Modulatory effect of baicalein on gene expression and activity of antioxidant enzymes in streptozotocin-nicotinamide induced diabetic rats

Oxidative stress plays the central role in the pathogenesis and progression of diabetic complications. The present study aims to investigate the beneficial effect of oral administration of flavone baicalein in streptozotocin-nicotinamide (STZ-NA) induced diabetic rats by measuring oxidative stress markers, antioxidant enzyme activities and expression analysis of antioxidant genes. Experimental diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (55 mg /kg b.wt), 15 min after the i.p. administration of NA. At the end of the experimental period, thiobarbituric acid reactive substances (TBARS), activities of antioxidant enzymes and expression levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) were measured in diabetic rats along with serum biochemical parameters namely total cholesterol (TC), total triglyceride (TG), aspartate transaminase (AST) alanine transaminase (ALT) and glycosylated hemoglobin (HbA1c). Oral administration of baicalein (40 mg/kg b.wt/day) demonstrated a significant ameliorative effect on all studied biochemical and oxidative stress parameters. Biochemical findings were corroborated by qPCR expression analysis which showed significant upregulation of antioxidant genes in diabetic rats. These results suggest that baicalein supplementation may reduce diabetes and its complications by suppressing oxidative stress and enhancing gene expression and antioxidant enzyme activities in diabetic rats.

Serum concentrations and renal expressions of IL-1 and TNF-a early after hemorrhage in rats under the effect of glibenclamide

ABSTRACT PURPOSE: To investigate changes in the serum concentration and renal expression of IL-1 and TNF-α cytokines in rats that received sevoflurane and glibenclamide prior to hemorrhage. METHODS: Two groups of sevoflurane-anesthetized Wistar rats (n=10): G1 (control) and G2 (glibenclamide, 1 µg/g i.v.); hemorrhage of 30% blood volume (10% every 10 min), with replacement using Ringer solution, 5 ml/kg/h. Serum concentrations of IL-1 and TNF-α were studied in the first hemorrhage (T1) and 50 min later (T2), renal expression, at T2. RESULTS: In serum, G1 TNF-α (pg/mL) was T1=178.6±33.5, T2=509.2±118.8 (p<0.05); IL-1 (pg/mL) was T1=148.8±31.3, T2=322.6±115.4 (p<0.05); in G2, TNF-α was T1=486.2±83.6, T2=261.8±79.5 (p<0.05); IL-1 was T1=347.0±72.0, T2= 327.3±90.9 (p>0.05). The expression of TNF-α and IL-1 in the glomerular and tubular cells was significantly higher in the G2 group. CONCLUSIONS: Hemorrhage and glibenclamide elevated TNF-α and IL-1 concentrations in serum and kidneys. High levels of TNF-α already present before the hemorrhage in the glibenclamide group may have attenuated the damages found in the kidneys after the ischemia event.

Pharmacological study of the mechanisms involved in the vasodilator effect produced by the acute application of triiodothyronine to rat aortic rings

A relationship between thyroid hormones and the cardiovascular system has been well established in the literature. The present in vitro study aimed to investigate the mechanisms involved in the vasodilator effect produced by the acute application of 10-8–10-4 M triiodothyronine (T3) to isolated rat aortic rings. Thoracic aortic rings from 80 adult male Wistar rats were isolated and mounted in tissue chambers filled with Krebs-Henseleit bicarbonate buffer in order to analyze the influence of endothelial tissue, inhibitors and blockers on the vascular effect produced by T3. T3 induced a vasorelaxant response in phenylephrine-precontracted rat aortic rings at higher concentrations (10-4.5–10-4.0 M). This outcome was unaffected by 3.1×10-7 M glibenclamide, 10-3 M 4-aminopyridine (4-AP), 10-5 M indomethacin, or 10-5 M cycloheximide. Contrarily, vasorelaxant responses to T3 were significantly (P<0.05) attenuated by endothelium removal or the application of 10-6 M atropine, 10-5 M L-NG-nitroarginine methyl ester (L-NAME), 10-7 M 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 10-6 M (9S,10R,12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i](1,6)benzodiazocine-10-carboxylic acid, methyl ester KT 5823, 10-2 M tetraethylammonium (TEA), or 10-7 M apamin plus 10-7 M charybdotoxin. The results suggest the involvement of endothelial mechanisms in the vasodilator effect produced by the acute in vitro application of T3 to rat aortic rings. Possible mechanisms include the stimulation of muscarinic receptors, activation of the NO-cGMP-PKG pathway, and opening of Ca2+-activated K+ channels.

Pharmacological evaluation of hyperin for antihyperglycemic activity and effect on lipid profile in diabetic rats.

Antihyperglycemic potential of hyperin at 25 and 50 mg/kg doses for 30 days to streptozotocin induced diabetic rats has been reported. In oral glucose tolerance test, hyperin treated rats showed a significant reduction in blood glucose level after 120 min. It was found that hyperin exhibited dose dependent and significant antihyperglycemic activity in streptozotocin induced diabetic rats which were nearly similar with standard drug glybenclamide. Activities of glucose-6-phosphatase, fructose-1,6-bisphosphatase, glycogen phosphorylase, glycosylated haemoglobin and level of serum urea and creatinine were significantly decreased in hyperin supplemented diabetic rats, dose dependently. Activities of hexokinase and glycogen synthase were increased with augmentation in liver glycogen, insulin and haemoglobin content in hyperin treated diabetic rats. General hematological parameters did not show any significant change in hyperin treated diabetic rats hence it is safe at these doses. Histopathological studies showed significant morphological changes in pancreatic β-cells of streptozotocin induced diabetic rats. A decreased number of secretory granules of β- cells were observed in diabetic rats and these pathological abnormalities were normalized after treatment with hyperin and standard drug glybenclamide. Further, hyperin decreases significant in serum total cholesterol, triglyceride, low density lipoprotein, very low density lipoprotein levels coupled with elevation of high density lipoprotein in diabetic rats. These results suggest that hyperin has a pivotal role in blood glucose level in streptozotocin induced hyperglycemia by improving the function of pancreatic islets and increasing glycolysis and decreasing gluconeogenesis.

Low glibenclamide concentrations affect endoplasmic reticulum stress in INS-1 cells under glucotoxic or glucolipotoxic conditions

BACKGROUND/AIMS: beta-Cell apoptosis caused by increased endoplasmic reticulum (ER) stress is an important pathogenic component of type 2 diabetes mellitus. In theory, sulfonylureas, used for the treatment of diabetes, can contribute to ER stress. We assessed changes in ER stress in pancreatic beta-cells under glucotoxic or glucolipotoxic conditions using low concentrations of the sulfonylurea, glibenclamide (GB). METHODS: Low concentrations of GB (10 or 100 nM) were added to INS-1 cells cultured under glucotoxic or glucolipotoxic conditions. The degree of viability, level of apoptosis and levels of markers associated with ER stress were measured. RESULTS: Apoptosis decreased in response to low concentrations of GB under glucolipotoxic but not glucotoxic conditions. Most ER stress markers decreased upon the addition of GB. Under glucotoxic conditions, changes in the levels of ER stress markers were not consistent. However, all decreased significantly under glucolipotoxic conditions. CONCLUSIONS: Low concentrations of GB exerted antiapoptotic effects through the attenuation of ER stress under glucolipotoxic conditions.

Evaluation of antinociceptive and antihyperglycemic activities in methanol extracts of whole plants of Alternanthera philoxeroides [Mart.] Griseb. [Amaranthaceae] in mice

The present study evaluated the antinociceptive and antihyperglycemic effects of crude methanol extract of whole plants of Alternanthera philoxeroides [Mart.] Griseb. [Amaranthaceae] in Swiss albino mice. Antinociceptive activity was evaluated by attenuation of the number of constrictions in acetic acid-induced gastric pain, while antihyperglycemic activity was evaluated through oral glucose tolerance tests in glucose-loaded mice. Dose-dependent and significant inhibitions in the number of constrictions were seen in mice administered with extract at doses of 50, 100, 200 and 400 mg per kg body weight. At these concentrations, the numbers of constrictions were reduced, respectively, by 31.0, 32.7, 37.9 and 44.8%. In comparison, a standard antinociceptive drug, aspirin reduced the number of constrictions by 37.9 and 67.2%, when administered at doses, respectively, of 200 and 400 mg per kg body weight. The extract also exhibited dose-dependent and significant antihyperglycemic activity when administered to mice at the aforementioned four doses. Serum glucose concentrations were reduced, respectively, by 36.3, 58.6, 65.0 and 65.6% at the four doses administered. The results compare favorably with a standard antihyperglycemic drug, glibenclamide, which when administered at a dose of 10 mg per kg body weight reduced serum glucose level by 42.7%. Taken together, the results obtained indicate that the extract merit further scientific studies towards discovery of components, which may prove beneficial in ameliorating pain, as well as high sugar levels of diabetic patients

Effect of glibenclamide on antinociceptive effects of antidepressants of different classes

OBJECTIVES: The purpose of this work was to determine whether the intraperitoneal administration of glibenclamide as a K ATP channel blocker could have an effect on the antinociceptive effects of antidepressants with different mechanisms of action. METHODS: Three antidepressant drugs, amitriptyline as a dual-action, nonselective inhibitor of noradrenaline and a serotonin reuptake inhibitor, fluvoxamine as a selective serotonin reuptake inhibitor and maprotiline as a selective noradrenaline reuptake inhibitor, were selected, and the effect of glibenclamide on their antinociceptive activities was assessed in male Swiss mice (25-30 g) using a formalin test. DISCUSSION: None of the drugs affected acute nociceptive responses during the first phase. Amitriptyline (5, 10 mg/ kg), maprotiline (10, 20 mg/kg) and fluvoxamine (20 and 30 mg/kg) effectively inhibited pain induction caused by the second phase of the formalin test. Glibenclamide (5 mg/kg) alone did not alter licking behaviors based on a comparison with the control group. However, the pretreatment of animals with glibenclamide (10 and 15 mg/kg) partially reversed the antinociceptive effects of fluvoxamine but not those of maprotiline. In addition, the highest dose of glibenclamide (15 mg/kg) partially prevented the analgesic effect of amitriptyline. CONCLUSION: Therefore, it seems that adenosine triphosphate-dependent potassium channels have a major role in the analgesic activity of amitriptyline and fluvoxamine.

Polyphenol (-)-Epigallocatechin Gallate during Ischemia Limits Infarct Size Via Mitochondrial K(ATP) Channel Activation in Isolated Rat Hearts

Polyphenol (-)-epigallocatechin gallate (EGCG), the most abundant catechin of green tea, appears to attenuate myocardial ischemia/reperfusion injury. We investigated the involvement of ATP-sensitive potassium (K(ATP)) channels in EGCG-induced cardioprotection. Isolated rat hearts were subjected to 30 min of regional ischemia and 2 hr of reperfusion. EGCG was perfused for 40 min, from 10 min before to the end of index ischemia. A nonselective K(ATP) channel blocker glibenclamide (GLI) and a selective mitochondrial K(ATP) (mK(ATP)) channel blocker 5-hydroxydecanoate (HD) were perfused in EGCG-treated hearts. There were no differences in coronary flow and cardiodynamics including heart rate, left ventricular developed pressure, rate-pressure product, +dP/dt(max), and -dP/dt(min) throughout the experiments among groups. EGCG-treatment significantly reduced myocardial infarction (14.5+/-2.5% in EGCG 1 micrometer and 4.0+/-1.7% in EGCG 10 micrometer, P<0.001 vs. control 27.2+/-1.4%). This anti-infarct effect was totally abrogated by 10 micrometer GLI (24.6+/-1.5%, P<0.001 vs. EGCG). Similarly, 100 micrometer HD also aborted the anti-infarct effect of EGCG (24.1+/-1.2%, P<0.001 vs. EGCG ). These data support a role for the K(ATP) channels in EGCG-induced cardioprotection. The mK(ATP) channels play a crucial role in the cardioprotection by EGCG.

Análisis de prácticas de prescripción y criterio médico sobre calidad y efectividad de la glibenclamida cubana / Analysis of practices of prescription and medical criterion on quality and effectiveness of Cuban glibenclamide

Una alerta epidemiológica sobre la prescripción de glibenclamida en dosis por encima del rango terapéutico recomendado por la bibliografía, motivó evaluar el conocimiento de los médicos sobre la prescripción del fármaco e identificar sus criterios acerca de la calidad y la efectividad de la tableta de producción nacional. Para lo cual se realizó un estudio de utilización de medicamentos clasificado como de consecuencias prácticas con elementos de factores que condicionan los hábitos de prescripción. Mediante una encuesta aplicada a médicos de atención primaria y hospitales en 32 municipios seleccionados, pudo evaluarse calidad de la prescripción y se obtuvo información sobre efectividad y posibles modificaciones en las características organolépticas y farmacológicas de la tableta de glibenclamida nacional. Se observó que el 82,8 por ciento de los encuestados tenía conocimientos adecuados de los casos en los que se prescribe glibenclamida. El 55,0 por ciento mostró inadecuados hábitos de prescripción de las dosis terapéuticas a utilizar y el 60 por ciento respondió combinar la terapéutica oral con la dieta. El 57,7 por ciento no refirió cambios de las características organolépticas y farmacológicas de la tableta y solo un 11,8 por ciento consideró que esta tiene un efecto inicial más demorado. El 56,3 por ciento considera que la efectividad es buena y solamente el 12,1 por ciento respondió que es baja. Se confirma la utilización de dosis de glibenclamida por encima del rango terapéutico recomendado, a pesar que la mayoría de los médicos posee conocimientos adecuados sobre la prescripción y considera que la efectividad del producto es buena. No puede confirmarse calidad deficiente del producto.

An epidemiological alert to the prescription of glibenclamide at doses over the therapeutic range recommended by the bibliography led us to evaluate the knowledge of the doctors on the prescription of the drug and to identify their criteria about the quality and effectiveness of the tablet of national production. To this end, a study on the utilization of drugs classified as of practical consequences was conducted with elements of factors conditioning the prescription habits. By a survey done to primary health care doctors in 32 municipalities selected, the quality of the prescription was evaluated and information on the effectivity and possible modifications in the organoleptic and pharmacological characteristics of the tablet of national glibenclamide was collected. It was observed that 82.8 percent of the surveyed had an adequate knowledge of the cases that were prescribed glibenclamide. 55.0 percent showed inadequate habits of prescription of the therapeutic doses to be used, and 60 percent preferred to combine oral therapeutics with diet. 57.7 percent did not refer changes of the organoleptic and pharmacological characteristics of the tablet and just 11.8 percent considered that its initial effect delayed more. 56.3 percent thought effectivity is good and only 12.1 percent said it was low. It was confirmed the use of doses of glibenclamide above the recommended therapeutic range, in spite of the fact that doctors had an appropriate knowledge on the prescription and considered that the effectiveness of the product was good. No deficiencies were found in the quality of the product.

Role of ion channel modifiers in reversal of morphine-induced gastrointestinal inertia by prokinetic agents in mice.

Prokinetic drugs like mosapride, domperidone etc, are used to treat gastrointestinal delay. Though the receptor-mediated actions of these agents have been studied, involvement of ion channels in reversing morphine-induced gastrointestinal inertia by prokinetic agents has not been explored. Charcoal meal test was used to measure small intestinal transit (SIT) in adult male Swiss albino mice. Animals were given ion channel modifiers and prokinetic drugs intragastrically. Reversal of morphine-induced gastrointestinal delay by mosapride was decreased significantly by CaCl2, minoxidil and glibenclamide. Similarly, domperidone's effect on morphine was decreased by CaCl2, nifedipine, minoxidil and glibenclamide significantly. The results reveal that ion channel modifiers counteract the prokinetic effects of mosapride or domperidone.

ATP-sensitive potassium channel blockers, glimepiride and glibenclamide reduces ischemia reperfusion-induced renal injury in rats by inhibition of neutrophil aggregation: comparative study of glimepiride versus glibenclamide and diazoxide

Renal ischemia is a complex neutrophils-mediated syndrome in which ATP-sensitive potassium channels are involved. Fall in intracellular ATP concentration induces opening of these channels resulting in massive influx of neutrophils .This exerts a crucial role in the patho-physiology of post-ischemic renal failure. Our study has used the ischemia reperfusion [I/R] model to asses the role of ATP-dependant potassium channel modulation, comparing the protective effects of glimepiride and glibenclamide on renal I/R inflammatory injury and neutrophil aggregation. As this protective effect in renal I/R stands in sharp contrast to the harmful effects on the cardiac tissues, our study evaluates the harmful effects of both sulfonylurea drugs on normal hearts and on ischemic reperfused hearts subjected to ischemic preconditioning protection afforded by diazoxide. One hundred and fourteen [114] adult albino rats were used; 72 of them were used for the in renal I/R study and 42 rats for the cardiac I/R experiment. In renal I/R study, rats were unilaterally nephrectomized, then all rats except the Sham operated control group, were subjected to renal I/R by ischemia 45 min and reperfusion 4 and 24 h, then divided into five groups: [1] renal ischemia-reperfusion, [2] renal I/R + solvent control, [3] renal I/R + diazoxide, [4] renal I/R + glibenclamide, [5] renal I/R + glimepiride. At the end of each reperfusion period, mean arterial pressure, urine volume, serum creatinine and urea, were measured. Then kidneys and lungs were taken for histological examination and determination of TNF-alpha levels, superoxide anion production and myloperoxidase activity. Cardiac I/R study, cardiac ischemia reperfusion model by left coronary artery ligation was used for evaluating the side effects of both sulfonylureas on both normal and ischemic preconditioning rat's hearts. Renal ischemia reperfusion induced marked renal dysfunction associated with significant increase in arterial pressure, TNF-alpha levels, superoxide anion production, and myloperoxidase activity. Treatment with glibenclamide or glemipiride, illustrated significant improvement in the reperfusion-induced injury in both kidney and lung, but glemipiride has no effect on superoxide anion production. However glibenclamide induced a significant improvement in these measurements as compared to glimepiride group. Before coronary artery ligation, neither diazoxide nor glimepiride pretreatment influenced significantly the electrocardiographic parameters [heart rates, T-waves voltages and ST segment elevation] in comparison with control group. On the other hand, glibenclamide supplementation induced a significant elevation in all these parameters. After left coronary artery ligation, reperfusion of the ischemic hearts caused a significant elevation in the measured electrocardiographic parameters. These elevations were significantly ameliorated by pretreatment with diazoxide. Administration of glibenclamide significantly abolished the protective effects of diazoxide, while pretreatment with glimepiride didn't abolish it. In conclusion, glimepiride offered some promise for therapy of renal I/R with minimizing the undesirable cardiac side effects

Hypoglycemic and hypolipidemic effects of alcoholic extract of Tribulus alatus in streptozotocin-induced diabetic rats: a comparative study with T. terrestris (Caltrop).

The extracts of both T. alatus and T. terrestris significantly decrease fasting glucose level in diabetic rats. After 4 and 6 hr, T. alatus extract showed significant reduction in glucose level as compared to T. terrestris. After 3 weeks of treatment with T. alatus extract, glucose level was significantly decreased to the normal level. Both the extracts also caused a significant decrease in the levels of glycosylated hemoglobin, total cholesterol, triglycerides and LDL-cholesterol. The percent of reduction in rats treated with T. alatus extract was significantly higher than that of the rats treated with T. terrestris. The results indicate that alcoholic extract of T. alatus possesses hypoglycemic activity in type-1 model of diabetes.

Effect of KATP channel openers on myogenic and neurogenic responses in goat urinary bladder.

Isolated goat detrusor muscle exhibited spontaneous contractility with an irregular amplitude and frequency. The spontaneity of detrusor muscle exhibited a mean amplitude as 11.99 +/- 0.83 mm and frequency as 1.37 +/- 0.16/min. KATP-channel openers namely, cromakalim or pinacidil (10(-7) - 10(-4) M) added cumulatively, elicited a concentration-related inhibition of both amplitude and rate of spontaneous contractions. The mean IC50 values for both amplitude and frequency for cromakalim were 3.3 x 10(-6) M and 2.9 x 10(-6) M, respectively; and for pinacidil were 2.0 x 10(-5) M and 1.5 x 10(-5) M, respectively. Glibenclamide, a KATP-channel blocker inhibited the cromakalim-induced concentration-related relaxation of spontaneous contractions with a significant increase in its mean IC50. ACh-induced concentration-related contractile response was inhibited in the presence of either cromakalim (10(-4) M) or pinacidil (10(-4) M). The mean EC50 value of ACh, in the presence of cromakalim (2.5 x 10(-3) M) was significantly increased as compared to the control (1.2 x 10(-6) M). In the presence of glibenclamide (10(-5) M) the inhibitory effect of cromakalim was significantly reduced with consequent decrease in the EC50 value (1.9 x 10(-5) M). Application of EFS (30 V and 5 ms) on goat urinary bladder strips at 1, 2, 5, 10, 20 and 30 Hz elicited frequency-related contractile responses. Both cromakalim and pinacidil caused a rightward shift in the frequency-related contractile response curve with significant increase in the mean EF25 and EF50 values, respectively. In the presence of glibenclamide (10(-4) M), the frequency-related inhibitory response curve was shifted to left with significant (P < 0.001) increase in the mean EF25, EF50 and EF75. The present results suggest that in the goat detrusor muscle, agonist and EFS-induced contractile responses were more potently inhibited by cromakalim than pinacidil with activation of glibenclamide sensitive KATP channels.

effect of a 6 month treatment course of male healthy rats by chlorpropamide and glibenclamide on vascular tone of aorta

Diabetes mellitus is the most common endocrine disorder with an ever-increasing prevalence. Cardiovascular complications are the major cause of death in diabetic patients. Type II diabetes mellitus is usually treated by sulfonylureas. There are controversial reports regarding cardiovascular side effects of these drugs. Conflicting evidences exist about side effects of the first and second-generation sulfonylureas. In this study, the vascular effects of chlorpropamide and glibenclamide [first and second generations of sulfonylureas respectively] were investigated in healthy male rats. Male rats were treated by the above-mentioned drugs for six months and the response of aortic rings to acetylcholine, isosorbide dinitrate and phenylephrine were studied and compared to normal control group. Data were analyzed by means of ANOVA test. There was no significant difference between the response of aortic rings of treated and control group to acetylcholine, isosorbide dinitrate and phenylepherine. Sulfonylureas through closing ATP dependent potassium channels, which exist in beta-cells of pancreas and other organs such as heart and vascular smooth muscles may affect the vascular tone. Based on the results of this study long term oral consumption of chlorpropamide and glibenclamide in normal rats did not affect aortic contractile property. Further studies are needed to clarify the vascular effects of sulfonylureas

Effects of calcium channel blocker, mibefradil, and potassium channel opener, pinacidil, on the contractile response of mid-pregnant goat myometrium.

The present study was undertaken to investigate the in vitro influence of mibefradil, a calcium channel blocker, and pinacidil, a potassium channel opener, on pregnant goat myometrial spontaneous rhythmic contractility and contractions induced with the agonist, oxytocin. Longitudinal strips from the distal region of uterus, collected from goats at midgestation, were mounted in an organ bath for recording isometric contractions. Mibefradil (10(-8)-10(-4) M) or pinacidil (10(-10)-10(-4) M), added cumulatively to the bath at an increment of 1 log unit, caused concentration-dependent inhibition of the spontaneous rhythmic contractions of isolated uterine strips. The rhythmic contraction was, respectively, abolished at 100 and 10 microM concentrations of mibefradil and pinacidil. In a concentration-dependent manner, mibefradil (1 and 10 microM) antagonized the contractions elicited with oxytocin (10(-5)-10(-2) IU). Pretreatment of uterine strips with glibenclamide (10 microM), a selective KATP channel blocker, caused a rightward shift of the concentration-response curve of pinacidil with a concomitant decrease in its pD2 value. Pinacidil (0.3, 1 and 3 microM), in a concentration-related manner, antagonized the oxytocin (10(-5)-10(-2) IU)-induced contractile response. The inhibition of spontaneous rhythmic contractions and antagonism of oxytocin-induced contraction by mibefradil in the pregnant goat myometrium may be related to the antagonism of voltage-dependent Ca2+ channels, while by pinacidil suggests that KATP channel could be a therapeutic target for tocolysis.

Effect of potassium channel modulators on toxicity of Cleistanthus collinus.

The study was conducted to determine the effects of boiled extract of Cleistanthus collinus on rats by observing ECG changes and electrolyte levels in serum and urine. Influence of minoxidil and glibenclamide on Cleistanthus collinus induced toxicity was determined. ED50 for arrhythmia, changes in contractility and heart rate were recorded using the isolated frog heart. Cleistanthus at low doses caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in rat. LD50 was found to be 1690 mg/kg. Minoxidil potentiated cardiac toxicity, whereas glibenclamide did not produce any significant change. High concentration of potassium in Cleistanthus extract hindered comparison of its levels. There was excretion of sodium even in the presence of hyponatraemia. Cleistanthus at low dose caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in isolated frog heart. ED50 for arrhythmia was found to be 1406 mg/kg. Acute toxicity was mainly due to depressive cardiac activity of Cleistanthus. It also caused renal failure. Potassium channel modulators did not have important role in acute cardiac toxicity treatment. Probably in chronic toxicity, electrolyte level changes are involved and potassium channel modulators might have a role.

Assessment of the possible capacity of the synthetic and-opioid receptor agonist DADLE in an experimental model of hypothermic ischemia and reperfusion in isolated rat heart - role of ATP-sensitive potassium channels

Efforts to prevent myocardial ischemia have focused on findings ways to block events associated with irreversible ischemic injury. The discovery of the endogenous cellular protective mechanism known as ischemic preconditioning [ipc] has risen hoping that natural pathways could be activated to help cells to overcome necrosis. Pharmacologic preconditioning has been tried to simulate ipc in cardio protection against ischemia. Aim: the aim of the present study is to assess the possible protective capacities of both [ipc] and the synthetic -opioid receptor agonist dadle in an experimental model of hypothermic ischemia and reperfusion [hir] in isolated rat heart, and to assess whether the effects of both protective measures are similarly mediated via k[atp] channels. Isolated rat hearts were divided into 7 groups: g1: is control normothermic [37°C] perfused hearts. G2 hearts were subjected to 45 min of hypothermic ischemia at 30°C, followed by 25 min of normothermic reperfusion [hir]. G3: ipc for 3 min followed by 5 min normothermic reperfusion then hir as g2. G4: dadle pretreatment [1 mg/kg] 30 min before isolated heart preparation, then the protocol of g2 was done. G5: DADLE pretreatment, then the protocol of G3. G6: glibenclamide [0.3 mg/kg] 60 min pretreatment followed by DADLE after 30 min, then the protocol of g2 was done g7: glibenclamide and dalde pretreatment, followed by protocol of g3. Both ipc and DADLE pretreatment and their combination in groups 3, 4, and 5, respectively, improved the post ischemic recovery in the form of significant increase in heart rate [hr], myocardial contractility, coronary flow [cf], and significant decrease in creative kinas [ck] in coronary effluent with a significant reduction of infarct size [is] to 6.6 +/- 1.5, 3.1 +/- 1.3, and 2.8 +/- 1.2%, respectively, when compared with g1 and g2 with is 17.2 +/- 2.2%. Glibenclamide pretreatment in g6 and g7 abolished this improvement in the post ischemic recovery when compared with groups 3, 4 and 5. The results of the present study indicate that ischemic prerconditioning [ipc] improves post ischemic recovery and reduces myocardial infract size in isolated rat heart. Pretreatment with -opioid receptor agnist DADLE mimicked the cardio protection induced by ipc, indicating an opiod receptor-mediated mechanism. Pharmacologic preconditioning by dasle and ipc has additional effects in improving the post ischemic recovery. Lastly, this cardioprotection induced by both can be abolished by the k[ATP] channel antagonist glibenclamide suggesting an involvement of the k[ATP] channel most probably mitochondrial k[ATP], as an important end-effecter of this potent cardio protective effect

Antidiabetic and antioxidant effects of S-methyl cysteine sulfoxide isolated from onions (Allium cepa Linn) as compared to standard drugs in alloxan diabetic rats.

Antidiabetic and antoxidant effects of S-methyl cysteine sulfoxide (SMCS) isolated from A. cepa and two standard drugs, glibenclamide and insulin were studied and compared in alloxan diabetic rats after using each of them for treatment for two months. These drugs ameliorated the diabetic condition significantly, viz. maintenance of body weight and control of blood sugar in rats. Further they lowered the levels of malondialdehyde, hydroperoxide and conjugated dienes in tissues exhibiting antioxidant effect on lipid peroxidation in experimental diabetes. This is achieved by their stimulating effects on glucose utilization and the antioxidant enzymes, viz. superoxide dismutase and catalase. The probable mechanism of action of SMCS and glibenclamide may be partly dependent on the stimulation of insulin secretions and partly due to their individual actions. In the amelioration of diabetes the standard drugs showed a better action, but as an antioxidant SMCS proved to be a better one.

Effect of ATP-dependent K+ channel openers and blockers on serum concentration of aldosterone in rats

There are many reports for involvement of ATP-sensitive potassium channels in pancreatic, cardiac and vascular smooth muscle cells. This study examined the effect of single doses of K+ channel openers; diazoxide, minoxidil and K+ channel blockers; chlorpropamide, glibenclamide on serum concentration of aldosterone in male rats. Blood samples were obtained 60 minutes after drug treatment and serum aldosterone level was determined by RIA. The basal serum aldosterone was 659.32 +/- 71.48 pg/ml and after diazoxide or minoxidil administration increased to 1188.53 +/- 99.45 pg/ml and 1392.69 +/- 177.83 pg/ml, respectively. Chlorpropamide or glibenclamide treatment did not produce any change in basal serum aldosterone concentration, but in early streptozotocin-induced diabetic rats decreased serum aldosterone level significantly [P<0.001]. Pretreatment with glibenclamide blocked aldosterone response to diazoxide but did not affect aldosterone response to exogenous ACTH to the same extent. Effect of diazoxide in insulin-treated rats was approximately similar to that of normal rats. Comparison of blood glucose concentration determined in normal, insulin treated and diabetic rats after different drug administration showed that there is no correlation between blood glucose level and the responses observed in serum hormone concentration. The results indicate that regulatory processes involved in the secretion of aldosterone are responsive to drugs affecting glibenclamide-sensitive K+ channels