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Results for “DIAZOXIDE”

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PubMed1978

Management of chlorpropamide-induced hypoglycemia with diazoxide.

Diazoxide, as demonstrated by the case we present, may be of substantial value in abolishing hypoglycemia and in preventing its recurrence. The mainstay of treatment for the patient with chlorpropamide toxicity is the constant close monitoring of clinical and laboratory parameters and the correction of hypoglycemia by administration of exogenous glucose when necessary. However, the need for exogenous glucose is reduced with the concomitant use of diazoxide. We therefore suggest that diazoxide should be considered as a part of the routine treatment of sulfonylurea-induced hypoglycemia.

Aged↗

PubMed2004

The anti-inflammatory effect of diazoxide in coronary artery bypass grafting.

Many therapeutic strategies have been designed to suppress the inflammatory response in patients undergoing coronary artery bypass grafting (CABG). Pharmacological preconditioning with diazoxide is an alternative in effective cardioprotective strategies, but more evidence is required to show its effect on the inflammatory response. Forty patients with stable angina who were scheduled for isolated elective CABG operations were randomized into control and diazoxide (DZX) groups. In the DZX group, 1.5 mg/kg diazoxide was infused intravenously in 5 min followed by a 5-min washout before commencing the cardiopulmonary bypass. In the control group, placebo infusion was given similarly. Blood samples for cytokine measurement were collected from the radial artery and coronary sinus perioperatively, and hemodynamic data were recorded. Thirty-six patients fulfilled the data collection. Cardiac index (CI) increased in both groups over time as compared with baseline. In the DZX group, the increase of CI was greater than that in the control group (P = 0.002). Systemic and coronary sinus plasma levels of IL-6, IL-8, and IL-10 increased significantly after reperfusion in both groups as compared with baseline (P < 0.05). IL-6 and IL-8 both reached the peak value at 6 h after cardiopulmonary bypass. IL-10 reached peak level at 20 min after reperfusion in both groups. There was significantly higher IL-10 in DZX groups (P = 0.015). The ratios of IL-6 to IL-10 and IL-8 to IL-10 were significantly lower in DZX groups than in controls (P = 0.025 and P = 0.041 for each, respectively). Pharmacological preconditioning with DZX in CABG patients shifts the circulating inflammatory cytokine balance toward the anti-inflammatory direction.

Aged↗

PubMed1986

Severe hypertension with cerebral symptoms treated with furosemide, fractionated diazoxide or dihydralazine. Danish Multicenter Study.

Emergency treatment of acute, severe hypertension defined as diastolic blood pressure (DBP) greater than or equal to 135 mmHg combined with cerebral symptoms was prospectively monitored in a randomized multicenter study including 64 patients. Treatment was divided into two periods. In the first hour the patients were observed in the supine position after being given 40 mg furosemide intravenously. If DBP remained greater than 125 mmHg (n = 52), the patients were put on fractionated diazoxide administered intravenously (n = 28) or dihydralazine administered intramuscularly (n = 24). Blood pressure (BP) decreased with diazoxide from an average of 241/149 mmHg to 180/111 mmHg after 5 hours and with dihydralazine from 237/149 to 161/101 mmHg. The inter-individual BP response varied considerably. A clear and identical regression in neurological symptoms was observed on both drug regimens. No new neurological symptoms were seen to develop. It is concluded that a gradual fall in BP can be obtained after fractionated dosage of diazoxide (i.v.) as well as after dihydralazine (i.m.). The indication of acute parenteral therapy compared to less aggressive oral treatment is discussed.

Adult↗

PubMed1976

Renal function, protein binding and pharmacological response to diazoxide.

1 The effect of rapid (10s) injections of diazoxide was studied in ten hypertensive patients with varying degrees of impairment of renal function. 2 There was a significant correlation between the patient's plasma urea concentration and reduction in mean arterial blood pressure. Diazoxide was also shown to be less highly protein bound in patients with renal failure. 3 It is suggested that the explanation for the increased hypotensive effect of diazoxide observed in patients with reduced renal function is related to higher unbound drug concentrations.

Adult↗

PubMed1981

A comparison of the effects of hydrallazine, diazoxide, sodium nitrite and sodium nitroprusside on human isolated arteries and veins.

1 Human common palmar digital arteries and dorsal metacarpal veins have been studied in vitro to investigate the responses of arterial and venous muscle to hydrallazine, diazoxide, nitroprusside and sodium nitrite. 2 Tissues were removed at autopsy, cut into helical strips and suspended in organ baths under identical conditions. The contractile response to noradrenaline was tested in the presence of the same concentrations of the vasodilator drugs in arteries and veins. 3 Hydrallazine antagonised contraction of arteries, but not veins to noradrenaline. Diazoxide, nitroprusside or sodium nitrite antagonised responses in both arteries and veins. Diazoxide and nitrite were more effective on arteries and nitroprusside was more effective on veins. 4 These results are in accord with clinical observations and confirm that there are differences in the susceptibility of human arterial and venous smooth muscle to vasorelaxant drugs.

Arteries↗

PubMedDate not supplied

Differing effects of the vasodilator drugs, prazosin and diazoxide on plasma renin activity in the dog.

1. The effects of intravenous (i.v.) administration of the vasodilator drugs prazosin or diazoxide on blood pressure and plasma renin activity were evaluated in the anaesthetized dog. 2. Prazosin and diazoxide both induced a rapid reduction in the mean arterial pressure to 73% and 75% of control values respectively. 3. Prazosin lowered plasma renin activity to 62% (P less than 0-025) of the control value whereas diazoxide raised plasma renin activity to 178% (P less than 0.05) of the control value. 4. The combination of vasodilatation and low renin activity observed following the administration of prazosin is unique, and may have clinical significance if these factors reduce the vascular complications of hypertension.

Animals↗

PubMed1978

Paradoxical enhancement of tolbutamide-induced insulin release by diazoxide in a patient with islet cell hyperplasia.

A case of islet cell hyperplasia in a ten year old black male with symptomatic fasting hypoglycemia was documented histopathologically. Provocative studies with glucose, tolbutamide, glucagon, and diazoxide were performed to test the insulin response of hyperplastic islets. The islets responded to glucose, glucagon, and tolbutamide. Diazoxide potentiated the tolbutamide-induced insulin response, and this effect of diazoxide was not blocked by propranolol. In the diagnostic work up of islet cell hyperplasia, dizoxide may paradoxically potentiate tolbutamide-induced insulin release, a finding which may falsely suggest progression of the disease.

Blood Glucose↗

PubMed2002

The effects of ischaemic preconditioning, diazoxide and 5-hydroxydecanoate on rat heart mitochondrial volume and respiration.

Studies with different ATP-sensitive potassium (K(ATP)) channel openers and blockers have implicated opening of mitochondrial K(ATP) (mitoK(ATP)) channels in ischaemic preconditioning (IPC). It would be predicted that this should increase mitochondrial matrix volume and hence respiratory chain activity. Here we confirm this directly using mitochondria rapidly isolated from Langendorff-perfused hearts. Pre-ischaemic matrix volumes for control and IPC hearts (expressed in microl per mg protein +/- S.E.M., n = 6), determined with (3)H(2)O and [(14)C]sucrose, were 0.67 +/- 0.02 and 0.83 +/- 0.04 (P < 0.01), respectively, increasing to 1.01 +/- 0.05 and 1.18 +/- 0.02 following 30 min ischaemia (P < 0.01) and to 1.21 +/- 0.13 and 1.26 +/- 0.25 after 30 min reperfusion. Rates of ADP-stimulated (State 3) and uncoupled 2-oxoglutarate and succinate oxidation increased in parallel with matrix volume until maximum rates were reached at volumes of 1.1 microl ml(-1) or greater. The mitoK(ATP) channel opener, diazoxide (50 microM), caused a similar increase in matrix volume, but with inhibition rather than activation of succinate and 2-oxoglutarate oxidation. Direct addition of diazoxide (50 microM) to isolated mitochondria also inhibited State 3 succinate and 2-oxoglutarate oxidation by 30 %, but not that of palmitoyl carnitine. Unexpectedly, treatment of hearts with the mitoK(ATP) channel blocker 5-hydroxydecanoate (5HD) at 100 or 300 microM, also increased mitochondrial volume and inhibited respiration. In isolated mitochondria, 5HD was rapidly converted to 5HD-CoA by mitochondrial fatty acyl CoA synthetase and acted as a weak substrate or inhibitor of respiration depending on the conditions employed. These data highlight the dangers of using 5HD and diazoxide as specific modulators of mitoK(ATP) channels in the heart.

Acyl Coenzyme A↗

PubMed1971

Use of diazoxide in hypertension with renal failure.

Treatment with intravenous and oral diazoxide was given to a group of 39 patients suffering from severe drug-resistant hypertension associated with renal impairment. Rapid initial and good long-term control of hypertension was achieved in all cases without the production of clinically significant postural hypotension. The side effects of diazoxide, including its diabetogenic effect, were easily controlled. There was a highly significant improvement in renal function in most patients on long-term oral diazoxide therapy.Diazoxide may have an important place in both the short- and long-term therapy of resistant hypertension, particularly in association with renal damage.

Adolescent↗

PubMed1981

Hazards of diazoxide in pulmonary hypertension.

The use of diazoxide in the treatment of pulmonary hypertension has been advocated recently. We describe three patients who responded less favourably. The first patient had cardiac arrest (asystole) after the acute bolus dose. After recovery only a slight increase in cardiac index was seen while pulmonary vascular resistance was unchanged. The second patient developed total atrioventricular block after the acute bolus dose. Ater recovery the cardiac index was unchanged while pulmonary vascular resistance was decreased. The third patient felt ill after the acute bolus dose, and the blood pressure dropped, but no conduction abnormalities were noted. The cardiac index rose slightly and the pulmonary vascular resistance was essentially unchanged. Long term treatment with oral diazoxide could not be administered to this patient because abdominal pain and distension developed. Because we lack reliable alternative treatment, it is justifiable to try diazoxide, provided great care is taken.

Abdomen↗

PubMed1997

Diazoxide treatment for insulinoma: a national UK survey.

A survey of UK patients receiving the drug diazoxide, revealed 40 patients with insulinoma on this treatment. Mean age (+/- SD) was 67 +/- 18 years, and 74% were female. Duration of treatment was 7 +/- 6 years (range 1-22). Most (55%) patients were treated with diazoxide because of tumour non-localisation (including failed previous surgery). Metastatic disease (20%) and poor surgical risk (10%) were other indications. Side-effects (notably fluid retention and hirsutism) were common (47%) but not troublesome. Treatment was highly effective--59% were symptom free and 38% had only occasional symptoms. Only one patient had frequent hypoglycaemia despite treatment. We conclude that diazoxide is effective in the management of insulinoma. Side-effects are common but not problematic. Treatment should be considered for all patients not cured by surgery, or unsuitable for surgical treatment.

Adult↗

PubMed1980

Clinical and haemodynamic effects of diazoxide in primary pulmonary hypertension.

Diazoxide was injected into the pulmonary artery in nine patients with primary pulmonary hypertension. There was no significant change in pulmonary artery pressure, which fell by more than 10 mmHg in only two patients. The pulmonary blood flow increased in all patients as a result of a fall in pulmonary vascular resistance (by 4 to 17 units). Systematic vasuclar resistance also fell as expected in all patients. Oral diazoxide was given to seven patients, two of whom showed sustained clinical improvement while remaining on treatment (400 to 600 mg daily). Five patients were unable to tolerate the drug, because of nausea and sickness (two), peripheral oedema requiring large doses of diuretics (four), diabetes (three), and postural hypotension (one). Hirsutes was troublesome in the two patients remaining on treatment. Diazoxide may be useful in the management of some patients with primary pulmonary hypertension, but its use is limited by the frequency of side effects. Our results suggest that examination of othe potent vasodilators may be worth while.

Administration, Oral↗

PubMed1988

Diazoxide unmasks glucose inhibition of insulin release by counteracting entry of Ca2+.

The interaction of diazoxide with the effects of glucose on the insulin-releasing mechanism was analyzed in beta-cell-rich pancreatic islets isolated from ob/ob mice. When added at a concentration of 400 microM to a medium containing 1.28 mM Ca2+, diazoxide converted glucose stimulation of insulin release into inhibition. Further addition of 2 mM theophylline restored the insulin secretory response to glucose. The paradoxical glucose inhibition of insulin release was accounted for by a diazoxide interaction with the entry of Ca2+, unmasking a capacity of the sugar to lower cytoplasmic Ca2+ below its resting concentration.

Animals↗

PubMed2003

Diazoxide triggers cardioprotection against apoptosis induced by oxidative stress.

Although mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels have been reported to reduce the extent of apoptosis, the critical timing of mitoK(ATP) channel opening required to protect myocytes against apoptosis remains unclear. In the present study, we examined whether the mitoK(ATP) channel serves as a trigger of cardioprotection against apoptosis induced by oxidative stress. Apoptosis of cultured neonatal rat cardiomyocytes was determined by flow cytometry (light scatter and propidium iodide/annexin V-FITC fluorescence) and by nuclear staining with Hoechst 33342. Mitochondrial membrane potential (DeltaPsi) was measured by flow cytometry of cells stained with rhodamine-123 (Rh-123). Exposure to H(2)O(2) (500 microM) induced apoptosis, and the percentage of apoptotic cells increased progressively and peaked at 2 h. This H(2)O(2)-induced apoptosis was associated with the loss of DeltaPsi, and the time course of decrease in Rh-123 fluorescence paralleled that of apoptosis. Pretreatment of cardiomyocytes with diazoxide (100 microM), a putative mitoK(ATP) channel opener, for 30 min before exposure to H(2)O(2) elicited transient and mild depolarization of DeltaPsi and consequently suppressed both apoptosis and DeltaPsi loss after 2-h exposure to H(2)O(2). These protective effects of diazoxide were abrogated by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microM) but not by the sarcolemmal K(ATP) channel blocker HMR-1098 (30 microM). Our results suggest for the first time that diazoxide-induced opening of mitoK(ATP) channels triggers cardioprotection against apoptosis induced by oxidative stress in rat cardiomyocytes.

Animals↗

PubMed1990

Relationship between thirst and diazoxide-induced hypotension in rats.

Diazoxide, a potent vasodilator and antidiuretic, was used to examine the relationship between hypotension and thirst in conscious rats with indwelling arterial and venous catheters. Bolus iv. injections (5-50 mg/kg) caused prompt, long-lasting, and dose-dependent reductions in mean arterial pressure (MAP) and stimulated drinking. Water intake and degree of hypotension were closely correlated when MAP was 10-65 mmHg below normal. At the time of drinking there were no significant changes in central venous pressure, plasma osmolality, or Na+ or K+ concentration. Plasma glucose increased approximately 35%, and blood volume increased approximately 10% (based on hematocrit changes and dilution of Evans blue). Captopril (100 mg/kg sc to block the renin-angiotensin system) enhanced the depressor response to diazoxide but abolished the dipsogenic response over the same range of arterial pressures tested in controls. Angiotensin II iv infusion restored drinking in captopril-treated animals. The combination of captopril and diazoxide did not block drinking to iv infusions of hypertonic saline or water deprivation. These results confirm that hypotension potently stimulates thirst and support the hypothesis that angiotensin II mediates the dipsogenic response in rats.

Angiotensin II↗

PubMed2001

Modulation of beta-cell ouabain-sensitive 86Rb+ influx (Na+/K+ pump) by D-glucose, glibenclamide or diazoxide.

The activity of the beta-cell Na+/K+ pump was studied by using ouabain-sensitive (1mM ouabain) 86Rb+ influx in beta-cell-rich islets of Umeå-ob/ob mice as an indicator of the pump function. The present results show that the stimulatory effect of glucose on ouabain-sensitive 86Rb+ influx reached its approximate maximum at 5mM glucose. Pre-treatment of the islets with 20mM glucose for 60 min strongly reduced the glucose-induced stimulation of the Na+/K+ pump. Pre-treatment (60 or 180 min) of islets at 0 mM glucose, on the other hand, did not affect the magnitude of the glucose-induced stimulation of 86Rb+ influx during the subsequent 5-min incubation. Glibenclamide stimulated the ouabain-sensitive 86Rb+ uptake in the same manner as glucose. The stimulatory effect showed its apparent maximum at 0.5 microM. Pre-treatment (60 min) of islets with 1 microM glibenclamide did not reduce the subsequent stimulation of the ouabain-sensitive 86Rb+ influx. The stimulatory effect of glibenclamide and D-glucose were not additive, suggesting that they may have the same mechanism of action. No direct effect of glibenclamide (0.01-1 microM) was observed on the Na+/K+ ATPase activity in homogenates of islets. Diazoxide (0.4mM) inhibited the Na+/K+ pump. This effect was sustained even after 60 min of pre-treatment of islets with 0.4mM diazoxide. The stimulatory effect of glibenclamide and D-glucose were abolished by diazoxide. It is concluded that nutrient as well as non-nutrient insulin secretagogues activate the Na+/K+ pump, probably as part of the membrane repolarisation process.

Animals↗

PubMed1982

Effects of diazoxide and hydrochlorothiazide on water permeability and sodium transport in the frog bladder.

The effects of diazoxide and hydrochlorothiazide on vasopressin-induced increments in osmotic water flow and sodium transport across the frog bladder were studied. Diazoxide enhanced the vasopressin-induced osmotic water flow of the bladder, but did not affect the cyclic AMP- or theophylline-induced water flow. Hydrochlorothiazide did not affect the vasopressin-induced water flow. Our results suggest that diazoxide increased the water flow by inhibiting the activity of phosphodiesterase in bladder epithelial cells, whereas hydrochlorothiazide did not. On the other hand, both drugs suppressed the short-circuit current of the bladder membrane and inhibited the Na,K-dependent ATPase activity of the kidney cells. These results suggest that both drugs decreased sodium transport in the bladder by inhibiting Na,K-dependent ATPase activity.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1990

Relaxation response to pinacidil and diazoxide in the mouse isolated distal colon.

Pinacidil and diazoxide induced concentration-related relaxations of the longitudinal muscle of the mouse distal colon. The relaxing effects of pinacidil and diazoxide were unaffected by tetraethylammonium, but were antagonized by tolbutamide and glibenclamide. Relaxations provoked by nifedipine were not counteracted by the two hypoglycaemic sulfonylureas. It is tempting to suggest that the relaxation response to pinacidil and diazoxide could reflect the ability of both compounds to interfere with membrane K+ channels sharing common pharmacological properties with the K+ATP channels recently described in other tissues.

Animals↗