Brzozowski T

Role of angiotensin-(1-7) in gastroprotection against stress-induced ulcerogenesis. The involvement of Mas receptor, nitric oxide, prostaglandins and sensory neuropeptides

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.

Nonsteroidal anti-inflammatory drug-induced experimental gastropathy: is gastric acid the major trigger?

The present commentary discusses the original findings by Zinkievich et al., who described the potential role played by gastric acid secretion in non-steroidal anti-inflammatory drug (NSAID)-induced ulcerogenesis in vivo. These authors attempted to assess the implication of gastric acid in NSAID-induced gastric damage and concluded that increased gastric acid secretion plays an essential role in NSAIDinduced gastrotoxicity and that it therefore should be of great importance to both basic and clinical investigators. Previous studies have addressed this issue and revealed that prostaglandins (PG) exert an inhibitory effect on gastric acid-producing parietal cells that is effectively eliminated by NSAIDs ingested at doses inhibiting the mucosal generation of PG. Thus, control of gastric acidity using acid-suppressive therapy has been proposed as an effective means of healing ulcers and controlling and preventing NSAID-associated upper gastrointestinal (GI) injury and ulcer complications. The relationship between the inflammatory and ulcerogenic properties of NSAIDs, their augmentation of gastric acid secretion and the expression and activity of proton pumps in response to NSAIDs need to be explored for a better understanding of NSAID-induced gastropathy. For many years, NSAIDs, such as aspirin, indomethacin and ibuprofen, have been widely prescribed (and are now available over the counter) mainly for their anti-inflammatory, antipyretic and analgesic effects. The major limitations of their clinical application arise from their serious GI side-effects, such as the induction of acute haemorrhagic erosions, potentiation of gastric ulcerogenic responses to various stimuli, exaggeration of colitis and impairment of the healing of pre-existing ulcers. The major NSAID representative, aspirin, is recommended prophylactically as a antithrombotic remedy, particularly in patients who are at high risk of recurrent myocardial infraction and for those who experience angina pectoris, as well as in healthy individuals in an attempt to prevent myocardial infarction. There is also experimental evidence that chronic aspirin treatment can attenuate vascular disturbances and normalize the increased blood pressure associated with metabolic syndrome. The beneficial effects of most NSAIDs, including aspirin and indomethacin, are attributed to their ability to irreversibly inhibit the enzyme cyclo-oxygenase (COX), thereby inhibiting synthesis of vasoprotective PG associated with inflammation and of the pro-aggregatory vasoconstrictor substance thromboxane A2. The adverse effects of NSAID may result from the shifting of the arachidonate cascade into overproduction of vasoconstrictor leukotrienes (LT), such as LTC4 and LTD4. 8–10

Ghrelin and Stress Protection

Ghrelin, identified in the gastric mucosa, is involved in control of food intake and growth hormone (GH) release. Besides being an appetite hormone, central and peripheral ghrelin exerts a potent protective action against gastric mucosal experimental injury induced by stress, an effect dependant on vagal activity and hyperemia mediated by nitric oxide synthase (NOS)-nitric acid (NO) and cyclo-oxygenase (COX)-prostaglandin (PG) systems and calcitonin gene related peptide (CGRP) released from sensory afferent nerves.