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Hyperglycemic hyperosmolar nonketotic coma following diazoxide, anesthesia and operation.

Unsuspected hyperglycemia caused prolonged postanesthetic coma in a nondiabetic patient treated with IV diazoxide and furosemide. The combined effect of these drugs with general anesthesia and surgical stress was postulated as the cause of the hyperglycemia. Blood glucose should be measured during and after general anesthesia in patients who are potential candidates for hyperglycemic hyperosmolar nonketotic coma.

Aged↗
PubMed2004

Difference in the cardioprotective mechanisms between ischemic preconditioning and pharmacological preconditioning by diazoxide in rat hearts.

BACKGROUND: Recent studies have implicated the opening of mitochondrial K(ATP) (mitoK(ATP)) channels and the production of reactive oxygen species (ROS) in the cardioprotective mechanism of ischemic preconditioning (IPC). METHODS AND RESULTS: The involvement of mitoK(ATP) channels and ROS in the cardioprotective effects of both IPC and the mitoK(ATP) channel opener diazoxide (DZ) was investigated in ischemic/reperfused rat hearts. The effects of IPC and DZ on myocardial high-energy phosphate concentrations and intracellular pH (pH(i)) were also examined using (31)P nuclear magnetic resonance spectroscopy. Although both the mitoK(ATP) channel inhibitor 5-hydroxydecanoate and the antioxidant N-acetylcysteine abolished the postischemic recovery of contractile function by DZ, neither of them inhibited that by IPC. IPC attenuated the decline in pHi during ischemia, but DZ did not (6.28+/-0.04 in IPC, p<0.05, and 6.02+/-0.05 in DZ vs 6.02 +/-0.06 in control hearts). DZ, but not IPC, reduced the decrease in ATP levels during ischemia (ATP levels at 20-min ischemia: 26.3+/-3.4% of initial value in DZ, p<0.05, and 8.1+/-3.0% in IPC vs 15.1+/-1.3% in control hearts). CONCLUSIONS: These results suggest that DZ-induced cardioprotection is related to ROS production and reduced ATP degradation during ischemia, whereas attenuated acidification during ischemia is involved in IPC-induced cardioprotection, which is not mediated through mitoK(ATP) channel opening or ROS production.

ATP-Binding Cassette Transporters↗
PubMed2003

Trimethoprim-sulfamethoxazole induced prolonged hypoglycemia in an infant with MHC class II deficiency: diazoxide as a treatment option.

Hyperinsulinemic hypoglycemia associated with trimethoprim-sulfamethoxazole (TMP-SMX) has generally been reported in adults who had renal impairment or in patients with AIDS using high dose TMP-SMX. We present a 5 month-old infant with immunodeficiency due to major histocompatibility complex class II expression defect, developing hypoglycemic convulsion on the third day of high dose TMP-SMX administration. High insulin and C-peptide levels were documented at the time of hypoglycemia. To overcome hypoglycemia while TMP-SMX tapered off, diazoxide was administered which resolved hypoglycemia in 2 months.

Blood Glucose↗
PubMed1987

Demonstration of glucose inhibition of insulin release in the presence of diazoxide.

beta-Cell-rich pancreatic islets from ob/ob mice were taken for measurements of insulin release in response to glucose after culture in RPMI 1640 medium. The stimulatory effect of 20 mmol/l glucose was converted into an inhibition when the medium was supplemented with 400 mumol/l diazoxide. Glucose inhibition of insulin release was observed when the islets had been cultured in the presence of 1 or 20 mmol/l glucose in media either containing or lacking Ca2+. The data provide further evidence for an inhibitory component in the action of glucose on insulin release, suggesting that glucose stimulation of the Ca2+ efflux is essential for the appearance of this inhibition.

Animals↗
PubMed2002

Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats.

OBJECTIVES: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. METHODS: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. RESULTS: DZ-treated animals showed lower fasting plasma insulin levels (P<0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P<0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P<0.001) and glucose-6-phosphatase (P<0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P<0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P<0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P<0.01), glycogen synthase activity (P<0.0001) and glycogen content (P<0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P<0.02). CONCLUSIONS: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.

Animals↗
PubMed1976

[The inhibition of spontaneous and oxytocin-stimulated uterine contractions in isolated rat uteri with diazoxide (author's transl)].

Diazoxide, a benzothiadizin derivative without diuretic effect, was tested for its tocolytic effectiveness in isolated uteri from pregnant and nonpregnant rats. Amplitude, frequency, basal tonus and duration of the total inhibition of labor pains were interpreted as parameters. Total or subtotal inhibition of amplitude and frequency could be obtained in all experiments. The duration of total inhibition of labor pains was between 3 and 27 minutes. Affect on the basal tonus was not consistant.

Animals↗
PubMed2004

Diazoxide enhances adipose tissue protein kinase B activation and glucose transporter-4 expression in obese Zucker rats.

BACKGROUND: Attenuation of hyperinsulinemia in obese Zucker rats by diazoxide (DZ) enhanced insulin sensitivity and insulin-stimulated glucose uptake in isolated adipocytes. To determine if these metabolic effects are due to changes in glucose transporter (Glut)-4 gene products and intracellular signaling, we studied the effects DZ on adipose tissue Glut-4 gene products, insulin receptor substrate (IRS)-1, total and phosphorylated protein kinase B (PKB)/Akt. MATERIAL/METHODS: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for 6 weeks. RESULTS: While adipose Glut-4 mRNA levels from control obese and lean rats were similar, Glut-4 protein content was 60% lower in obese than lean animals (p<0.05). DZ treatment increased mRNA in both obese (1.4 fold) and lean (1.7 fold) animals compared to controls (p<0.05), which was associated with a 3.7 fold and a 1.4 fold increase in Glut-4 protein content in DZ obese (p<0.01) and lean (p<0.05) rats, respectively. IRS-1 protein expression was lower in obese compared to lean rats (p<0.01) and was enhanced in DZ-treated obese (p<0.02) and lean (p<0.05) rats. While the PKB/Akt protein levels were similar in both strains, obese had lower p-Akt levels than lean rats (p<0.01). DZ-treated obese and lean rats had higher levels of p-Akt than their controls (p<0.05). CONCLUSIONS: Chronic suppression of hyperinsulinemia in obese Zucker rats improved intracellular insulin signaling and Glut-4 gene expression, corresponding to enhanced glucose uptake in isolated adipocytes. The discrepancy between adipose tissue Glut-4 mRNA and protein content in response to DZ treatment suggests post-transcriptional regulatory effects resulting from enhanced metabolic efficiency of insulin action.

Adipose Tissue↗
PubMed2005

Diazoxide attenuates insulin secretion and hepatic lipogenesis in zucker diabetic fatty rats.

BACKGROUND: Attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes and leptin resistance, decreased weight gain, improved lipid profile and prevented diabetes. Since the opposing effects of insulin and leptin regulate hepatic lipogenesis, we studied effects of insulin suppression on key insulin-sensitive genes regulating hepatic lipogenesis. MATERIAL/METHODS: DZ (150 mg/kg/day) or vehicle [pair-fed (PF) and control (C)] was administered to pre-diabetic obese ZDF and ZDF lean (ZL) rats for 8 weeks. RESULTS: Hepatic glucose transporter-2 protein expression decreased only in DZ-ZDF rats (p<0.001). However, insulin receptor substrate-1/2 protein expressions were enhanced in DZ-ZDF (p<0.02) and DZ-ZL (p<0.03) rats corresponding to increased phosphorylated protein kinase B levels in both strains (p<0.03). DZ increased glycogen synthase expression in ZDF (p<0.005) and ZL (p<0.002) rats. DZ reduced expression of sterol regulatory element-binding protein-1c, (p<0.0001), fatty acid synthase (p<0.002), acetyl CoA carboxylase (p<0.001), hormone-sensitive lipase (p<0.005), and peroxisome proliferator agonist receptor-gamma (p<0.02) in ZDF rats, without altering expressions of acyl CoA oxidase, peroxisome proliferator receptor-alpha, and carnitine palmitoyl transferase-1. DZ decreased hepatic triglycerides (p<0.001), long chain acyl-CoA (p<0.001) and cholesterol (p<0.01) contents only in ZDF rats, but increased glycogen content in both strains (p<0.02). CONCLUSIONS: Suppression of hyperinsulinemia by DZ enhanced hepatic insulin sensitivity and decreased expression of key genes regulating hepatic lipogenesis without altering genes regulating lipid oxidation; implying that attenuation of hyperinsulinemic state by DZ enhances metabolic efficiency of insulin and is therapeutically beneficial.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2005

[Diazoxide preconditioning combined with subsequent hypothermia alleviates anoxia-re-oxygenation injury: experiment with rat hippocampal neurons].

OBJECTIVE: To observe the alleviative effects of preconditioning with diazoxide (DZ), a mitochondrial ATP-sensitive potassium channel opener, combined with subsequent hypothermia on anoxia-re-oxygenation injury. METHODS: Hippocampal neurons of new-born SD rat were cultured. DZ of the concentration of 250 micromol/L was added into the culture fluid. The group of preconditioned cultured neurons were re-divided into 4 subgroups to be treated by hypothermia of different levels: 37 degrees C, 34 degrees C, 30 degrees C, and 22 degrees C, and then were derived of oxygen for 4 hours. The group of neurons without addition of DZ was re-divided into 4 subgroup too to be exposed to different temperatures and then underwent anoxia-re-oxygenation as described above. Thus the experiment was performed on 8 subgroups in total. Twenty-four hours after re-oxygenation the neurons were stained with dimethyl sulfoxide and their levels of absorptivity were measured so as to calculate the survival rate. Modified thiobarbital method was used to detect the concentration of malondialdehyde (MDA) in the culture fluid. Fluorescence probe Fluo-3-AM was added to detect the Ca(2+) concentration in the neurons. RESULTS: The survival rates of the DZ-preconditioned neurons of the 22 degrees C, 30 degrees C, and 34 degrees C subgroups were (94 +/- 8)%, (73 +/- 9)%, (67 +/- 8)% respectively, all significantly higher than that of the 37 degrees C subgroup (57 +/- 6%, all P < 0.01), with significant differences between the 22 degrees C subgroup and the 30 degrees C and 34 degrees C subgroups (both P < 0.01). The survival rates of the non-DZ-preconditioned neurons of the 22 degrees C, 30 degrees C, and 34 degrees C subgroups were 66 +/- 10%, 52 +/- 910%, 48 +/- 9% respectively, all significantly higher than that of the 37 degrees C subgroup (41% +/- 7%, all P < 0.01), with significant differences between the 22 degrees C subgroup and the 30 degrees C and 34 degrees C subgroups (both P < 0.01). The survival rates at different temperatures in the DZ-preconditioned group were all significantly higher than those in the corresponding non-preconditioned subgroups (all P < 0.01). The MDA concentration in the culture fluid of the 22 degrees C subgroup was significantly lower than those of the 30 degrees C, 34 degrees C, and 37 degrees C subgroups in both the DZ-preconditioned and non-preconditioned groups (all P < 0.01). The MDA concentrations of the preconditioned subgroups at different temperatures were all significantly lower than those of the corresponding non-preconditioned subgroups (all P < 0.01). The fluorescent value of the intracellular Ca(2+) of the 22 degrees C subgroup was significantly lower than those of the 30 degrees C, 34 degrees C, and 37 degrees C subgroups in both the DZ-preconditioned and non-preconditioned groups (all P < 0.01). The fluorescent value of the intracellular Ca(2+) of the preconditioned subgroups at different temperatures were all significantly lower than those of the corresponding non-preconditioned subgroups (all P < 0.01). CONCLUSION: Hypothermia alleviates the anoxia-re-oxygenation injury: DZ preconditioning enhances the neuroprotection by hypothermia.

Animals↗
PubMed2006

Diazoxide preconditioning plus subsequent hypothermia increased resistance of rat cultured hippocampal neurons against hypoxia-reoxygenation injury.

BACKGROUND: Cerebral ischemia-reperfusion/hypoxia-reoxygenation insult triggers lots of pathophysiological and biochemical events that separately affect the evolution of cerebral damage. Accordingly, all known effective neuroprotective measures should be taken to get the optimal efficacy of therapy. This study was undertaken to investigate whether diazoxide (DZ) preconditioning combined with the following hypothermia could contribute to synergistic neuroprotection compared with either hypothermia or DZ preconditioning alone. METHODS: Cultured for 9-10 days in vitro, the hippocampal neurons of SD rats were preconditioned with DZ 0 micromol/L or DZ 250 micromol/L for 1 hour per day and this treatment lasted for 3 days. Subsequently, neurons were subjected to deprivation of oxygen for 4 hours at 37 degrees C, 34 degrees C, 30 degrees C and 22 degrees C, respectively. This experiment consisted of 8 groups (4 temperature groups and 4 combination groups) and each group contained 12-well or 2-dish cells. Survival rate, expression of Bcl-2, fluorescence magnitude of intracellular calcium, and concentration of malondialdehyde (MDA) were determined at 24 hours after reoxygenation. RESULTS: The survival rate and expression of Bcl-2 were both increased in individually hypothermic conditions compared with those at 37 degrees C (P < 0.05), whereas intracellular calcium and MDA did the opposite exhibition simultaneously (P < 0.05). 22 degrees C contributed to a higher survival rate and greater expression of Bcl-2 in comparison with other hypothermia (P < 0.05). Preceding administration of 250 micromol/L DZ took the similar effects on the neurons like hypothermia. Moreover, compared with individual hypothermia or DZ preconditioning, the neuronal survival rate and expression of Bcl-2 in the combination group were increased significantly (P < 0.05), whereas the calcium fluorescence density and concentration of MDA were reduced further (P < 0.05). 250 micromol/L DZ preconditioning combined with 22 degrees C provided a maximal neuroprotection. CONCLUSIONS: Compared with either individual hypothermia or DZ preconditioning, the combination of both treatments conferred synergistic protection for cultured hippocampal neurons in vitro against hypoxia-reoxygenation insult.

Animals↗
PubMed2006

Diazoxide preconditioning alleviates apoptosis of hippocampal neurons induced by anoxia-reoxygenation in vitro through up-regulation of Bcl-2/Bax protein ratio.

Activating mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels is a critical event of pharmacological preconditioning, which can enhance neuronal ability against various insults. mitoK(ATP) channels are abundant in neurons and can be selectively opened by diazoxide (DZ). The aim of this study was to determine whether DZ could restrain neuronal apoptosis induced by anoxia-reoxygenation and to reveal the effect of DZ preconditioning on the expressions of Bcl-2 and Bax proteins in cultured hippocampal neurons. Cultured for 9~10 d in vitro, the hippocampal neurons of Sprague-Dawley rats were assigned to the following 5 groups randomly: Control, DZ 0 mumol/L, DZ 30 mumol/L, DZ 100 mumol/L, DZ 100 mumol/L+5-hydroxydecanoate (5-HD, a selective mitoK(ATP) channel blocker) 100 mumol/L. Prior to oxygen deprivation, the hippocampal neurons except those in the control group were treated with DZ or DZ+5-HD for 1 h per day and this treatment persisted for 3 d. Thereafter, neurons were subjected to anoxia for 4 h and followed by reoxygenation. At 24 h of reoxygenation the neuronal survival rates were measured by MTT method, while the apoptotic rates were assayed by annexin V-FITC staining. The expressions of Bcl-2 and Bax proteins were detected with immunocytochemistry and evaluated by Western blot. Anoxia-reoxygenation injury reduced the survival rates and increased apoptotic rates significantly. In comparison with those in other groups, the survival rate in DZ 100 mumol/L group was increased by about 15%, whereas the apoptotic rate was decreased by almost 12% simultaneously. 5-HD could abolish the neuroprotection afforded by 100 mumol/L DZ. Bcl-2 and Bax proteins in the control normoxic neurons were both expressed slightly, while anoxia-reoxygenation led to high expression of Bax protein. The administration of 100 mumol/L DZ enhanced the expression of Bcl-2 protein by nearly 60%, whereas Bax protein was reduced by approximately 30%. Lower concentrations of DZ had no detectable effects on the expressions of Bcl-2 and Bax proteins. However, beneficial effects of DZ on the expressions of Bcl-2 and Bax proteins were reversed after the co-treatment with 5-HD. In conclusion, 100 mumol/L DZ prevented cultured hippocampal neurons from apoptosis induced by anoxia-reoxygenation possibly through up-regulating the expression of Bcl-2 protein and down-regulating the expression of Bax protein.

Animals↗
PubMed1991

A case of insulin-secreting tumor successfully treated with diazoxide.

A 72-year-old patient was referred to our hospital because of a hypoglycemic crisis possibly due to an insulin secreting-tumor. Although its localization was assumed to be at the head of the pancreas as assessed by transhepatic venography with sampling, no mass lesion was detected by selective angiography, ultrasound, computerized axial tomography, magnetic resonance imaging and 67Ga-citrate scan. The patient was treated with diazoxide, because of poor localization and his age, insulin secretion was improved after both 30 and 60 min in the 75 g oral glucose tolerance test. The total amount of urinary C-peptide excretion decreased from 70.8 to 29.2 mcg/day. Thereafter, no hypoglycemic symptoms were observed during his admission. No side effects except mild liver damage were observed.

Aged↗
PubMed1979

[The haemodynamic principle of action of diazoxide (hypertonalum) in the treatment of acute hypertensive crises in late pregnant women (author's transl)].

In ten hypertensive late pregnant women with passing crises of hypertension cardiovascular analysis with the method of quantitative sphygmometry, the unbloody recording of the blood pressure and the direct electronic measuring of the pulse wave velocity were made before and after the intravenous injection of 300 mg Diazoxid (Hypertonalum). This drug is recommended to the treatment of severe preeclampsia and eclampsia because of lessening the arterial blood pressure and the total peripheral resistance, increasing the heart rate, stroke volume and cardiac output.

Acute Disease↗
PubMed1977

[The inhibition of prostaglandin induced uterine contractions by diazoxide in vitro (author's transl)].

The tocolytic efficiency of Diazoxide, a benzothiadiazine derivative with pronounced musculotropic action, was tested on the isolated uteri of non-gravid and gravid rats. Regular uterine contractions were induced by the prostaglandines E2 and F2 alpha. Their amplitude and frequency could be suppressed totally or subtotally. Contraction intervals lasted 4--22 min. The basal tone was reduced in most cases.

Animals↗
PubMed1984

Reversal of pentamidine-induced hypoglycaemia with oral diazoxide.

Hypoglycaemia is a common and occasionally life-threatening complication of therapy with pentamidine isethionate. We observed inappropriately elevated insulin levels in a patient with Pneumocystis carinii pneumonia and pentamidine-induced hypoglycaemia. Oral diazoxide was effective in reversing the marked hypoglycaemia. Pentamidine may exert its hypoglycaemic effect by stimulating insulin secretion from the pancreas.

Adult↗
PubMed1983

Acute treatment of hypertension with slow infusion of diazoxide.

We have treated 81 patients who had hypertension with slow intravenous infusion of diazoxide (15 mg/min; 5 mg/kg of body weight). Blood pressure was reduced effectively both in patients with severe hypertension (n = 40) and in patients with a hypertensive crisis (n = 34); the decrease of mean arterial pressure (delta MAP) being -17.0% +/- 1.2% (mean +/- SEM) and -19.7% +/- 1.5%, respectively. However, the delta MAP was significantly greater in patients with preeclampsia (-26.0% +/- 3.0%). In all instances BP fell gradually and then decreased only slightly after discontinuation of the infusion. Thus, the potentially hazardous, steep, and exaggerated fall of BP, observed after bolus injections, can be avoided. Electrocardiographic signs of myocardial ischemia were seen in two patients. No other serious side effects were observed. We conclude that, even in patients with a hypertensive crisis, slow infusion is a safe and effective procedure for the reduction of BP.

Adult↗