Ali Akbar Nekooeian

Enhanced anti-ulcer effect of pioglitazone on gastric ulcers in cirrhotic rats: The role of nitric oxide and IL-1β

BACKGROUND The frequency of gastrointestinal ulcerations is higher in cirrhotic patients than in the normal population. It has been shown that pioglitazone exhibits gastroprotective actions. This study was designed to investigate the effect of pioglitazone, on the gastric mucosal lesions in cirrhotic rats. METHODS Different groups of bile duct-ligated and sham animals received solvent, or 5, 10 or 15 mg/kg pioglitazone, for 5 days in the last days of 28-day period of cirrhosis. On day 28, rats were killed 1 h after oral ethanol administration and the area of gastric lesions was measured. The serum of rats was also collected to evaluate serum concentrations of TNF-α and IL-1β. Histopathologic examination of liver specimens was also done with hematoxylin-eosin to show possible toxicity of pioglitazone in cirrhosis. RESULTS Pretreatment with pioglitazone dose dependently attenuated gastric lesions induced by ethanol in both sham and cirrhotic rats, but this effect was more prominent in cirrhotic ones. L-NAME, a non-selective inhibitor of nitric oxide synthase, decreased pioglitazone-induced gastric healing effect in cirrhotic rats, while aminoguanidine, a selective inducible nitric oxide synthase inhibitor, increased pioglitazone-induced gastric healing effect in the same group. The protective effect of pioglitazone was accompanied by a fall in serum IL-1β level. CONCLUSIONS Chronic treatment with pioglitazone exerts a more prominent gastroprotective effect on the stomach ulcers of cirrhotic rats compared to control group probably due to constitutive nitric oxide synthase induction or inducible nitric oxide synthase inhibition. Suppression of IL-1β could be another mechanism in pioglitazone-induced healing effect of gastric ulcers in cirrhotic rats.

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

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.

Solid plexiglass clips to induce reproducible renal hypertension in the rat

Objective: The objective of this study was to induce reproducible renal hypertension in rats using plexiglass clips, and to compare it with that induced by silver clips. Materials and Methods: Saw blades (0.21-0.22 mm thick ) were used to make clips (4 x 2 x 2 mm) from a piece of 2-mm thick plexiglass. Rats were subjected to sham-operation or placement of plexiglass or silver clips around left renal artery, and 4 weeks later their mean blood pressure (MBP, mmHg), heart rate (HR, bpm), and heart weight (HW), left kidney weight (LKW), right kidney weight (RKW) and body weight (BW, g) were determined. The RKW, LKW and HW were calculated as a percentage of body weight. Results: Four weeks after sham-operation or placement of clips around renal artery, MBP, HW and RKW were significantly higher and LKW was significantly lower in left renal artery-clipped rats using plexiglass or silver clips than sham-operated ones. There was also no significant differnce among the values of HR or BW from the 3 groups. Moreover, there was no significant difference among MBP, HR, LKW, RKW or BW from sham-operated or renal artery-clipped rats. Conclusion: The findings suggest that placement of solid plexiglass clips around left renal artery resulted in hypertension comparable to that induced by silver clips.

Candesartan Attenuates Ischemic Brain Edema and Protects the Blood-Brain Barrier Integrity from Ischemia/Reperfusion Injury in Rats

Background: Angiotensin II (Ang II) has an important role on cerebral microcirculation; however, its direct roles in terms of ischemic brain edema need to be clarified. This study evaluated the role of central Ang II by using candesartan, as an AT1 receptor blocker, in the brain edema formation and blood-brain barrier (BBB) disruption caused by ischemia/reperfusion (I/R) injuries in rat. Methods: Rats were exposed to 60-min middle cerebral artery (MCA) occlusion. Vehicle and non-hypotensive doses of candesartan (0.1 mg/kg) were administered one hour before ischemia. Neurological dysfunction scoring was evaluated following 24 h of reperfusion. Animals were then decapitated under deep anesthesia for the assessments of cerebral infarct size, edema formation, and BBB permeability. Results: The outcomes of 24 h reperfusion after 60-min MCA occlusion were severe neurological disability, massive BBB disruption (Evans blue extravasation = 12.5 ± 1.94 µg/g tissue), 4.02% edema, and cerebral infarction (317 ± 21 mm3). Candesartan at a dose of 0.1 mg/kg, without changing arterial blood pressure, improved neurological dysfunction scoring together with significant reductions in BBB disruption (54.9%), edema (59.2%), and cerebral infarction (54.9%). Conclusions: Inactivation of central AT1 receptors, if not accompanied with arterial hypotension, protected cerebral micro-vasculatures from damaging effects of acute stroke.

Effects of oleuropein in rats with simultaneous type 2 diabetes and renal hypertension: a study of antihypertensive mechanisms

The mechanism of oleuropeins antihypertensive effects was examined in rat model of simultaneous type 2 diabetes and renal hypertension (diabetic hypertensive). Five groups of male Sprague-Dawley rats including a control, a diabetic-hypertensive group receiving vehicle, and three diabetic-hypertensive groups receiving oleuropein at 20, 40, or 60 mg/kg/day were used. The duration of diabetes was 10 weeks; during the last 4 weeks of which, animals were hypertensive and received vehicle or oleuropein. Systolic blood pressure, glucose and malondialdehyde, heart rate, and maximal response to phenylephrine (PE) in the absence of nitro-l-arginine methyl ester (l-NAME) of oleuropein-treated groups were significantly lower than those of vehicle-treated group. Erythrocyte superoxide dismutase, maximal response to PE in the presence of l-NAME, and maximal response to acetylcholine (Ach) of oleuropein-treated groups were significantly higher than those of vehicle-treated group. The findings indicate that antihypertensive effects of oleuropein might be partly mediated by improving the release of nitric oxide, and antioxidant and sympathoplegic activities.

Oleuropein offers cardioprotection in rats with simultaneous type 2 diabetes and renal hypertension

Objectives: The study aimed at examining the role of oxidative stress in cadioprotective effects of oleuropein in a rat model of simultaneous type 2 diabetes and renal hypertension. Materials and Methods: Five groups of male Sprague-Dawley rats including a control group, a diabetic-hypertensive group receiving vehicle, and three diabetic-hypertensive groups receiving oleuropein at 20, 40, or 60 mg/kg/day were used. Blood pressure and glucose, serum malondialdehyde, and erythrocyte superoxide dismutase were measured, and animals hearts with ischemia/reperfusion injuries were used using Langendorff technique. Results: Blood pressure, blood glucose, serum malondialdehyde, infarct size, coronary effluent creatine kinase-MB, and coronary resistance of diabetic-hypertensive group were significantly higher than those of the control group, while those of the oleuropein-receiving groups were significantly lower than those of the diabetic hypertensive group receiving the vehicle. Erythrocyte superoxide dismutase, left ventricular developed pressure, and rate of rise and rate of decrease of ventricular pressure of diabetic-hypertensive group were significantly lower than those of the control group. These parameters as well as heart rate of oleuropein-receiving groups were significantly higher than those of the diabetic-hypertensive group. Conclusion: The findings indicate that oleuropein offered cardioprotection, which might be partly mediated by its antioxidant properties.

Simultaneous renal hypertension and type 2 diabetes exacerbate vascular endothelial dysfunction in rats

Despite the high rate of occurrence of both diabetes and hypertension in humans, the cardiovascular effects of the two conditions have not been investigated when they occur simultaneously. Thus this study examined the vascular effects of simultaneous type 2 diabetes and renal hypertension on endothelial function. Serum malondialdehyde and systolic blood pressure (SBP) were measured, glucose tolerance test (GTT) was performed, and concentration‐response to phenylephrine (PE) in the absence and presence of nitro‐l‐arginine methyl ester (l‐NAME), acetylcholine and sodium nitroprusside were conducted on aortic rings from diabetic control, type 2 diabetes, sham‐operated, renal hypertensive, and simultaneous type 2 diabetes plus hypertension rats respectively. Hypertension, diabetes, and simultaneous diabetes and hypertension were associated with either increased or decreased maximal responses (Emax) of PE dependent on in the presence or absence of l‐NAME. There was also increased serum malondialdehyde and decreased Emax of acetylcholine. Thus simultaneous hypertension and diabetes caused a greater decrease in Emax of acetylcholine compared to that seen with either diabetes or hypertension alone higher than that seen in hypertension. The blood glucose during GTT was lower than that seen in diabetes groups. Thus simultaneous type 2 diabetes and the SBP was renal hypertension is associated with improved glucose tolerance, but with further deterioration of endothelial dysfunction compared with either condition alone.

Oleuropein improves glucose tolerance and lipid profile in rats with simultaneous renovascular hypertension and type 2 diabetes

Abstract Oleuropein mediates most of the beneficial effects of olive products. This study examined the role of oxidative stress in the effects of oleuropein on lipid profile and blood glucose in rats with simultaneous renovascular hypertension and type 2 diabetes. Eight groups (n = 7–9 each) of male Sprague-Dawley rats including a control, a type 2 diabetic, a renovascular hypertensive, a sham, a simultaneously hypertensive diabetic receiving vehicle, and 3 simultaneously hypertensive-diabetic receiving 20, 40, or 60 mg/kg/day oleuropein were used. Four weeks after treatment, blood glucose, lipid profile, and biomarkers of oxidative stress were measured, and glucose tolerance test (GTT) was performed. Simultaneously hypertensive diabetic rats had significantly higher blood pressure, blood glucose, and serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride and malondialdehyde. They also had lower serum high-density lipoprotein cholesterol, erythrocyte superoxide dismutase, and impaired glucose tolerance. Oleuropein significantly reduced blood pressure, blood glucose, and serum total cholesterol, LDL-C, triglyceride and malondoaldehyde. It also increased serum high-density lipoprotein cholesterol, erythrocyte superoxide dismutase, and improved glucose tolerance. The findings show that the model is associated with impaired glucose tolerance, and adverse lipid profile. They also show that oleuropein, partly by an antioxidant mechanism, improves glucose tolerance and changed lipid profile favorably.

Right ventricular pressure elevated in one-kidney, one clip Goldblatt hypertensive rats

ABSTRACT Both renal and respiratory diseases are common with high mortality rate around the world. This study was the first to compare effects of two kidneys, one clip (2K1C) and one-kidney, one clip (1K1C) Goldblatt hypertension on right ventricular pressure during normal condition and mechanical ventilation with hypoxia gas. Male Sprague–Dawley rats were subjected to control, 2K1C, or 1K1C groups. Twenty-eight days after the first surgery, animals were anesthetized, and femoral artery and vein, and right ventricle cannulated. Systemic arterial pressure and right ventricular systolic pressures (RVSP) were recorded during ventilation the animals with normoxic or hypoxic gas. RVSP in the 1K1C group was significantly more than the control and 2K1C groups during baseline conditions and ventilation the animals with hypoxic gas. Administration of antioxidant Trolox increased RVSP in the 1K1C and control groups compared with their baselines. Furthermore, there was no alteration in RVSP during hypoxia in the presence of Trolox. This study indicated that RVSP only increased after 28 days induction of 1K1C but not 2K1C model. In addition, it seems that the response to hypoxic gas and antioxidants in 1K1C is more than 2K1C. These data also suggest that effects of 1K1C may partially be related to reactive oxygen species (ROS) pathways.

Antihypertensive effects of new dihydropyridine derivatives on phenylephrine-raised blood pressure in rats

Changes in the substitutions at C-3 and C-5 positions of 4-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine have led to changes in potency of the compounds. The objective of the present study was to examine the hypotensive effects of 5 newly synthesized dihydropyridine derivatives of nifedipine in rats with phenylephrine-raised blood pressure. Anesthetized Sprague-Dawley rats were randomly assigned to 19 groups of 7 animals each. Control group received the vehicle dimethylsulfoxide (0.05 mL), 3 groups were given nifedipine at 100, 300, or 1000 μg/kg, and 5 other groups each composed of 3 subgroups administered one of the 5 new dihydropyridine compound at 100, 300, or 1000 μg/kg. All animals were initially infused with 20 µg/kg/min phenylephrine for 45 min, and were then given a bolus of either dimethylsulfoxide, nifedipine, or new dihydropyridine compounds 20 min after the commencement of phenylephrine infusion. Blood pressure and heart rate (HR) of the animals were measured before and at the end of phenylephrine infusion, or 25 min after injection of vehicle or compounds. Compared to dimethylsulfoxide, nifedipine, and new 1, 4-dihydropyridine derivatives caused significant reductions in MBP. Moreover, cyclohexyl propyl, phenyl butyl, and cyclohexyl methyl analogs of 1, 4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazoyl)-3,5-pyridinedicarboxylase at 100 μg/kg, phenyl butyl, and cyclohexyl methyl analogs at 300 μg/kg, and cyclohexyl methyl analogs at 1000 μg/kg reduced MBP similar to nifedipine. There was no significant difference between HR of all groups before and after administration of the compounds. The findings indicated that changes in substitution at C-3 and C-5 positions of 2-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine were associated with changes in hypotensive activity of the compounds.