The increased gastroprotective effect of pioglitazone in cholestatic rats: role of nitric oxide and tumour necrosis factor alpha

Abstract

The prevalence of gastric ulcers is high in cholestatic patients, but the exact mechanism of this increased frequency remains uncertain. It has been shown that pioglitazone accelerates the healing of pre-existing gastric ulcers. The present study was designed to investigate the effect of pioglitazone, on the gastric mucosal lesions in cholestatic rats. Cholestasis was induced by surgical ligation of common bile duct and sham-operated rats served as control. Different groups of sham and cholestatic animals received solvent or pioglitazone (5, 15, 30 mg/kg) for 7 days. On the day eight rats were killed after oral ethanol administration and the area of gastric lesions was measured. The serums of rats were also collected to determine serum levels of tumour necrosis factor alpha (TNF-α), IL-1β and bilirubin. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than sham-operated ones. Pretreatment with pioglitazone dose-dependently attenuated gastric lesions induced by ethanol in both sham and cholestatic rats, but this effect was more prominent in cholestatic ones. The effect of pioglitazone was associated with a significant fall in serum levels of TNF-α in cholestatic rats. L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor, and decreased pioglitazone-induced gastroprotective effect in cholestatic rats, while aminoguanidine, a selective inducible NOS inhibitor, potentiated pioglitazone-induced gastroprotective effect in the cholestatic rats. Chronic treatment with pioglitazone exerts an enhanced gastroprotective effect on the stomach ulcers of cholestatic rats compared to sham rats probably due to constitutive NOS induction and/or inducible NOS inhibition and attenuating release of TNF-α.

Pioglitazone Normalizes Insulin Signaling in the Diabetic Rat Retina through Reduction in Tumor Necrosis Factor α and Suppressor of Cytokine Signaling 3

“…These findings were observed in vivo as well as in cultured REC and Müller cells treated with pioglitazone. Our findings are in agreement with work in cholestatic rats treated with pioglitazone for gastric ulcer (33). Similar results of decreased TNF␣ after pioglitazone were also noted in the fat tissues of db/db mice (34).…”

Acute exercise inhibits gastric emptying of liquids in rats: influence of the NO-cGMP pathway

“…On the day of the experiment, the animals were randomly treated with vehicle (0.9% NaCl, 0.1 mL/100g, ip ) or one of the following agents: the muscarinic receptor antagonist (atropine, 1.0 mg/kg, ip ) (17), the NO non-selective inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10 mg/kg, ip ) (18), the cGMP selective inhibitor 1H-(1,2,4)oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 5.0 mg/kg, ip ) (19), the i-NOS non-selective inhibitor (aminoguanidine 10 mg/kg, ip ) (20), the CRF receptor antagonist (astressin 100 µg/kg, ip ) (21), or the VIP receptor antagonist Lys 1 , Pro 2,5 , Arg 3,4 , Tyr 6 (100 µg/kg, ip ) (19). Thirty minutes after pretreatment, the rats were subjected to the formerly specified sedentary or acute exercise protocols.…”

Taurine mitigates bile duct obstruction-associated cholemic nephropathy: effect on oxidative stress and mitochondrial parameters

“…Rats were treated as follows: 1) sham-operated (vehicle-treated); 2) bile duct ligated (BDL); 3) BDL + taurine (500 mg/kg, oral); 4) BDL + taurine (1000 mg/kg, oral) [48]. TAU was administered for seven consecutive days, and its effect on the cholestasis-induced renal injury was assessed [46,49].…”