-(1-7), an antagonist of Ang-(1-7) Mas receptors], AVE 0991 (5-formyl-4-methoxy-2-phenyl-1[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]-phenyl]-methyl]-imidazole), the agonist of Ang-(1-7) receptor, as well as the inhibition of nitric-oxide (NO) synthase, the suppression of cyclo-oxygenase (COX)-1 (indomethacin, SC-560 [5-(4-chloro-phenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl-pyrazole]), the activity COX-2 (rofecoxib), and denervation with capsaicin. The mRNA expression of constitutively expressed nitric-oxide synthase (cNOS), inducible nitric-oxide synthase (iNOS), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α was analyzed by reverse transcription polymerase chain reaction. The WRS lesions were dose-dependently reduced by pretreatment with Ang-(1-7), which also caused an increase in gastric blood flow (GBF) and luminal content of NO. COX-1 and COX-2 inhibitors or L-NNA (N5-[imino(nitroamino)methyl]-L-ornithine) reversed the reduction in lesion number and the rise in GBF evoked by Ang-(1-7). Ang II augmented the WRS lesions, decreased GBF and increased the plasma IL-1β and TNF-α levels. Capsaicin denervation attenuated the reduction of Ang-(1-7)-induced gastric lesions and the rise in GBF; these effects were restored by supplementation with calcitonin gene-related peptide (CGRP). The cNOS mRNA was upregulated while iNOS, IL-1β and TNF-α mRNAs were downregulated in Ang-(1-7)-pretreated rats. We conclude that Ang-(1-7), in contrast to Ang II, which worsened WRS ulcerogenesis, affords potent gastroprotection against WRS ulcerogenesis via an increase in GBF mediated by NO, endogenous prostaglandins, sensory neuropeptides, and anti-inflammatory action involving the inhibition of proinflammatory markers iNOS, IL-1β, and TNF-α.

Topics: Angiotensin I; Angiotensin II; Animals; Anti-Ulcer Agents; Capsaicin; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytokines; Denervation; Enzyme Inhibitors; Gastric Mucosa; Interleukin-1beta; Male; Neuropeptides; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Prostaglandins; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Regional Blood Flow; Renin-Angiotensin System; Sensory Receptor Cells; Stomach; Stomach Ulcer; Tumor Necrosis Factor-alpha