ONO-1714, a new inducible nitric oxide synthase inhibitor, attenuates diaphragmatic dysfunction associated with cerulein-induced pancreatitis in rats

Mikawa, Katsuya; Kodama, Susumu; Nishina, Kahoru; Obara, Hidefumi

doi:10.1097/00003246-200106000-00027

Cited by 22 publications

(13 citation statements)

References 22 publications

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“…Also, our observations confirmed that overproduction of NO arising from the iNOS was associated with the development of acute pancreatitis as shown by marked hyperamylasemia, increased pancreas water content, and histologically extensive acinar cell vacuolization. Our data confirm previous observations of enhanced iNOS expression and increased NO metabolites during acute pancreatitis (7,21,24,29,30). Because the amount of NO produced by cNOS is too small to be reflected in the changes of NO levels, the induction of iNOS, presumably in macrophages and vascular smooth cells, may be responsible for the large release of NO in acute pancreatitis (7).…”

Section: Discussionsupporting

confidence: 89%

The Role of Nitric Oxide in Experimental Cerulein Induced Pancreatitis

Kwon

Kim

et al. 2003

J Korean Med Sci

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An enhanced formation of nitric oxide (NO), due to the induction of inducible nitric oxide synthase (iNOS), has been implicated in the pathogenesis of shock and inflammation, but its role in acute pancreatitis still remains controversial. To clarify the role of NO in acute pancreatitis, the present experiment investigated the expression of iNOS and the effect of NOS inhibition on cerulein-induced pancreatitis in rats. Group I received intraperitoneal (ip) injection of normal saline. Group II received two ip injections of cerulein (20 g/kg). Group III received injections of N G -nitro-L-arginine methyl ester (L-NAME) (30 mg/kg) with cerulein. Group IV received Larginine (250 mg/kg) with cerulein and L-NAME. The expression of iNOS in the pancreas was examined by western blot analysis. The plasma concentration of NO metabolites was measured. The severity of pancreatitis was assessed by measuring serum amylase, pancreas water content and histopathological examination. Compared with controls, the cerulein group displayed significantly increased expression of iNOS and raised plasma NO metabolites. Treatment with L-NAME significantly decreased hyperamylasemia, plasma NO level, and the extent of pancreatic injury. Treatment with L-arginine reversed the effects of L-NAME. These findings suggest that an enhanced formation of NO by iNOS plays an important role in the development of acute pancreatitis, and inhibition of NO production has the beneficial effects in reducing pancreas injury.

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Section: Discussionsupporting

confidence: 89%

The Role of Nitric Oxide in Experimental Cerulein Induced Pancreatitis

Kwon

Kim

et al. 2003

J Korean Med Sci

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“…[20,21,22] In the present study co-treatment of animals with raxofelast, an inhibitor of lipid peroxidation, reduced the levels of MAL, prevented the depletion of pancreatic GSH and markedly attenuated the severity of pancreatitis. As a matter of fact, raxofelast caused a reduction in the biochemical signs of pancreatitis, such as the increased serum amylase and lipase activity, improved the histological picture and decreased tissue edema.…”

Section: Discussionsupporting

confidence: 51%

Lipid Peroxidation Inhibition Reduces NF-κB Activation and Attenuates Cerulein-induced Pancreatitis

Altavilla¹,

Famulari²,

Passaniti³

et al. 2003

Free Radical Research

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Increased lipid peroxidation, enhanced nuclear factor kappa-B (NF-kappaB) activation and augmented tumor necrosis factor-alpha (TNF-alpha) production have been implicated in cerulein-induced pancreatitis. We investigated whether lipid peroxidation inhibition might reduce NF-kappaB activation and the inflammatory response in cerulein-induced pancreatitis. Male Sprague-Dawley rats of 230-250g body weight received administration of cerulein (80 microg/kg s.c. for each of four injections at hourly intervals). A control group received four s.c. injections of 0.9% saline at hourly intervals. Animals were randomized to receive either raxofelast, an inhibitor of lipid peroxidation (20 mg/kg i.p. administered with the first cerulein injection) or its vehicle (1 ml/kg of a 10% DMSO/NaCl solution). All these rats were sacrificed 2 h after the last injection of either cerulein or its vehicle. Raxofelast administration (20 mg/kg i.p. with the first cerulein) significantly reduced malondialdehyde (MDA) levels, an index of lipid peroxidation (CER + DMSO = 3.075 +/- 0.54 micromol/g; CER + raxofelast = 0.693 +/- 0.18 micromol/g; p < 0.001), decreased myeloperoxidase (MPO) activity (CER + DMSO = 22.2 +/- 3.54 mU/g; CER + raxofelast = 9.07 +/- 2.05 mU/g, p < 0.01), increased glutathione levels (GSH) (CER + DMSO = 5.21 +/- 1.79 micromol/g; CER + raxofelast = 15.71 +/- 2.14 micronol/g; p < 0.001), and reduced acinar cell damage evaluated by means of histology and serum levels of both amylase (CER + DMSO = 4063 +/- 707.9 U/l; CER + raxofelast = 1198 +/- 214.4 U/l; p < 0.001), and lipase (CER + DMSO = 1654 +/- 330 U/l; CER + raxofelast = 386 +/- 118.2 U/l; p < 0.001), Furthermore, raxofelast reduced pancreatic NF-kappaB activation and the TNF-alpha mRNA levels and tissue content of mature protein in the pancreas. Indeed, lipid peroxidation inhibition might be considered a potential therapeutic approach to prevent the severe damage in acute pancreatitis.

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“…Our hypothesis that an overproduction of NO by ecNOS and/or iNOS plays a key role in the proposed pathophysiologic sequelae of acute pancreatitis is further supported by numerous studies demonstrating beneficial effects of nonselective NOS inhibitors in acute pancreatitis [149][150][151][152] as well as after pancreatic cold [153] and warm ischemia-reperfusion [154]. These beneficial effects include the prevention of progressive and severe hypotension [150], the reduction in multiorgan oxidative stress [149] and bacterial translocation [152], as well as the attenuation of diaphragmatic dysfunction [151] in acute experimental pancreatitis.…”

Section: Potential Candidates Mediating Vasoconstriction/vasodilationmentioning

confidence: 74%

“…These beneficial effects include the prevention of progressive and severe hypotension [150], the reduction in multiorgan oxidative stress [149] and bacterial translocation [152], as well as the attenuation of diaphragmatic dysfunction [151] in acute experimental pancreatitis.…”

Section: Potential Candidates Mediating Vasoconstriction/vasodilationmentioning

confidence: 99%