Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Insights in the mechanisms underlying the anti-ulcer activity of nicorandil.

This study was conducted to investigate possible mechanisms underlying the gastroprotective effect of nicorandil on experimentally-induced gastric lesions in rats. The rats were randomly assigned to vehicle (saline or tween 80), nicorandil (2 mg/kg), glibenclamide (2 mg/kg), nicorandil plus glibenclamide- and cimetidine (50 mg/kg)-pretreated groups, in addition to the non-stressed control group, to demonstrate whether the KATP channel opening activity contributed to nicorandil's gastroprotection. Gastric lesions were induced by water immersion-restraint stress (WIRS) and ulcer indices were determined. Gastric juice parameters (pH, free and total acid output, and pepsin and mucin concentrations) were determined for each group. Another group of rats was divided into control, saline-pretreated and nicorandil (2 mg/kg)-pretreated subgroups. The rats were subjected to 5 h of WIRS and the stomachs were used for determination of gastric mucosal levels of lipid peroxides, histamine, prostaglandin E2 (PGE2) and total nitrites. Nicorandil displayed significant protection against gastric lesions formation. Glibenclamide, when administered concomitantly with nicorandil, abolished its protective effects. Nicorandil significantly reduced gastric acid secretion and pepsin concentration, but upon co-administration with glibenclamide, these effects were blocked. Additionally, nicorandil significantly reduced gastric mucosal lipid peroxides and total nitrites back to near normal levels and significantly increased gastric mucosal PGE2, but did not alter significantly histamine levels. The results confirm a gastroprotective effect for nicorandil, the mechanism of which comprises KATP channel opening, free radical scavenging, PGE2 elevation, decrease of proteolytic activity and acid output and prevention of the detrimental increase of nitric oxide during WIRS, probably, by inhibiting iNOS activity.

Investigation of the mechanisms underlying the gastroprotective effect of nicorandil.

AIM: This study investigated possible mechanisms underlying the gastroprotective effect of nicorandil on experimentally-induced gastric lesions in rats. METHODS: Rats were randomly assigned to vehicle-, nicorandil (10 mg/kg)-, glibenclamide (6 mg/kg)-, nicorandil + glibenclamide- and cimetidine-pretreated groups, in addition to non-stressed control group, to demonstrate whether the K(ATP )channel opening contributed to nicorandil's gastroprotection. Lesions were induced by water immersion-restraint stress (WIRS) and ulcer indices were determined. Gastric juice parameters (pH, acid output, pepsin and mucin concentrations) were determined. Another set of rats was divided into control, saline-pretreated and nicorandil (10 mg/kg)-pretreated groups. Rats underwent WIRS and their stomachs were used for determination of gastric mucosal lipid peroxides, histamine, PGE(2), and total nitrites levels. RESULTS: Nicorandil displayed significant protection against gastric lesions formation, abolished by concomitant administration of glibenclamide. Nicorandil significantly reduced gastric acid and pepsin secretion, but upon coadministration with glibenclamide, these effects were blocked. Additionally, nicorandil significantly reduced gastric mucosal lipid peroxides and total nitrites, but did not affect PGE(2) and histamine levels. CONCLUSION: Results confirm a gastroprotective effect for nicorandil, the mechanism of which comprises K(ATP) channel opening, free radical scavenging, decrease of pepsin and acid secretion and prevention of the detrimental rise in nitric oxide during WIRS.