Liraglutide Effect on Ventricular Transient Outward K + Channel and Connexin-43 Protein Expression.

BACKGROUND: Human glucagon-like peptide-1 analogue, Liraglutide, has shown cardioprotective effects in animal and clinical studies of type 2 diabetes mellitus. This study was conducted to assess the effect of Liraglutide on diabetes-induced myocardial electrical remodeling. MATERIALS AND METHODS: A rat model of type 2 diabetes mellitus was induced by high-fat diet and low dose Streptozotocin (35 mg/kg). Diabetic rats were randomized into 4 subgroups (n=6-7): diabetic-untreated, diabetics treated with Liraglutide, diabetics treated with Ramipril, and diabetics treated with Metformin in addition to a control group. Changes in serum glucose, insulin, lipid profile and revised quantitative insulin sensitivity check index (QUICKI index) were assessed. QT and QTc intervals were measured and the degree of cardiac interstitial and perivascular fibrosis was examined. The expression of myocardial Ito channel α subunits, gap junction protein; Kv 4.2/4.3 and connexin 43 (Cx43) respectively, were assessed by western blotting and immunohistochemistry. RESULTS: Similar to Ramipril, both Liraglutide and Metformin effectively inhibited the diabetes-induced myocardial hypertrophy and fibrosis. However, Liraglutide treatment significantly improved Kv 4.2/4.3 and Cx43 expression/distribution and prevented diabetes-related QTc interval prolongation. CONCLUSIONS: We have shown that pathological alterations in myocardial Cx43 expression and distribution, in addition to reduced Ito channel expression, may underlie the QTc interval prolongation in high-fat diet/STZ rat model of type 2 diabetes mellitus. The beneficial effects of Liraglutide, as those of Ramipril, on cardiac electrophysiology could be at least attributed to its direct ability to normalize expression and distribution of Cx43 and Ito channels in the diabetic rat heart.

Renoprotective effects of aliskiren on adenine-induced tubulointerstitial nephropathy: possible underlying mechanisms.

The present study investigated the possible renoprotective effect of direct renin inhibitor (aliskiren) on renal dysfunctions, as well as its underlying mechanisms in rat model of adenine-induced tubulointerstitial nephropathy. Forty male Sprague-Dawley rats were randomized into 4 groups; normal group, aliskiren group (normal rats received 10 mg/kg aliskiren), adenine group (animals received high-adenine diet for 4 weeks and saline for 12 weeks), and adenine + aliskiren group (animals received adenine for 4 weeks and aliskiren 10 mg/kg for 12 weeks). It was found that adenine caused significant decrease in body mass, Hb, HR, serum Ca(2+), eNOS and nrf2 expression, GSH, and catalase in kidney tissues with significant increase in arterial blood pressure (ABP), serum creatinine, BUN, plasma renin activity (PRA), K(+) and P, urinary albumin excretion (UAE), caspase-3, and MDA (lipid peroxidation marker) in kidney tissues compared to normal group (p < 0.05). Administration of aliskiren caused significant improvement in all studied parameters compared to adenine group (p < 0.05). We concluded that aliskiren has renoprotective effect against adenine-induced nephropathy. This might be due to inhibition of PRA, attenuation of oxidative stress, activation of Nrf2 and eNOS genes, and suppression of caspase-3.

The preventive effect of ß3 adrenoceptor stimulation against experimentally induced reflux esophagitis.

UNLABELLED: A ß3 adrenoceptor agonist plays an important regulatory role in stimulation of thermogenesis and lipolysis and it appears to have anti-ulcer and spasmolytic effects. So the present aim was to examine the effect of BRL 37344 (a selective B3 adrenoceptor agonist) on reflux esophagitis. METHODS: Forty-eight rats were divided into twelve sham-operated with BRL 37344 and/or omeprazole with or without indomethacin. RE was induced in rats, then gastric acid output, pH, plasma nitric oxide (NO), esophageal PGE2, malondialdehyde (MDA) and reduced glutathione (GSH) were measured and the esophageal injury was assessed by macroscopic damage score. RESULTS: Pretreatment with BRL significantly increased plasma NO, GSH, decreased acid output, esophageal MDA and esophageal injury in comparison to pretreatment. In addition, there was a no significant increase in esophageal PGE2. CONCLUSION: It can be concluded that BRL 37344 has an anti-oxidant protective effect in rats with RE.

Heparin modulation on hepatic nitric oxide synthase in experimental steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome, and has been etiologically associated with insulin resistance (IR). The histopathology of NAFLD ranges between simple steatosis and nonalcoholic steatohepatitis (NASH), with or without fibrosis. The aim of the present study was to examine the effect of heparin on steatohepatitis and hepatic-induced nitric oxide synthase (iNOS) expression in mice. Male mice were divided into four groups, which included the normal basal diet (control), high fat (HF) diet, HF diet + heparin (treatment group) and heparin control groups. After eight weeks from the initiation of the experiment, blood was collected and livers were harvested for biochemical analysis and histological studies. Serum levels of aspartate aminotransferase, alanine aminotransferase, hepatic triglyceride (TG) and hydroxyproline, as well as the IR, superoxide anion generation and mRNA expression of the hepatic iNOS enzyme were evaluated. Liver specimens were processed for histopathological and immunohistopathological evaluation. Heparin administration decreased the levels of the liver enzymes, IR, superoxide generation, hepatic TG, hydroxyproline and iNOS expression when compared with the HF diet group. These changes were associated with an improvement in inflammation and fibrosis observed via histopathological examination. Therefore, heparin treatment attenuates hepatic injury in steatohepatitis.

Effect of renin inhibition on adipokines in diabetic rats.

Insulin resistance predicts development of type 2 diabetes mellitus (DM). Adipocytes release tumor Necrosis factor-alpha (TNF-α), and adiponectin. They modulate whole-body insulin sensitivity . The disturbance in the relationship between good and bad adipokines may cause insulin resistance. The renin-angiotensin aldosteron system (RAAS) plays a role in DM and the consequence of cardiovascular complications development. It is considered as a target for therapy. The present objective examined the relationship between renin angiotensin system and DM. There were, Group (1): Normal non obese rats, Group (2): Obese diabetic rats, Group (3): Obese diabetic rats with telmisartan, Group (4): Obese diabetic rats with enalapril, Group (5): Obese diabetic rats with aliskiren. There was a significant increase in serum glucose, lipid profile [triglycerides (TGs), low-density lipoprotein cholesterol (LDL), total serum cholesterol (TC)], tumor Necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and a significant decrease in adiponectin associated with minor changes in superoxide dismutase (SOD) activity in the obese diabetic rats. Administration of telmisartan, enalapril and or aliskiren caused a significant improvement in serum lipid profile and adiponectin, a minor improvement in SOD activity, a decrease in TNF-α and or MDA. Renin angiotensin blockers significantly improve the metabolism and oxidative dysfunctions in Type 2 DM and aliskiren may show a promising powerful therapy.

Treatment for hepatitis C virus-induced portal hypertension in leukemic children.

Children with acute leukemia are at high risk of hepatitis C infection, either by immunosuppression secondary to chemotherapy or by multiple transfusions of blood products during the course of the disease. Hepatitis C virus (HCV) infection constitutes a major problem during management of acute leukemia due to resultant portal hypertension or bleeding esophageal varices. Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma in leukemic survivors. The effect of amlodipine treatment on children with acute lymphoblastic leukemia (ALL) having portal hypertension secondary to HCV infection during maintenance chemotherapy has been studied. Sixty male children (mean age 11.83 ± 1.1 years) with ALL in remission and have HCV infection were included. Diagnosis of HCV infection was confirmed by real-time PCR. Thirty patients received 5 mg amlodipine orally per day for 4 weeks and compared to another 30 patients received placebo therapy and 30 age- and sex-matched children as a control group. Amlodipine significantly reduced the elevated portal blood pressure to normal level in doses which did not interfere with mechanism of action of chemotherapy (p ≤ 0.001). Treatment with amlodipine can be used to control portal hypertension in leukemic children having HCV-induced portal hypertension. HCV in leukemics could be virtually eliminated by proper testing of the blood transfusion pool.

Influence of age on pain sensitivity in response to paw pressure and formalin injection in rats: a role of nitric oxide.

The effect of age on pain response to paw pressure and intraplantar formalin injection in rats is elucidated. Pain responses evoked by mechanical pressure on hind paw and intraplantar injection of formaldehyde (5%) into the hind paw were evaluated in groups of adult, young and aged male Sprague Dawley rats, after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of L-arginine or NG-nitro-L-arginine methyl ester (L-NAME). Nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining was done in the two groups. The results show that pain response was reduced in the aged rats and enhanced pain response to paw pressure in aged rats only. L-arginine (i.c.v.) had no effect on pain response to paw pressure in the two groups but enhanced biphasic pain response to formalin. L-NAME (i.p. and i.c.v.) suppressed pain response to paw pressure in the two groups. L-NAME (i.c.v.) suppressed pain response to formalin during the acute phase and enhanced it during the late phase. NADPH-diaphorase activity was significantly greater in young rats. In conclusion, pain response is blunted in the aged rats. NO might be involved in mechanical nociception in aged rats and in formalin-induced nociception in both groups. NO blockade has an antinociceptive effect on pain response. Central NO has dual role in pain response evoked by formalin.

Pentoxifylline and local honey for radiation-induced burn following breast conservative surgery.

INTRODUCTION: Breast-conserving therapy is currently the standard of management of breast cancer cases. Radiotherapy is an integral part of it; however, it has several complications. Radiation induced burn is a common complication of radiotherapy that requires more effective lines of management rather than the classically used ones. We investigated whether the addition of pentoxifylline (PTX) alone or in combination with topical honey is effective in its management compared to the standard measures. METHODS AND MATERIALS: In this prospective study, patients were randomly allocated into three groups each of 50 cases. Group A received standard burn treatment (control group). Group B received additionally 400 mg PTX twice daily. Group C received the same treatment as Group B with adding topical purified honey ointment. Patients were assessed initially and subsequently after 4 and 12 weeks, for projected coetaneous surface area (PCSA) of burn, pain severity, limitation of movement and exudation. RESULTS: There was a striking regression of the mean PCSAs of lesions among groups B and C at 12 weeks, with reduction rates (86±61%) and (76±58%) respectively (p<0.0001***). The addition of honey was associated with marked pain relieving effect and rescue of proper motion. Finally, honey was associated with shorter duration of treatment as 74% of group C patients completely recovered after 12 weeks, compared to only 54% and 36% of groups B and A in order. CONCLUSION: Combination of PTX and honey is an ideal measure for treatment of radiation-induced burn following breast conservative surgery.

Cyclooxygenase-2 inhibitor celecoxib in a rat model of hindlimb ischemia reperfusion.

Acute ischemia-reperfusion (IR) of the limbs initiates both local and systemic injuries by triggering a systemic inflammatory response. Cyclooxygenase-2 (COX-2), an endogenous inducible enzyme, rises in response to inflammation. The aim of this work is to investigate the role of celecoxib, a selective COX-2 inhibitor, in abrogating remote organ dysfunction after hindlimb IR in rats by comparing it with a standard hemorrheologic drug (pentoxifylline). Rats were divided into 4 groups (n = 6 each), group I (sham control, received saline and was kept under anaesthetic for 7 h). Group II (IR, subjected to 1 h of hindlimb tourniquet ischemia and 6 h reperfusion). Group III and IV (pretreated with 200 mg/kg pentoxifylline or 10 mg/kg celecoxib, respectively, intragastrically for 7 days before IR induction). Administration of pentoxifylline or celecoxib produced significant reduction in SGPT, serum creatinine, malondialdehyde, and tumor necrosis factor-alpha and significant increase in blood pH, blood adenosine triphosphate, and reduced glutathione compared with the IR group (p < 0.05). There was no significant difference among the pretreated groups. Histopathologic findings of the IR lung showed alveolar destruction, inflammatory cells infiltration, mast cell degranulation, and necrosis of the gastrocnemius muscle fibres. These changes were attenuated in the pretreated groups. In conclusion, celecoxib can ameliorate IR induced remote organ injury to a similar extent as pentoxifylline through its antiinflammatory and antioxidant action.