Cardioprotective effects of losartan and diminazene against the ischemia/reperfusion injury in hyperthyroidism rats.

Hyperthyroidism is a condition where the thyroid gland produces high levels of thyroid hormone. Heart diseases are one of the main complications of hyperthyroidism. Several studies have shown that losartan (LOS) and diminazene aceturate (DIZE) possess cardioprotection effects against cardiac hypertrophy, ischemic heart disease, and heart failure. The research aimed to investigate the cardioprotection of LOS, DIZE, and their combination in the case of levothyroxine (LT4)-induced cardiomyopathy in rats. Hyperthyroidism was induced by LT4 in drinking water (12 mg/L) for 28 days. LOS (10 mg/kg, orally) and/or DIZE (15 mg/kg, subcutaneously) were administrated in rats with hyperthyroidism for 28 days. Decreased serum creatine kinase myoglobin and lactate dehydrogenase levels and cardiac hypertrophy by DIZE and combination therapy in hyperthyroidism rats have been reported. Cardiac hemodynamic findings showed that DIZE and its combination with LOS decreased the LT4-mediated left ventricular developed pressure (LVDP), rate pressure product (RPP), and RPP recovery percentage. Elevated cardiac oxidative stress and inflammation were confirmed by decreasing cardiac superoxide dismutase (SOD) activity and increasing the total oxidative stress and tumor necrosis factor-alpha (TNF-α) levels. SOD activity and TNF-α level were reversed by LOS and DIZE administration, respectively. Generally, DIZE and combination therapy with LOS improved cardiac dysfunction caused by hyperthyroidism in rats, whereas LOS alone has not been able to effectively respond to this dysfunction.

Reduction of cisplatin-induced renal and hepatic side effects in rat through antioxidative and anti-inflammatory properties of Malva sylvestris L. extract.

BACKGROUND: Cisplatin is widely used in the chemotherapy of solid organ cancers. However, its application is associated with serious side effects in various organs including the kidneys and liver. OBJECTIVES: The aim of this study was to investigate the effects of mallow extract on the side effects of cisplatin in the kidneys and liver. METHODS: Hydroalcoholic extract of mallow, at doses of 200, 400, and 600 mg/kg BW, was administered to the animals for seven days intraperitoneally (ip). Animals in the Cis + Mallow group received a dose of cisplatin (8 mg/kg, ip) on the third day. Renal and hepatic functional disturbances were evaluated by measuring concentrations of creatinine, urea-nitrogen, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the plasma. In order to assess oxidative stress, malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured in the kidney tissue. Then, degree of mRNA expressions of TNF-α and ICAM-1 were measured to examine renal inflammation. Hematoxylin and Eosin (H & E) staining of kidney and liver tissues was performed to study tissue damage and leukocyte infiltration. RESULTS: Cisplatin increased levels of plasma creatinine, urea-nitrogen, AST, and ALT; levels of tissue damage and leukocytes infiltration in the kidneys and liver; and MDA level and expression of pro-inflammatory factors in the kidney tissue. Meanwhile, it decreased FRAP level in the kidney tissue. Pretreatment by mallow extract resulted in significant improvement in all measured variables although 200-mg and 400-mg doses yielded better results. CONCLUSION: Results showed that mallow supplement protects the kidneys and liver against side effects of cisplatin, and reduces the resultant oxidative stress and inflammation.

Ethyl acetate fraction of Allium hirtifolium improves functional parameters of isolated hearts of diabetic rats.

OBJECTIVE: Allium hirtifolium (Persian shallot) has a hypoglycemic effect on diabetic animals. The aim of this study was to assess the effect of the ethyl acetate fraction of Allium hirtifolium on the function of isolated hearts of diabetic rats. METHODS: The control and diabetic animals were randomly divided into four groups: saline- or extract-treated controls (n=10 and n=6, respectively) and saline- or extract-treated diabetic rats (n=8 and n=9, respectively), which received normal saline or extract for four weeks by daily gavage. The hearts were perfused according to the Langendorff method. Cardiac function parameters, including left ventricular developed pressure (LVDP), heart rate (HR), rate pressure product (RPP; LVDP×HR), and dp/dt were measured. RESULTS: The findings of this study showed that in the extract-treated diabetic rats, LVDP (94.5±9.1 mm Hg, mean±SEM), HR (249±15 beats/min), RPP (22732±1246) and +dp/dt (2598±230) at the baseline were significantly higher than those in the saline-treated diabetic animals, (71.5±4.0), (189±6), (13923±984), and (1701±124), respectively. Furthermore, RPP and HR were also significantly higher than the corresponding values obtained in the saline-treated diabetic rats after ischemia. CONCLUSION: Besides blood glucose lowering action, oral administration of the ethyl acetate fraction of Allium hirtifolium significantly improved the baseline and post-ischemic cardiac function parameters in streptozotocin-induced diabetic rats.

Co-encapsulation of pancreatic islets and pentoxifylline in alginate-based microcapsules with enhanced immunosuppressive effects.

Alginate-based scaffolds have received considerable attention for biomedical application because of their biocompatibility and ease of preparation. The application of alginate hydrogels for encapsulation of pancreatic islets is known as a potential treatment for type I diabetes. In this study, dextran-spermine coated microcapsules of alginate containing pancreatic islets were prepared, and then co-cultured with lymphocytes for 7 days. In addition, to prevent fibrosis and evaluating the effect of anti-inflammatory drugs, pentoxifylline was loaded in the inner layer of microcapsules. Intact and encapsulated islets in an external solution of pentoxifylline were taken as two separate controls in this study. Infrared and scanning electron microscope analyses showed polyelectrolyte complex formation between alginate and dextran-spermine. In vitro tests showed that interleukin-2 secretion from lymphocytes co-cultured with encapsulated islets containing pentoxifylline in the inner layer of microcapsules was 63.6 % lower than the corresponding value for encapsulated islets without the anti-inflammatory drug.

The Possible Mechanisms of the Impaired Insulin Secretion in Hypothyroid Rats.

Although the insulin secretion deficit in hypothyroid male rats has been documented, the underling mechanisms of the effect of hypothyroidism on insulin secretion are not clear. Isolated islets of the PTU-induced hypothyroid and control rats were exposed to glibenclamide, acetylcholine, and nifedipine in the presence of glucose concentrations of 2.8 or 8.3 and 16.7 mmol/L. Glucokinase and hexokinase specific activity, glucokinase content, and glucose transporter 2 protein expression were also determined in the isolated islets. Isolated islets from the hypothyroid rats showed a defect in insulin secretion in response to high glucose. In the presence of glibenclamide or acetylcholine, the isolated islets from the hypothyroid and control rats stimulated by glucose concentration of 16.7 mmol/L secreted similar amounts of insulin. In the presence of glucose concentrations of 8.3 mmol/L and 16.7 mmol/L, nifedipine was able to diminish insulin secretion from isolated islets of both groups, indicating that probably the defect may not arise from L type calcium channels or the steps beyond depolarization or the elements involved in the acetylcoline signaling pathway. Glucokinase content and hexokinase specific activity were also the same in the control and hypothyroid groups. On the other hand, glucokinase specific activity and glucose transporter 2 protein expression were significantly (p<0.001 and p<0.01 respectively) lower in the islets isolated from the hypothyroid rats (6.50 ± 0.46 mU/min/mg protein and 0.55 ± 0.09 arbitrary unit) compared to the controls (10.93 ± 0.83 mU/min/mg protein and 0.98 ± 0.07 arbitrary unit) respectively. In conclusion, the results of this study indicated that hypothyroidism reduced insulin secretion from isolated pancreatic islets, which confirms the finding of the previous studies; in addition, the insulin secretion deficit observed in hypothyroid rats may arise from the abnormalities in some parts of the glucose sensor apparatus of the pancreatic islets including glucokinase activity and glucose transporter 2 protein expression.

The possible mechanisms by which maternal hypothyroidism impairs insulin secretion in adult male offspring in rats.

Previous studies have recently shown that maternal hypothyroidism leads to impaired glucose metabolism and reduced insulin secretion in adult offspring in rats. The aim of this study was to locate the defect in the insulin secretion pathway induced by maternal hypothyroidism. Pregnant Wistar rats were divided into two groups; the control group consumed water, while the hypothyroid (FH) group received water containing 0.025% 6-propyl-2-thiouracil during gestation. An intravenous glucose tolerance test was carried out on 5-month-old male offspring. In in vitro studies, the effects of various secretagogues and inhibitors acting at different levels of the insulin secretion cascade were investigated, and insulin content, insulin secretion and glucokinase activity of the islets were compared. Although insulin content of the FH islets did not differ from that of control islets, insulin secretion from FH islets was reduced when it was challenged by glucose or arginine. Compared with control islets, activities of both hexokinase and glucokinase were also significantly decreased in the FH islets. Although, in both groups, increasing glibenclamide and nifedipine concentrations in the presence of 16.7 mmol l(-1) glucose increased and decreased insulin secretion, respectively, the percentage of changes in secretion of FH islets was significantly lower compared with control islets. The response of FH islets to high extracellular potassium concentration and diazoxide was also significantly lower than that of the control islets. These findings demonstrate that impaired insulin secretion in the FH group is probably related to alterations in different steps of the insulin secretion pathway and not in the insulin pool of ß-cells.

The effects of acetazolamide on ischemia reperfused isolated hearts of 2- and 8-week-old rabbits.

OBJECTIVE: To investigate the effects of acetazolamide on the ischemia-reperfused isolated hearts of 2- and 8-week-old rabbits. METHODS: This study was conducted at the Kermanshah Medical Biology Research Center, Kermanshah, Iran from March to September 2011. Two- (n=17) and 8-week old (n=17) rabbits were separately divided into 2 control (n=9), and test (n=8) groups. Isolated hearts were subjected to 35 minutes ischemia and 30 minutes reperfusion. Acetazolamide (100 microgr/l) was added to the perfusion solution for 10 minutes before ischemia in the test group. Cardiac parameters including ventricular pressure, heart rate (HR), and rate pressure product (RPP) were measured. Data sets were analyzed by t-test. RESULTS: Following acetazolamide administration the change percentage of HR was significantly different in the 2-week (91 +/- 1.1%) compared with the 8-week (96 +/- 0.8%) test groups (p=0.0016). Recovery percentage of RPP in reperfusion was lower (p=0.005) in the 8- (28.9 +/- 3.4%) than the 2-week test groups (45.2 +/- 3.5%). CONCLUSION: The 2-week hearts elicited more rapid response to carbonic anhydrase (CA) inhibition than the 8-week group. However, acetazolamide does not exacerbate ischemia-reperfusion (I/R) injury in the 2-week hearts. Therefore, it was revealed that after inhibition of CA, the age dependent pattern of I/R injury was similar to that of the normal hearts. Inspite of the CA important role in the normal heart function, it is not a determining factor in I/R injury in different ages.

The effect of Zizyphus spina-christi leaf extract on the isolated rat aorta.

OBJECTIVE: To investigate the effect of Zizyphus spina christi leaf hydroalcoholic extract (ZLHE) on the isolated rat aorta. METHODS: The rings of the endothelium intact and denuded thoracic aorta of Male and female Sprague Dawley rats were placed in Krebs-Henseleit solution to measure isometric contractile force. To study the involvement of voltage dependent L type calcium channels, concentration of 10 ?M verapamil was applied. Potassium chloride (50 mM) was also added to the organ bath to compare the effect of extract and KCl. Potassium concentration of the extract at 2.5 and 5 mg/ml was measured. RESULTS: ZLHE induced contraction in the endothelium intact and denuded aorta dose dependently and significantly (P < 0.0001). Also, the response to extract at 5 mg/ml was similar to that of KCl (50 mM). The application of verapamil reduced the contraction in the endothelium intact and denuded aorta by 66.7 +/- 3.1% (mean +/- SEM.) and 71.6 +/- 3.8% respectively. CONCLUSION: The results showed the vasoconstrictive effect of ZLHE which was not endothelium-dependent and largely blocked by verapamil, suggesting that the voltage-dependent Calcium channels play a pivotal role in the mechanism of action.

The effect of repeated diazepam administration on myocardial function in the ischemia-reperfused isolated rat heart.

OBJECTIVE: To evaluate whether repeated diazepam administration affects the heart in ischemia-reperfusion. METHODS: This study was performed at the Medical Biology Research Center, Kermanshah, Iran, from March to September 2008. Four groups of rats were subjected to a daily injection of diazepam (group 1 [0.5 mg/kg for 21 days], group II [2.5 mg/kg for 5 days], and group III [5 mg/kg for 5 days] intraperitoneally), and saline solution (21 days) in the control groups. Isolated, perfused hearts were subjected to 40 minutes global ischemia, and 45 minutes reperfusion. The left ventricular developed pressure (LVDP), heart rate, and coronary flow were measured. Rate pressure product (RPP) was calculated. In reperfusion, released lactate dehydrogenase (LDH) enzyme in effluent was measured. RESULTS: It was observed that the recovery of the RPP and LVDP in reperfusion significantly decreased in the test group III (n=9) in comparison to the control (n=8). During the reperfusion period, the released LDH significantly increased in test group II (n=8) and group III in comparison with the control. CONCLUSION: The results show that repeated administration of diazepam (5 mg/kg for 5 days) reduced the cardiac performance in reperfusion, and significantly exacerbated the ischemia-reperfusion injury. It is probably mediated by the changing of cardiac susceptibility in ischemia due to repeated administration of diazepam.

The effects of diazepam in cardio depressant concentration on the function of isolated rat heart in ischemia-reperfusion.

OBJECTIVE: To investigate the effects of cardio depressant concentration of diazepam on the function of isolated rat heart in ischemia-reperfusion. METHODS: This study was performed at the Medical Biology Research Center, Kermanshah, Iran from November 2006 to March 2007. Isolated, perfused rat hearts were subjected to 40 minutes normothermic global ischemia and 45 minutes reperfusion. Diazepam (100 microM) was added to the perfusion solution for 10 minutes before ischemia in the test group. Different cardiac variables including left ventricular developed pressure, heart rate, and coronary flow (CF) were measured. Rate pressure product (RPP) was calculated, during the ischemic period time until onset of ischemic contracture and maximum contracture were determined. In reperfusion, released lactate dehydrogenase enzyme in effluent was measured and cardiac functional recovery was determined. RESULTS: It was found that diazepam significantly decreased RPP and increased CF before ischemia. In the diazepam group (n=10), during ischemia, maximum contracture was significantly lower than the control group (n=14). Also, diazepam significantly increased functional recovery and coronary flow in reperfusion. CONCLUSION: Diazepam (100 microM) significantly decreased maximum contracture during ischemia, improved the recovery of myocardial function and CF in reperfusion. The results show that the cardio depressant concentration of diazepam is safe and relatively protective in the ischemia-reperfused isolated rat heart. These effects may be mediated by inhibition of calcium current in cardiomyocytes.