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PubMed1983

Diazoxide infusion test in patients with single benign insulinoma.

The diazoxide infusion test (600 mg i.v. over a 1-hour period) was performed in 12 patients bearing single benign islet B-cell adenoma and in 6 normal subjects. Blood glucose, plasma insulin and glucagon concentrations were measured every 15 min during the infusion and thereafter up to 150 min. In insulinoma patients, blood glucose levels failed to increase significantly while in the control group a significant rise starting from 30 min persisted throughout the test (p less than 0.05 or less). Plasma insulin mean levels decreased significantly in normal subjects from 30 to 60 min (p less than 0.05), while they were significantly suppressed in hypoglycemic patients from 15 to 120 min (p less than 0.02). Diazoxide administration induced in the normal group a significant decrease in glucagon levels (p less than 0.02 from 30 to 150 min) whereas no such suppression occurred in patients. In our experience, insulin response to diazoxide infusion in patients with insulinoma may provide additional information for diagnosis.

Adenoma, Islet Cell↗

PubMed1984

Leucine-induced hypoglycemia in a family: effect of diphenylhydantoin, oxprenolol, and diazoxide.

The present report describes a mother and 2 children with leucine-induced hypoglycemia (LIH). Hypoglycemic episodes following high-protein meals first appeared at age 4-7 months. Leucine-stimulation tests triggered marked hyperinsulinism and hypoglycemia in the children and a milder but abnormal response in the mother. To evaluate the therapeutic effects and to study the mechanism of hyperinsulinism in LIH, the leucine test was repeated under treatment with diphenylhydantoin, oxprenolol (a beta-blocker), and diazoxide. Diazoxide abolished hyperinsulinism; diphenylhydantoin did not affect the response to leucine; and oxprenolol, tested in the mother only, increased hyperinsulinism and hypoglycemia. Our results indicate that LIH is an autosomal dominant disorder; LIH may persist into adulthood with milder clinical symptoms and chemical response to leucine; diazoxide is the treatment of choice in LIH. Considering the effects of the three agents on stimulated release of insulin, it is concluded that leucine triggers hyperinsulinism by a mechanism different from that of glucose and beta-adrenergic receptors.

Adult↗

PubMed2001

Downregulation of protein kinase C inhibits activation of mitochondrial K(ATP) channels by diazoxide.

BACKGROUND: The mitochondrial K(ATP) (mitoK(ATP)) channel has been shown to confer short- and long-term cardioprotection against prolonged ischemia via protein kinase C (PKC) signaling pathways. However, the exact association between PKC or its isoforms and mitoK(ATP) channels has not yet been clarified. The present study tested the hypothesis that the activity and translocation of PKC to the mitochondria are important for cardiac protection elicited by mitoK(ATP) channels. Methods and Results-PKC was downregulated by prolonged (24-hour) treatment with phorbol 12-myristate 13-acetate (4 microgram/kg body weight) before subsequent experiments in rats. Langendorff-perfused rat hearts were subjected to 40 minutes of ischemia followed by 30 minutes of reperfusion. Effects of PKC downregulation on the activation of mitoK(ATP) channels and other interventions on hemodynamic, biochemical, and pathological changes were assessed. Subcellular localization of PKC isoforms by Western blot analysis and immunocytochemistry demonstrated that PKC-alpha and PKC-delta were translocated to the sarcolemma and that PKC-delta was translocated to the mitochondria after diazoxide treatment. In hearts treated with diazoxide (80 micromol/L), a significant improvement in cardiac function and an attenuation of cell injury were observed. In PKC-downregulated hearts, protection was abolished because mitoK(ATP) channels could not be activated by diazoxide. CONCLUSIONS: These data suggest that PKC activation is required for the opening of mitoK(ATP) channels during protection against ischemia and that this effect is linked to isoform-specific translocation of PKC-delta to the mitochondria.

Adenosine Triphosphate↗

PubMed2002

Compound heterozygosity for the common sulfonylurea receptor mutations can cause mild diazoxide-sensitive hyperinsulinism.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder characterized by dysregulation of insulin secretion and prolonged hypoglycemia. Mutations in the genes of both subunits of the beta-cell KATP channel, Kir 6.2 (potassium channel) and SUR1 (sulfonylurea receptor) have been associated with the autosomal recessive form of this disorder. It was previously demonstrated that patients harboring SUR1 mutations often do not respond well to diazoxide. A patient is reported of compound heterozygosity for the 2 most common mutations previously reported to be associated with PHHI in Ashkenazi Jews; splice mutation of intron 32 (3993-9G-->A) and deletion of phenylalanine at position 1388. Relatively low glucose utilization (<10 mg/kg/min) was needed to maintain blood gllucose concentrations. In addition, treatment with diazoxide was highly effective. We suggest that diazoxide unresponsiveness is not always present in patients with SUR1 mutations and that the probable cause of the milder phenotype in this compund heterozygote state

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

Effects of diazoxide on the cardiovascular response to tracheal intubation.

The efficacy of 2 or 3 mg/kg diazoxide given 2.5 min before laryngoscopy in attenuating the cardiovascular responses to laryngoscopy and intubation was studied in 30 patients undergoing elective surgery. Data were compared with those from 10 control patients receiving saline. Anaesthesia was induced using 5 mg/kg thiopentone given intravenously and tracheal intubation was facilitated with 0.2 mg/kg vecuronium bromide. Patients receiving saline showed a significant increase in mean arterial pressure and rate-pressure product associated with tracheal intubation. The increases following tracheal intubation were significantly reduced (P less than 0.05) in diazoxide-treated patients compared with those in the control group, but there were no significant differences in heart rate following tracheal intubation among the three groups. Data suggest that diazoxide can be used as a supplement during induction of anaesthesia to attenuate the hypertensive response associated with laryngoscopy and tracheal intubation.

Adult↗

PubMed1987

Insulin-related changes in the subcellular distribution of insulin receptors in intact rat liver: effects of acute hypoinsulinemia induced by diazoxide, somatostatin, and xylazine.

The effects of inhibitors of insulin secretion on the concentration of plasma insulin and on the subcellular distribution of hepatic insulin receptors have been examined in rats. Liver plasma membranes, Golgi fractions, and a total particulate fraction were prepared various times after the injection of diazoxide (10 mg), xylazine (0.5 mg), and somatostatin (20 micrograms as a bolus followed by a 20 micrograms/15-min infusion), solubilized by Triton X-100, and examined for specific insulin binding. Injection of each of these drugs caused a 4- to 8-fold decrease in plasma insulin concentration, and concomitantly, a 25-35% decrease in insulin binding to Golgi fractions; a 10% increase in insulin binding to plasma membranes also occurred in diazoxide-treated rats. Insulin binding to the total particulate fraction was unaffected. These changes achieved maximum by 10-30 min and underwent complete reversal in 1 h. The decrease in insulin binding to Golgi fractions resulted exclusively from a change in receptor number and was accompanied by a 4- to 6-fold decrease in the content of extractable insulin in these fractions; the latter observation suggests that receptor internalization, rather than receptor synthesis, is diminished. The effects of diazoxide on plasma insulin concentration, insulin binding to Golgi fractions, and insulin content of Golgi fractions were fully prevented by tolbutamide, a stimulant of insulin secretion. These results show that acute hypoinsulinemias in rats are accompanied by changes in the subcellular distribution of hepatic insulin receptors that are opposite to those previously observed in acute hyperinsulinemias. Furthermore, both in acute hyperinsulinemic and hypoinsulinemic models, a significant correlation is observed between plasma insulin concentration on the one hand, and insulin binding to Golgi fractions as well as insulin content of Golgi fractions on the other. It is concluded that the extent to which hepatic insulin receptors are internalized is a function of their occupancy by endogenous hormone, and that, at least under acute conditions, receptor internalization is one major mechanism involved in receptor regulation.

Animals↗

PubMed1993

Modification of insulin resistance by diazoxide in obese Zucker rats.

Hyperinsulinism, insulin resistance, and decreased number of insulin receptors are characteristic of obesity in both humans and experimental animals. To assess the role of insulin in developing obesity, diazoxide (DZ), an inhibitor of glucose-stimulated insulin secretion, was administered for 8 weeks to 7-week-old female Zucker rats in two concentrations, 50 mg/kg.day (LD-DZ), and 100 mg/kg.day (HD-DZ). The obese and lean rats were divided into three subgroups: diazoxide (DZ), pair-fed (PF), and control (C) groups (n = 6 rats/subgroup-genotype). Diazoxide-treated obese and lean animals showed significantly lower postabsorptive plasma insulin concentrations (P < 0.005) than their respective obese and lean PF and C subgroups. HD-DZ obese rats consumed more calories (P < 0.001), yet gained less weight (P < 0.05) than PF and C rats. The plasma glucose concentrations in the postabsorptive state and during glucose tolerance tests in HD-DZ obese rats were significantly lower than those in PF and C rats (P < 0.01) despite a decrease in their plasma insulin concentrations (P < 0.01), whereas HD-DZ lean rats displayed a diabetic response (P < 0.01). The adipocyte-specific insulin receptor binding was dose-dependently increased in both lean and obese DZ animals (P < 0.01). DZ had a dual effect on insulin metabolism; it decreased insulin secretion and increased insulin receptor binding. This dual effect was associated with improved glucose tolerance and a decrease in weight gain in obese rats.

Adipose Tissue↗

PubMed2006

A rare case of adult-onset nesidioblastosis treated successfully with diazoxide.

A 54-year-old man was admitted to our hospital for evaluation of hypoglycemia. He had frequent episodes of loss of concentration before dinner. The ratio of IRI to plasma glucose (PG) was 0.8-1.0. Abdominal CT revealed no pancreatic tumor, and angiography of splenic artery showed no definite tumor stain within the pancreas. Based on the results of selective arterial calcium stimulation and hepatic venous sampling (ASVS), the provisional diagnosis was a small insulinoma in the pancreatic body. The patient underwent subtotal distal pancreatectomy. However, histopathological and immunohistochemical examinations of the resected tissue showed hypertrophy of islets of Langerhans islands and beta cells around pancreatic ducts. The final diagnosis was adult-onset nesidioblastosis. Postoperatively, the patient continued to exhibit hyperinsulinemia and nighttime hypoglycemia. Octreotide, voglibose and diet therapies failed to improve the nocturnal hypoglycemia. However, treatment with diazoxide at a starting dose of 200 mg/day resulted in immediate amelioration of nocturnal hypoglycemia. This is the first Japanese adult case of nesidioblastosis treated successfully with diazoxide. This case report suggests that diazoxide may be effective for adult-onset nesidioblastosis in a manner similar to that described for pediatric cases.

Angiography↗

PubMedDate not supplied

Long-term diazoxide treatment in persistent hyperinsulinemic hypoglycemia of infancy: a patient report.

Long-term diazoxide and somatostatin analogue have been used in the treatment of persistent hyperinsulinemic hypoglycemia of infancy albeit with some side effects. We report a case with persistent hyperinsulinemic hypoglycemia who has been on diazoxide therapy for 4.5 years. Diazoxide treatment maintained normoglycemia without causing any side effects, including hypertrichosis.

Blood Glucose↗

PubMed1999

Different effects of tolbutamide and diazoxide in alpha, beta-, and delta-cells within intact islets of Langerhans.

Interaction between the different types of cells within the islet of Langerhans is vital for adequate control of insulin release. Once insulin secretion becomes defective, as in type 2 diabetes, the most useful drugs to increase insulin release are sulfonylureas. It is well-known that sulfonylureas block K(ATP) channels, which results in depolarization of the membrane that provokes calcium influx and increases intracellular calcium concentration ([Ca2+]i), which thereby triggers insulin secretion. The sulfonamide diazoxide produces the opposite effect: it activates K(ATP) channels, resulting in a decreased insulin secretion. Despite such evidence, little is known about the effect of sulfonylureas and sulfonamides in non-beta-cells of the islet of Langerhans. In this article, we describe the effects of tolbutamide and diazoxide on [Ca2+]i in alpha-, beta-, and delta-cells within intact islets of Langerhans. Tolbutamide elicits an increase in [Ca2+li in beta- and delta-cells, regardless of glucose concentrations. Remarkably, tolbutamide is without effect in alpha-cells. When diazoxide is applied, glucose-induced [Ca2+]i oscillations in beta- and delta-cells are abolished, whereas [Ca2+]i oscillations in alpha-cells remain unaltered. Furthermore, the existence of sulfonylurea receptors is demonstrated in beta-cells but not in alpha-cells by using binding of glybenclamide-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) combined with immunostaining for insulin and glucagon.

Animals↗

PubMed2006

The mitochondrial K-ATP channel opener, diazoxide, prevents ischemia-reperfusion injury in the rabbit spinal cord.

Paraplegia resulting from ischemia is a catastrophic complication of thoracoabdominal aortic surgery. The current study was designed to investigate the effects of diazoxide (DZ) on mitochondrial structure, neurological function, DNA damage-repair, and apoptosis in spinal cord ischemia-reperfusion injury. Rabbits were subjected to 30 minutes of spinal cord ischemia and reperfusion (1 hour) with or without diazoxide (n = 6 in each group) by clamping and releasing the infrarenal aorta. The neurological functional score was significantly improved in the DZ-treated ischemia-reperfusion injury group. Electron microscopic studies demonstrated that mitochondrial damage in the spinal cord after injury was significantly reduced by DZ. Mitochondrial superoxide and hydrogen peroxide levels were also markedly decreased in the DZ-treated injury group compared with the untreated group. DZ decreased levels of the oxidative DNA damage product 8-oxoG and increased levels of the DNA repair enzyme OGG-1. Furthermore, DZ inhibited apoptosis via caspase-dependent and -independent pathways. These studies indicate for the first time that the mitochondrial K-ATP channel opener diazoxide improves neurological function after spinal cord ischemia and reperfusion by diminishing levels of reactive oxygen species, decreasing DNA oxidative damage, and inhibiting caspase-dependent and -independent apoptotic pathways while preserving mitochondrial structure.

Animals↗

PubMed1976

Angina-like syndrome with diazoxide therapy for hypertensive crisis.

In 14 patients with hypertensive crisis treated with diazoxide, close monitoring of blood pressure, heart rate, and symptoms was performed. Standard 12-lead electrocardiograms were recorded before and after diazoxide. All patients showed a significant fall in blood pressure after drug administration. Seven patients (50%) showed significant ST-T changes after diazoxide. Six patients (43%) developed substernal discomfort demonstrated by substernal pain of tightness. Five patients (35%) had both chest discomfort and ST-T changes. One of these patients with substernal pain and ST elevation had evidence of acute myocardial infarction with serial enzyme studies. In the patients with significant ST-T changes, the average fall in blood pressure was significantly greater than the average fall in blood pressure in the patients without significant ST-T changes. These findings suggest that both ST-T changes and substernal discomfort were due to myocardial ischemia secondary to a sudden severe drop in blood pressure.

Adolescent↗

PubMed1976

[Effect of diazoxide on blood pressure, PRA and plasma aldosterone in hypertensive patients (author's transl)].

Intravenous diazoxide (300 mg) was administered to 29 hypertensive patients previously classified in subgroups according to their plasma renin and urinary aldosterone levels. The blood pressure was measured before and periodically after injection and plasma renin activity (PRA) and plasma aldosterone before and after 2 hours. The mean systolic and diastolic blood pressure fell notably from 193/118 to 155 93 mmHg; whereas PRA increased from 7.51 to 13.21 ng/ml/3 hrs and plasma aldosterone did not change significantly (71.3 and 102.8 ng%). Examining the individual sub-groups, a significant decrease in blood pressure was observed in 15 patients with low, posture unresponsive PRA, both in subjects with normal urinary aldosterone and those with surgically proven primary aldosteronism. In the former only the mean PRA showed a slight but sigificant increase, while in the latter the changes for both PRA and aldosterone were not significant. In the subgroups of patients with normal renin and urinary aldosterone the arterial pressure also significantly and promptly decreased. However, in this group the mean PRA substantially increased whereas the plasma aldosterone levels remained constant. The same blood pressure decline was observed in those patients with high PRA and aldosterone, including 1 case of pheocromocytoma. The mean PRA showed a further modest increase while the plasma aldosterone did not change significantly. These results indicate that the antihypertensive action of diazoxide is similar in the different types of hypertension (volume, vasoconstrictor or mixed form according to Laragh's classification), being independent of the basal plasma renin and aldosterone levels. Furthermore, the response of the blood pressure to diazoxide is not related in any way to the induced changes in PRA and plasma aldosterone values.

Adrenal Gland Neoplasms↗

PubMed1975

Verapamil and diazoxide antagonism of agonist-induced contractions of aortic strips from normal and spontaneously hypertensive rats (SHR).

The vulnerability of aortic strips from 50-52 week old Spontaneously Hypertensive Rats (SHR) and normotensive Wistar-Kyoto (WKY) controls to the inhibitory or relaxing effects of the calcium antagonists verapamil and diazoxide was studied. Verapamil produced concentration-dependent inhibition (antagonism) of KCl, PGE2, and methoxamine-induced contraction of aortic strips from SHR and WKY. KCl and PGE2-induced contraction of SHR tissue were less readily antagonized by verapamil compared to WKY preparations. The reverse was seen with methoxamine-induced contraction. The slope of the verapamil inhibition curve of KCl-induced contraction was significantly steeper for aortic strips form WKY. Verapamil and diazoxide also produced concentration-dependent relaxation of KCl-induced contraction of aortic strips, no significant differences being noted in SHR and WKY responses. Results are compatible with the hypothesis that arterial smooth muscle from SHR is characterized by a more tightly bound pool or source of activator Ca++ which is released by certain agonists. Failure to observe a significant difference in verapamil or diazoxide induced relaxation of KCl contracted tissues from SHR or WKY suggests that in the tonic phase of KCl contraction, transmembrane fluxes of Ca++ in SHR and WKY are equally vulnerable to the Ca++ channel inhibitory effect of the antagonists.

Animals↗

PubMed1975

Diazoxide in the management of severe hypertension.

Fourteen patients with severe hypertension have been given i.v. diazoxide in a dosage of 5 mg/kg b.wt. The material comprised 2 patients with malignant nephrosclerosis, 4 with chronic nephropathy and severe reduction of renal function, 1 patient with chronic pyelonephritis, 1 with renovascular hypertension and 6 patients with essential hypertension and in malignant phase. All patients attained a controllable blood pressure. Eight patients remaining needed only one injection, while the remaining patients required 2-5 injections, and concomitant furosemide therapy. The retinopathy improved in most patients and renal function was unchanged in the azotemic patients. No serious adverse effects were seen, except one hypotensive episode. Diazoxide is easy to handle, dosage can be predetermined, monitoring is simple and we find diazoxide to be a valuable drug in severe hypertension.

Adult↗

PubMed1975

[Diazoxide test in the diagnosis of arterial hypertension: modifications in the levels of renin and aldosterone in blood of patients with various restrains of the renal function].

The AA. have applied the diazoxide test for the screening of primary hiperaldosteronism to 22 nephropatic patients suffering from hypertension and with different degrees of renal function. In 22 patients an increase in PRA and aldosterone values always followed the diazoxide infusion. Only one patient, likely suffering from primary aldosteronism, showed no increase in PRA and aldosterone values. The diazoxide infusion had no influence on renal, pancreatic and cardiovascular function. Therefore, this can be considered as a valid test easy to be performed in a short time, also in nephropatic patients who are very sensitive to pharmacological noxae.

Adolescent↗

PubMed2004

[Fluorine-containing analog of diazoxide prevented apoptosis in neonatal cardiomyocytes during anoxia-reoxygenation].

In experiments on the primary culture of isolated neonatal rat cardiomyocytes it was established that anoxia-reoxygenation activated the process of programmed cell death, apoptosis. The amount of apoptotic cells (defined by fragmentation of a nucleus with Hoechst 33342 staining) during anoxia-reoxygenation was increased in 2.1 fold (P < 0.05). The amount of living and necrotic cells was not changed significantly. Apoptosis of neonatal cardiomyocytes during anoxia-reoxygenation was prevented by activation of ATP-dependent potassium (K(ATP)) channels with diazoxide. Synthesized by us the fluorine-containing analogue of diazoxide had the similar effect: the amount of apoptotic cells was decreased to 3.7% that was similar to control meaning. Application of glybenclamide, which completely abrogated the action of diazoxide and its fluorine-containing analogue, allows us to assert that antiapoptotic effect of the substances mentioned above depends on K(ATP) channels opening.

Animals↗

PubMed1988

Diazoxide-induced long-term hyperglycemia. I. Preservation of B-cell insulin-releasing capacity.

Although several models of experimental diabetes mellitus are currently available, none of them appears to be optimally suited to study the possible deleterious effect of sustained hyperglycemia upon biochemical and functional variables in pancreatic islet cells in the absence of chronic stimulation of secretory activity. In the present study, oral diazoxide administration (0.33 g/Kg body wt. thrice per day for three days) to rats was used to cause both hypoinsulinemia and hyperglycemia (greater than or equal to 10.0 mM), the latter persisting, albeit at a somewhat lower level, for at least 1-2 days after cessation of diazoxide treatment. Ten hours after the last administration of diazoxide, the secretory response of isolated islets to D-glucose over 90 min incubation was not impaired. It is proposed that such a model may help to dissociate the influence of hyperglycemia itself upon islet cell behaviour from the consequences of sustained hypersecretion of insulin.

Animals↗