sildenafil-citrate and Stomach-Ulcer

Sildenafil (SIL) has potential as an interesting gastroprotective drug. However, the pathways of its protective effect still needs to be clarified, and its use as a potential gastroprotective agent validated. This study aims to evaluate the effects of SIL via modulation of oxidative stress in a NSAID-induced gastric lesion model. Male Swiss mice were divided into six groups: control (CON, water), nonsteroidal anti-inflammatory drug (NSAID, water), proton pump inhibitor (PPI, 30 mg/kg of lansoprazole), SIL 5 (5 mg/kg), SIL 25 (25 mg/kg) and SIL 50 (50 mg/kg). The animals were treated by gavage (a single dose) after 24 hours of fasting, and gastric lesions were performed after 30 minutes, with indomethacin (40 mg/kg, by gavage). After 6h, the animals were killed and the stomach was removed to evaluate reactive oxygen species (ROS) production, oxidation of macromolecules, quantification of antioxidant enzymes, DNA fragmentation, apoptosis and macroscopic and histologic analysis of gastric lesions. SIL exerts a dose-dependent gastroprotective effect against NSAID-induced mucosal injury, also reducing cytoplasmic levels of ROS and consequent oxidative damage to macromolecules. In addition, SIL increases nitric oxide bioavailability, antioxidant enzymes and gastric cellular viability, as well as restoring important factors involved in gastroprotection. Our results demonstrate that different doses of SIL prevent indomethacin-induced gastric ulcer in mice via different, but complementary antioxidant, antigenotoxic and antiapoptotic mechanisms.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Male; Mice; Sildenafil Citrate; Stomach Ulcer

The purpose of our investigative work has been to determine whether there can be therapeutic roles in the administration of sildenafil citrate, heparin and several neuropeptides on an animal model where gastric ulcers were induced with acetic acid, and to compare their efficacy.. The animals were divided into 13 groups, with 4 animals in each. Gastric ulcers was induced in the animals of 12 groups with one untreated group being left as the control (Group I - control; given normal saline (NS)). The other groups were: Group II (ulcer+NS); Group III (5mg/kg sildenafil citrate, low dose); Group IV (10mg/kg sildenafil citrate, high dose); Group V (0.6mg/kg heparin, low dose); Group VI (6mg/kg heparin, high dose); Group VII (20nmol/kg des-acyl ghrelin); Group VIII (40nmol/kg des-acyl ghrelin); Group IX (4nmol/kg acyl ghrelin); Group X (8nmol/kg acly ghrelin); Group XI (20pmol/kg Nesfatin-1); Group XII (15nmol/kg Obestatin) and Group XIII (5nmol/kg Neuropeptide Y). Gastric neuropeptide expression was measured using an immunohistochemical method, and the amount in circulation was detected using ELISA. To compare with no treatment, the controls and other treatment groups, we recorded loss of the surface epithelium of the stomach, erosion, bleeding and inflammatory cell infiltration in the upper halves of the gastric glands.. The muscularis and the layers beneath it were, however, apparently normal. The gastric mucosa healed with little or no inflammation when sildenafil citrate, low dose heparin, ghrelin, NUCB2/Nesfatin-1, obestatin, Neuropeptide Y were administered.. Overall the data indicate that low dose heparin, and especially sildenafil citrate and neuropeptides, can be used clinically as an alternative approach in the treatment of the gastric ulcer.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Gastric Mucosa; Heparin; Neuropeptides; Rats, Sprague-Dawley; Sildenafil Citrate; Stomach Ulcer

Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase. Sildenafil, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy. Activation of ATP-sensitive potassium channels (K(ATP)) is involved in gastric defence. Our objective was to evaluate the role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage.. Rats were treated with L-NAME (1 or 3 mg kg(-1), i.p.) or with L-arginine (200 mg kg(-1), i.p.) + L-NAME (3 mg kg(-1), i.p.), the guanylate cyclase inhibitor, ODQ (10 mg kg(-1), i.p.), glibenclamide (0.1, 0.3, 1 or 3 mg kg(-1), i.p.) or with glibenclamide (1 mg kg(-1), i.p.) + diazoxide (3 mg kg(-1), i.p.). After thirty minutes, the rats received sildenafil (1 mg kg(-1), by gavage), followed by intragastric instillation of absolute ethanol (4 ml kg(-1)) to induce gastric damage. One hour later, gastric damage (haemorrhagic or ulcerative lesions) was measured with a planimetry programme. Samples of stomach were also taken for histopathological assessment and for assays of tissue glutathione and haemoglobin.. Sildenafil significantly reduced ethanol-induced gastric damage in rats. L-NAME alone, without L-arginine, significantly reversed the protection afforded by sildenafil. Inhibition of guanylate cyclase by ODQ completely abolished the gastric protective effect of sildenafil against ethanol-induced gastric damage. Glibenclamide alone reversed sildenafil's gastric protective effect. However, glibenclamide plus diazoxide did not alter the effects of sildenafil.. Sildenafil had a protective effect against ethanol-induced gastric damage through the activation of the NO/cGMP/K(ATP) pathway.

Topics: Animals; Arginine; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Diazoxide; Disease Models, Animal; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Glutathione; Glyburide; Guanylate Cyclase; Hemoglobins; KATP Channels; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Peptic Ulcer Hemorrhage; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Potassium Channel Blockers; Purines; Quinoxalines; Rats; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Stomach Ulcer; Sulfones

Although sildenafil (Viagra) and other phosphodiesterase V (PDE V) inhibitors are increasingly recognized for their use in the treatment of male erectile dysfunction and perhaps more recently pulmonary artery hypertension, less is known of their potential beneficial effects in other situations. Medeiros et al., in the current issue of the British Journal of Pharmacology, report that sildenafil dramatically reduces alcohol-induced gastric damage in rats. The authors provide convincing evidence that such protection not only occurs via the nitric oxide (NO)/cGMP pathway, but also involves regulation of ATP-sensitive potassium channels. Therefore, in addition to exerting anti-impotence efficacy, PDE V inhibitors may provide significant beneficial effects from mucosal injury induced by alcohol.

Topics: Animals; Arginine; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Ethanol; Gastric Mucosa; Glutathione; Guanylate Cyclase; Hemoglobins; KATP Channels; Nitric Oxide; Nitric Oxide Synthase; Peptic Ulcer Hemorrhage; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Signal Transduction; Sildenafil Citrate; Stomach Ulcer; Sulfones

To investigate the protective effects of sildenafil citrate (SC) on indomethacin-induced gastric ulcer in a rat model.. Gastric ulcers were induced by oral ingestion of indomethacin. Thirty rats were used in the study. The rats were divided into 3 groups, and given either SC (n=10) at a dose of 50 mg/kg or omeprazole (n=10), or no treatment (n=10, the control group). In addition to the measurements of ulceration areas, the sum of gastric tissue nitrite (NO2-) and nitrate (NO3-) were evaluated as an indicator of gastric tissue NO level. All the measurements were done at 6th hour of oral administration of indomethacin.. The mean values of ulceration areas were 4.0+/-2.31, 3.0+/-2.00, and 21.4+/-8.43 in the SC, omeprazole and control groups, respectively. The mean values of ulceration areas in the SC-treated group was lower than that of the control group. The contents of NO were 32.2+/-3.05, 24.8+/-3.23 and 21.0+/-0.82 (micromol/g protein) in gastric tissue in indomethacin, SC, omeprazole and control groups, respectively, The content of NO in the SC-treated groups was significantly higher than control group (p<0.001).. Sildenafil citrate may have a role in protecting gastric mucosa from the damage caused by indomethacin. This effect may be associated with the increased level of NO in gastric tissue.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Disease Models, Animal; Female; Indomethacin; Nitric Oxide; Omeprazole; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Stomach Ulcer; Sulfones