A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats

Self Cite

225

193

Bleeding and delayed healing of ulcers are well recognized clinical problems associated with the use of aspirin and other nonsteroidal antiinflammatory drugs, which have been attributed to their antiaggregatory effects on platelets. We hypothesized that antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors, such as vascular endothelial growth factor (VEGF), from platelets. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily oral treatment with vehicle, aspirin, or ticlopidine (an ADP receptor antagonist) was started 3 days later and continued for 1 week. Ulcer induction resulted in a significant increase in serum levels of VEGF and a significant decrease in serum levels of endostatin (an antiangiogenic factor). Although both aspirin and ticlopidine markedly suppressed platelet aggregation, only ticlopidine impaired gastric ulcer healing and angiogenesis as well as reversing the ulcerassociated changes in serum levels of VEGF and endostatin. The effects of ticlopidine on ulcer healing and angiogenesis were mimicked by immunodepletion of circulating platelets, and ticlopidine did not influence ulcer healing when given to thrombocytopenic rats. Incubation of human umbilical vein endothelial cells with serum from ticlopidine-treated rats significantly reduced proliferation and increased apoptosis, effects reversed by an antibody directed against endostatin. Ticlopidine treatment resulted in increased platelet endostatin content and release. These results demonstrate a previously unrecognized contribution of platelets to the regulation of gastric ulcer healing. Such effects likely are mediated through the release from platelets of endostatin and possibly VEGF. As shown with ticlopidine, drugs that influence gastric ulcer healing may do so in part through altering the ability of platelets to release growth factors.angiogenesis ͉ ticlopidine ͉ aspirin ͉ proliferation ͉ endothelium

Section: Discussionmentioning

confidence: 60%

“…The rats were fasted for 18 h. Under halothane anesthesia, acetic acid (0.5 ml, 80% vol͞vol) was applied to the serosal surface of the stomach for 1 min via a 3-ml syringe barrel (16,17). The abdomen was sutured closed and the rats were returned to their cages.…”

Section: Methodsmentioning

confidence: 99%

Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release

Elliott

Cirino

et al. 2001

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225

193

“…NO-releasing nonsteroidal anti-inflammatory drugs (NONSAIDs) are a recently described class of NSAID derivatives generated by adding an NO-releasing moiety to parental NSAIDs (22)(23)(24). NO-NSAIDs not only lack the gastrointestinal damaging effect of classical NSAIDs, but the slow release of NO in a biological microenvironment also confers novel activities not shared by parent molecules (24).…”

Section: Portal Hypertension Resulting From Increased Intrahepatic Rementioning

confidence: 99%

NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension

Fiorucci

Antonelli

Morelli

et al. 2001

118

Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension

“…On day 10 after ulcer induction, the rats were anesthetized with halothane, and a blood sample was drawn from the descending aorta for measurement of serum VEGF and endostatin. The stomach was then removed and the ulcer area was measured planimetrically in a blind manner (16). A longitudinal section of tissue that included the ulcer base and both sides of ulcer margins was fixed in 4% neutral buffered formalin (4°C) and then embedded in paraffin and sectioned.…”

Section: Methodsmentioning

confidence: 99%

“…These effects have been suggested to be due to inhibition of angiogenesis (12). NO-releasing COX inhibitors, on the other hand, exhibit gastric safety similar to the selective COX-2 inhibitors (13-15), but have been reported to accelerate gastric ulcer healing (16) or to abolish the delay of ulcer healing induced by a conventional COX inhibitors (17). It is possible that some of the differences in the effects of these newer COX inhibitors on ulcer healing could be attributable to divergent effects on angiogenesis.…”

mentioning

confidence: 99%

Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance

Soldato

Wallace

2002

Self Cite

132

105

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet͞serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib-or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti-and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro-and antiangiogenic growth factors.nitric oxide ͉ angiogenesis ͉ nonsteroidal antiinflammatory drug ͉ endothelium ͉ growth factors