Effects of diazoxide in experimental acute necrotizing pancreatitis

OBJECTIVE: We aimed to assess the effects of diazoxide on the mortality, pancreatic injury, and inflammatory response in an experimental model of acute pancreatitis. METHODS: Male Wistar rats (200-400 g) were divided randomly into two groups. Fifteen minutes before surgery, animals received physiological (0.9%) saline (3 mL/kg) (control group) or 45 mg/kg diazoxide (treatment group) via the intravenous route. Acute pancreatitis was induced by injection of 2.5% sodium taurocholate via the biliopancreatic duct. Mortality (n=38) was observed for 72 h and analyzed by the Mantel-Cox Log-rank test. To study pancreatic lesions and systemic inflammation, rats (10 from each group) were killed 3 h after acute pancreatitis induction; ascites volume was measured and blood as well as pancreases were collected. Pancreatic injury was assessed according to Schmidt's scale. Cytokine expression in plasma was evaluated by the multiplex method. RESULTS: Mortality at 72 h was 33% in the control group and 60% in the treatment group (p=0.07). Ascites volumes and plasma levels of cytokines between groups were similar. No difference was observed in edema or infiltration of inflammatory cells in pancreatic tissues from either group. However, necrosis of acinar cells was lower in the treatment group compared to the control group (3.5 vs. 3.75, p=0.015). CONCLUSIONS: Treatment with diazoxide can reduce necrosis of acinar cells in an experimental model of acute pancreatitis, but does not affect the inflammatory response or mortality after 72 h.

Potassium channel openers exhibit cross-tolerance with morphine in two experimental models of pain / Los abridores de canales de potasio exhiben tolerancia cruzada con la morfina en dos modelos experimentales de dolor

OBJECTIVE: The study was performed to assess the effect of potassium channel openers on morphine tolerance and vice-versa. METHODS: Swiss albino mice of either gender weighing between 25-30 g were used for the study. The study assesses the effect of potassium channel openers (cromakalim, diazoxide and minoxidil) on morphine tolerance and vice-versa, using formalin and tail-flick tests. RESULTS: The antinociceptive effect of cromakalim and minoxidil was significantly reduced when administered to morphine-tolerant mice, in both the behavioural tests. However, reduced analgesic effect of diazoxide was observed on morphine-tolerance in the formalin test but not in the tail-flick test. Tolerance was observed when morphine was administered to animals chronically treated with any of the potassium channel openers. The same effect was observed when morphine was injected into a group treated with a combination of morphine and any of the potassium channel openers. CONCLUSIONS: This study, therefore, suggests that both morphine and potassium channel openers are cross-tolerant. However, such interaction occurs at the level of potassium channels rather than at the level of receptors.

OBJETIVO: El estudio fue realizado para evaluar el efecto de los abridores de canales de potasio en la tolerancia a la morfina, y viceversa. MÉTODOS: Para el estudio, se usaron ratones albinos suizos de ambos sexos que pesaban entre 25-30 g. El estudio evalúa el efecto de los abridores de canales de potasio (cromacalina, diazóxido y minoxidil) en la tolerancia a la morfina, y viceversa, usando la prueba de la sacudida de la cola y la prueba de la formalina. RESULTADOS: El efecto antinociceptivo de la cromacalina y el minoxidil fue significativamente reducido cuando se le administró a los ratones tolerantes a la morfina, en ambas pruebas conductuales. Sin embargo, se observó un efecto analgésico reducido de diazóxido sobre la tolerancia a la morfina en la prueba de la formalina, pero no en la prueba de la sacudida de la cola. Se observó tolerancia al administrar morfina a animales crónicamente tratados con cualquiera de los abridores de canales de potasio. El mismo efecto fue observado cuando se inyectó la morfina al grupo tratado con una combinación de morfina y cualquiera de los abridores de canales de potasio. CONCLUSIONES: Por consiguiente, este estudio sugiere que tanto la morfina como los abridores de canales de potasio son tolerantes cruzados. Sin embargo, tal interacción ocurre a nivel de los canales de potasio más bien que a nivel de los receptores.

[Effects of phenylephrine, calcium, Acetylcholine and Diazoxide on isolated Aorta of preeclamptic rats]

Preeclampsia, one of the most significant health problems in human pregnancy, is a leading cause of fetal mortality and maternal death. Alteration in vascular response to vasopressors and vasodilators is proposed as a major change in the context of preeclampsia. The aim of the present study was to investigate the responsiveness of preeclamptic rat aorta to some vasopressors and vasodilators. This experimental study was carried out in the pharmacology department of Shiraz University of Medical Sciences in 2008. Thirty pregnant rats were randomly divided into two groups [15 rats in each group]: case group received L-NAME at a dose of 50 mg/kg through drinking water from day 11 of pregnancy. Control group received only tap water. On the 22[nd] gestational day, all rats were anesthetized and killed; thoracic aorta was isolated, cut into 2-3 mm rings and mounted in organ bath. The isolated aortic rings were then exposed to cumulative concentrations of phenylepherine [Ph] and calcium, separately and contractions were measured by isometric transducers. To study the relaxing responses of aortic segments to vasodilators, the effects of cumulative concentrations of acetylcholine [Ach] and diazoxide on aortic rings precontracted with Ph and potassium were recorded, respectively. SPSS software and unpaired T-Test were used for data analysis. Potency of phenyepherine to contract rat aorta was significantly higher in preeclamptic rats compared to normal pregnant group [P= 0.014] but there was no significant difference in Ph-induced maximum contraction between two groups. Potency of Ach and its maximum relaxation effect was significantly lower in preeclamptic rats compared to controls, [p values were 0.026 and 0.004, respectively]. There were no statistically significant differences in the contractile responses of calcium and relaxing effects of diazoxide between two groups. Experimental preeclampsia increases the sensitivity of rat aorta to alpha- adrenergic receptor agonists and decreases the endothelium-dependent relaxation of it. It seems that the functions of voltage-operated calcium channels and ATP-dependent potassium channels do not change in experimental preeclampsia

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

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

Inhibitory Effect of Ketoifen on Contractions of Rat Isolated Bladder

Ketotifen is a benzocycloheptathiophene with a range of pharmacological activities. The present study was carried out to evaluate the action of ketotifen on isolated rat bladder contractions induced by KCl and acetylcholine, compared with the effects of other drugs. Ketotifen [5 micro M] reduced the response to acetylcholine on rat isolated bladder without altering the maximum response and shifted the acetylcholine concentration-response curve to the right 16 - fold. Ketotifen also reduced the KC1response, while atropine only inhibited the response to acetylcholine. Diazoxide inhibited bladder - induced contraction only at high concentration [500 micro M]. This study shows that ketotifen is a relaxant of isolated rat bladder. As the inhibition of contractile overactivity of the bladder is the basis of treatment of bladder instability, provided that a similar effect will be seen in vivo, then ketotifen may have clinical benefits for treatment of this condition

effect of diazoxide of theophylline on blood glucose and liver cyclic amp levels during endotoxemia in mice

The effect of diazoxide or theophylline on blood glucose and liver cyclic AMP levels during endotoxaemia in mice were compared. Administration of endotoxin resulted in a decrease in both parameters after eight and twelve hours. Diazoxide administered at seven hours post- endotoxin improved blood glucose and liver cyclic AMP levels at both eight and twelve hours post-endotoxin. Theophylline administration, using the same time schedule, increased liver cyclic AMP level but increased blood glucose slightly. Differences in the effect of both drugs is probably due to their possible different effect on insulin release

Efeito do nitroprussiato de sódio e do diazóxido sobre a hemodinâmica renal: estudo com microesferas radioativas / Effect of sodium nitroprusside and diazoxide on renal hemodynamics: study with radioactive microspheres

O nitroprussiato de sódio e o diazóxido, dois potentes hipotensores, foram estudados em cäes normais e cäes tornados hipertensos pela infusäo de noradrenalina, através das técnicas de clearance e microesferas radioativas. Em animais normotensos, doses hipotensoras de nitroprussiato produziram vasodilataçäo renal com aumento do fluxo sangüíneo renal, acompanhado de queda do clearance de creatinina. A administraçäo em dose única endovenosa de Diazóxido causou hipotensäo arterial, com reduçäo da resistência vascular renal e aumento significante do fluxo sangüíneo renal, acompanhado de queda do clearance de creatinina. Em cäes hipertensos pela infusäo endovenosa de noradrenalina, a administraçäo de nitroprussiato de sódio, em dose suficiente para normalizar a pressäo arterial, diminuiu a resistência vascular renal, sem alterar o fluxo sangüíneo renal e, principalmente, sem modificar o clearance de creatinina (de 1,45 ñ 0,20 para 1,57 ñ 0,24ml/min/kg peso). A injeçäo de diazóxico em cäes igualmente hipertensos, diminuiu a resistência vascular renal, com aumento significante do fluxo sangüíneo renal e manutençäo do clearance de creatinina (de 1,68 ñ 0,22 para 1,67 ñ 0,29ml/kg peso). Os dois vasodilatadores produziram, tanto nos animais normotensos como nos hipertensos, redistribuiçäo do fluxo sangüineo cortical para os néfrons profundos, sem relaçäo com a excreçäo urinária de sódio, que se manteve inalterada nos cäes normais e com queda nos hipertensos. Estes resultados indicam que as duas drogas produzem vasodilataçäo renal, com queda da filtraçäo glomerular nos animais normotensos, porém com manutençäo da filtraçäo glomerular em animais previamente hipertensos por infusäo de noradrenalina

Efeitos do diazóxido sobre a pressäo intracraniana e o diâmetro dos vasos piais: estudo experimental em cäes / Effects of the diazoxide in intracranial pressure and the diameter of pial vessels: experimental study in dogs

Várias drogas têm sido utilizadas em neurocirurgia para evitar o aumento da pressäo intracraniana e o espasmo de vasos cerebrais. O diazóxido, um agente hipotensor de açäo direta sobre a musculatura lisa dos vasos ainda näo foi estudado. Dessa maneira resolvemos pesquisar os efeitos dessa droga, administrada por via venosa (3 mg.kg-1) sobre a pressäo intracraniana e o diâmetro dos vasos piais em 16 cäes. Os animais foram divididos em dois grupos de 8. No grupo 1 foi estudado o efeito do diazóxido sobre a pressäo intracraniana, medida através de uma agulha colocada na cisterna magna, ligada a um transdutor e a um fisiógrafo. Ao mesmo tempo se registrava a pressäo arterial e se media o pH, PaO2 e PaCO2, nos tempos 1 (antes) 2,3 e 4 (1,15 e 30 min) após a injeçäo da droga. No grupo 2, media-se o diâmetro de arteríolas e vênulas piais através de uma perfuraçäo na regiäo craniana parieto-temporal e fotografia dos vasos piais nos mesmos tempos empregados no grupo anterior. Eram realizadas também medidas da pressäo arterial e dos gases sangüíneos. Observou-se que o diazóxido determina hipotensäo arterial logo após a sua injeçäo venosa, que persiste por 30 minutos. Ao mesmo tempo induz aumento significante do diâmetro das arteríolas piais. Näo há variaçäo significante da pressäo intracraniana e das vênulas piais. Esses resultados sugerem a possibilidade do uso dessa droga na profilaxia e no tratamento de espasmos vasculares cerebrais