Effect of carvedilol versus propranolol on acute and chronic liver toxicity in rats.

Non-selective ß-blockers have largely been used for prophylaxis of bleeding from gastroesophageal varices, but their hepatic effects and their influence on the development of varices has yet to be clarified. This study examined whether carvedilol would reduce acute and chronic liver injury in rats in comparison to propranolol. Experiment (1) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) administered daily for 7 days by gavage on paracetamol (1500 mg/kg i.p.) -induced acute liver injury in rats. Experiment (2) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) by gavage daily for 8 weeks on CCl4 -induced chronic liver injury in rats. Biochemical markers and histopathology of the livers were studied. Liver perfusion studies were carried out on CCl4 treated rats. Experiment (1) Carvedilol significantly improved the functional state of the liver in paracetamol-induced acute toxic hepatitis to a greater extent than propranolol. This was evidenced by a greater reduction in elevated serum levels of ALT and AST, hepatic MDA and TNF-α, attenuation of the paracetamol-induced decrease in GSH, together with improvement in the histological architecture of the liver. Experiment (2) Carvedilol was superior to propranolol against CCl4-induced hepatic injury and fibrogenesis. It suppressed hepatic inflammation, attenuated hepatic oxidative stress, and inhibited HSC activation. Carvedilol also decreased portal perfusion pressure. These results suggest that carvedilol might be a therapeutic anti-fibrogenic candidate against hepatic fibrosis, protecting the liver from acute and chronic toxic injury, in addition to lowering portal pressure.

The potential antiepileptic activity of astaxanthin in epileptic rats treated with valproic acid.

OBJECTIVES: Epilepsy is a neurological disease characterized by sudden, abnormal, and hyper- discharges in the central nervous system (CNS). Valproic acid (VPA) is commonly used as a broad-spectrum antiepileptic therapeutic. However, in many cases, patients develop resistance to VPA treatment due to overwhelming oxidative stress, which in turn might be a major catalyst for disease progression. Therefore, antioxidants can potentially become therapeutic agents by counteracting reactive oxygen species (ROS)-mediated damage. The present study is aimed to evaluate the potential antiepileptic effect of astaxanthin (ASTA) in pentylenetetrazol (PTZ) induced epileptic model rats that are chronically treated with VPA for 8 weeks. METHOD: Fifty-male Wistar rats were randomly divided into five groups: Non-PTZ group, PTZ, PTZ/VPA, PTZ/ASTA, and PTZ/VPA/ASTA treated groups. RESULTS: PTZ/VPA treated group showed a neuroprotective effect with improvement in antioxidant levels, behavioral test, and histopathological changes induced by PTZ. VPA also exhibited an anti-inflammatory effect as its treatment resulted in the reduction of tumor necrosis factor-α (TNF-α). ASTA exhibited an anticonvulsant effect and enhanced anti-inflammatory effect as compared to VPA. During the combined therapy, ASTA potentiated the antiepileptic effect of the VPA by reducing the oxidative stress and TNF-α as well as increased the glutathione (GSH) levels. Also, there were substantial improvements in the behavioral and histopathological changes in the VPA/ASTA treated group as compared to the VPA treated group. CONCLUSION: ASTA could have an antiepileptic and anti-inflammatory effect by reducing ROS generation. Therefore, co-administration of both the therapeutics (VPA/ASTA) has a synergistic effect in treating epilepsy and could potentially minimize recurrence and/or exacerbation of seizures.

Aliskiren and valsartan in combination is a promising therapy for hypertensive renal injury in rats.

Neither ACEI nor ARBs completely repress the RAAS. Aliskiren is a newer agent that inhibits renin. However, it increases the biosynthesis and secretion of renin and prorenin, that might induce renal tissue damage. This study was conducted to investigate the renoprotective effects of aliskiren and valsartan the ARB, either alone or in combination, on hypertensive nephropathy induced by L-NAME. Aliskiren (50 mg/kg/daily i.p.), valsartan (10 mg/kg daily i.p.) alone or in half dose combination were administered with L-NAME (30-40 mg daily in drinking water) for 8 weeks. Aliskiren and valsartan significantly reduced systolic blood pressure, proteinuria, serum creatinine, blood urea nitrogen, oxidative stress, and structural renal injury although not to the same extent. Valsartan reduced systolic blood pressure and proteinuria in L-NAME treated rats more significantly than aliskiren. However, glomerular collapse index and the expansion of interstitial tissue were significantly attenuated by aliskiren than by valsartan. Cotreatment with aliskiren and valsartan markedly reduced the oxidative stress and further reduced the glomerular collapse and the expansion of interstitial tissue compared with aliskiren monotherapy. CONCLUSION: These results suggest that therapies aimed at different targets within the RAAS may have additional effects in attenuating structural injury in experimental hypertensive nephropathy.

Trimetazidine potentiates the antiepileptic activity and ameliorates the metabolic changes associated with pentylenetetrazole kindling in rats treated with valproic acid.

Oxidative stress is implicated in epileptogenesis as well as in the metabolic changes associated with increased risk of atherosclerotic vascular disease in epilepsy. The present work investigated the impact of the antioxidant trimetazidine (TMZ) on the antiepileptic activity of valproic acid (VPA) and on the metabolic and histological changes in hippocampal, aortic, and hepatic tissues associated with epilepsy and (or) VPA. Rats were divided into non-pentylenetetrazole (non-PTZ) group subdivided into control and VPA-treated groups, and PTZ-treated group subdivided into PTZ, PTZ/VPA, PTZ/TMZ, and PTZ/VPA + TMZ groups. VPA treatment in PTZ rats resulted in an antioxidant effect with improvement in oxidative stress, metabolic and histopathological changes induced by PTZ in hippocampus, aortic, and hepatic tissues. TMZ exhibited anticonvulsant activity and potentiated the anticonvulsant effect of VPA. Combination of TMZ with VPA induced a greater reduction in oxidative stress, improvement in the metabolic and histopathological changes compared to VPA treatment. In contrast, VPA administration in non-PTZ-treated rats induced a pro-oxidative effect, associated with metabolic and histopathological changes in aortic and hepatic tissues. These findings suggest that co-administration of TMZ with VPA in epilepsy might antagonize not only the oxidative stress associated with epilepsy but might also counteract a potential pro-oxidative effect of VPA.

Low-dose carvedilol protects against acute septic renal injury in rats during the early and late phases.

Recent findings from septic acute renal injury studies have implicated the mitochondrion as an important factor in kidney injury, and that increased sympathetic nerve activity may contribute to the induction of organ failure. This study investigated the impact of a nondepressor dose of carvedilol, which is a beta-adrenoreceptor antagonist with antioxidant activity, on septic renal injury induced in rats with cecal ligation and puncture (CLP). Three groups of rats were studied. The first group was the sham-operated control. The other 2 groups of rats underwent CLP, and were administered either the vehicle or carvedilol (2.0 mg/kg body mass, by intraperitoneal (i.p.) injection, daily for 2 days as well as 30 min prior to CLP). Kidney function, inflammatory parameters, mitochondrial function, and renal perfusion pressure (RPP) were investigated at 6 and 18 h after CLP. Carvedilol did not significantly induce hypotension, and it significantly improved RPP and renal dysfunction induced with CLP, together with significant reductions in serum levels of interleukin 6 and tumor necrosis factor-alpha. Septic kidney injury mediated increased levels of malondialdehyde and protein carbonyls. Carvedilol also attenuated the decrease in kidney mitochondrial glutathione and nicotinamide adenine dinucleotide phosphate dehydrogenase. Further, intracellular renal edema and inflammation induced with CLP were reduced with carvedilol. These findings suggest renoprotective effects of carvedilol in sepsis.

Hepatoprotective effects of early pentoxifylline administration on hepatic injury induced by concanavalin A in rat.

Tumor necrosis factor alpha (TNF-α) plays an important role in the pathogensis of hepatitis C virus (HCV) infection induced liver injury. This study aimed to evaluate the effects of TNF-α inhibition with pentoxifylline (PTX) on concanavalin A (Con A)-induced hepatic injury in rats. The rats were distributed among 3 groups: (i) control group (1 mL saline·week(-1) by intravenous injection (i.v.)); (ii) Con A treatment group (20 mg Con A·(kg body mass)(-1)·week(-1), i.v.), and (iii) rats treated with Con A and with PTX (200 mg PTX·(kg body mass)(-1)·day(-1), per oral) group. Blood samples and livers were collected at the end of weeks 1, 2, 4, and 8 of Con A treatment. Portal pressure (PP) was measured at the end of week 8. The administration of PTX was found to confer significant protection against the injurious effects of Con A on the liver, by reducing serum levels of aspartate aminotransferase, alanine aminotransferase, hepatic TNF-α, and malondialdehyde. Histopathological examination revealed that treatment with PTX significantly suppressed early inflammation, reduced alpha smooth muscle actin, and the apoptosis of hepatocytes induced by Con A. Moreover, PTX significantly (P < 0.05) reduced PP, and quantitative analyses of the area of fibrosis induced by treatment with Con A showed a significant reduction at the end of week 8. We conclude that rats treated with PTX revealed a more or less normal hepatocyte architecture as well as marked improvement in fibrosis and PP.

Chronic pantoprazole administration and ischemia--reperfusion arrhythmias in vivo in rats--antiarrhythmic or arrhythmogenic?

BACKGROUND: The safety of all proton pump inhibitors (PPIs) in patients with intrinsic cardiac disease has not been well studied. In the present study, the effect of PPI pantoprazole on ventricular arrhythmias induced by either ischemia or ischemia-reperfusion (I/R) was studied. METHODS: The left main coronary artery (LAD) was ligated for 30 or 10 min followed by a 30-min reperfusion in anesthetized rats. Rats were pretreated with pantoprazole (1.3 mg/kg) or vehicle by gastric gavage (daily for 3 weeks) before ligation. Serum electrolytes levels were measured by the end of the third week before coronary ligation. Lactate dehydrogenase (LDH) activity and nitric oxide (NO) concentrations were measured at the end of the ischemia and IR injury. RESULTS: Pantoprazole caused significant hyperkalemia by the end of third week compared with vehicle-treated rats. After LAD ligation (30 min), ventricular premature contractions (VPC), ventricular tachycardia (VT) and ventricular fibrillation (VF) were recorded in rats of the vehicle ischemia group. Pantoprazole pretreatment aggravate these arrhythmias and increased mortality. A 10-min period of ischemia followed by a 30-min reperfusion induced high incidence of VT (100%) and VF (80%) in the vehicle-treated group. The group of rats administered pantoprazole had significantly lower incidence and durations of VT and VF together with reduction of mortality rate. Pantoprazole significantly reduced serum LDH activity and NO release from myocardial tissue after both ischemia and I/R injury. CONCLUSION: Pantoprazole aggravated ischemia-induced arrhythmias but had a significant antiarrhythmic effect on I/R-induced ventricular arrhythmias.