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PubMed1981

Cardiovascular effects of dihydralazine diazoxide and minoxidil alone or associated with propranolol in renal hypertensive rats.

Cardiovascular effects after intravenous administration of dihydralazine (0.5 mg/kg), diazoxide (10 mg/kg) and minoxidil (1 mg/kg) were studied in normotensive (NT) and renal hypertensive rats (HT) pretreated or not for seven consecutive day with propranolol (5 mg/kg per os). The hypotension induced by the three vasodilators in NT and HT rats was caused by decreased peripheral resistance and, in the case of minoxidil in HT rats by decreased cardiac output as well. Propranolol pretreatment of HT rats decreases the hypotensive effect induced by the three vasodilators. In the cases of dihydralazine and diazoxide, this effect is due to a lesser decrease of peripheral resistance; with minoxidil, it results from the absence of decreased cardiac output. Pretreatment of hypertensive rats with propranolol (5 mg/kg per os) for one week had no effect on blood pressure, but decreased heart rate and cardiac output and increased peripheral vascular resistance. Despite these cardiovascular modifications, the reactiveness to intravenous isoprenaline (1 to 4 microgram/kg) was the same in control and propranolol pretreated animals.

Animals↗

PubMed1978

[Hemodynamics and metabolic parameters during use of the antihypertensive agent diazoxide].

The antihypertensive remedy diazoxide (hyperstat) was applied in 11 patients with hypertension of the clinical stages III and IV. The patients were applied a single intravenous injection of 20 ml = 300 mg diazoxide. The behaviour of blood pressure, pulse, blood sugar and cortisol level as well as of the blood supply in rest of the musculature of the extremities was tested and evaluated. Within 1 minute after the injection the systolic blood pressure decreased by 12%, the diastolic by 20%. After an above all show increase of the diastolic blood pressure once more a slight decrease of the systolic blood pressure followed after 90 minutes, which lasted several hours. Also after 24 hours the blood pressure did not reach the original value. The increase of the pulse rate was clinically not relevant. The blood glucose increased in the 5th minute, after 15 minutes it reached its culmination point and, beginning with the 30th minute it showed a decreasing tendency. The initial values were got after 180 minutes. After the 15th minute began a relative short-term decrease of the plasma cortisol, which, however, again increased after 60 minutes. On the other hand the occlusion-plethysmographic investigations of the veins showed an increasing blood flow in rest up to 3 hours after the injection.

Adult↗

PubMed1995

[Potassium channel activators: comparative structural study of pinacidil, diazoxide and cromakalim].

A conformational analysis has been performed with SYBYL starting from the energy optimized (Tripos force field) X-ray conformation of (R,S)-pinacidil. The geometry of four selected low energy conformers has been reoptimized using the AM1 semiempirical Molecular Orbital method (MOPAC 5.0), and the total energy of the optimized conformers has been compared. In spite of an apparent structural dissimilarity, a good analogy has been found between the calculated isopotential map of diazoxide and that of at least one selected low energy conformer of pinacidil. It has been suggested that, unlike cromakalim, the low but observable activity of pinacidil on pancreatic B-cells could be explained by adoption for this compound of a conformation having a diazoxide-like stereoelectronical imprint which could assume a similar interaction on the same biological receptor.

Antihypertensive Agents↗

PubMed1975

Oral diazoxide contraindicated in severe hypertension with renal failure.

Diazoxide was given orally to nine hypertensive patients with renal failure and its effect on blood pressure and on glucose metabolism was studied. There was no long-term antihypertensive effect. During treatment insulin release and glucose assimilation after an intravenous glucose load were frankly impaired, but this impairment was reversible after stopping the treatment. Two major complications (diabetic ketoacidosis and pancreatitis) were observed. In view of these observations, the authors are of the opinion that oral diazoxide is contraindicated in the treatment of hypertension in patients with renal failure.

Acute Disease↗

PubMed1977

The management of severe preeclampsia and eclampsia with intravenous diazoxide.

Twelve patients with either severe preeclampsia (9) or eclampsia (3) were treated with intravenous diazoxide, 300-mg bolus, for the reduction of diastolic blood pressure (less than or equal 110 torr) after the usual and customary measures had been initiated to include parenteral MgSO4 and diazepam. Diazoxide precipitously decreased both systolic and diastolic blood pressure proportionately (35-50%); the nadir was invariably reached in 5-15 minutes. Diastolic pressure never fell below 50 torr, and mean arterial pressure always exceeded 70 torr. Oliguria was not apparent. The vasodepressor response was fairly persistent for 4 hours in all but 3 patients; 2 of these received a second 300-mg dose. Significant changes in fetal heart activity (bradycardia, dysrhythmia) were observed in only 1 patient. Labor was immediately ablated in all patients, but could be restimulated with oxytocin. All pregnancies were terminated within 7 hours (mean, 3.7 hours), seven of them by cesarean section. Eleven newborns did well. We conclude that the immediate reduction in maternal arterial blood pressure is without apparent hazard to the mother as well as the fetus.

Adolescent↗

PubMed1998

The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury.

The diazoxide derivative IDRA 21 and other positive modulators of (AMPA)-type glutamate receptors are considered potential memory-enhancing agents. However, AMPA receptor activation contributes to CA1 hippocampal neuron damage from global ischemia in rodents, raising the possibility that 7-chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21) or drugs with similar actions may worsen ischemic neuronal injury. Here we demonstrate that glutamate plus IDRA 21 kills cultured rat hippocampal neurons by AMPA receptor activation, and, in vivo, 12 and 24 mg/kg of IDRA 21 given orally increases CA1 neuron loss produced by 10 minutes of global ischemia. Treating patients with drugs that potentiate AMPA receptor activation will have to consider these potential effects, particularly when coexistent with conditions in which excessive activation of AMPA receptors may occur (eg, stroke, seizures).

Animals↗

PubMed1976

[Leucine sensitive hypoglycemia. Follow-up studies under treatment with diazoxide (author's transl)].

Since 1969 leucine sensitive hypoglycemia has been diagnosed in 4 infants. Elevated serum insulin levels suggested hyperinsulinism; in 1 infant islet cell hyperplasia was demonstrated by morphological examination of pancreatic tissue. All cases were treated with diazoxide and have been followed under therapy for periods ranging from 4 months to 6 1/4 years. The upper limit of dosage was 15 mg/kg. The blood glucose values promptly became normal in 2 infants under this regimen. The development of these patients was normal. In the 2 other infants treatment was effective only after the additional restriction of daily protein intake to 2-2.5 g/kg. Severe cerebral damage occurred in one of these infants due to recurrent episodes of hypoglycemia, causing further development to be considerably restricted; the other one developed satisfactorily but with moderate mental retardation. Both children are suffering from cerebral convulsions. In all patients hypertrichosis was the only side effect.

Blood Glucose↗

PubMed2004

Diazoxide prevents mitochondrial swelling and Ca2+ accumulation in CA1 pyramidal cells after cerebral ischemia in newborn pigs.

Diazoxide (DIAZ), an opener of mitochondrial ATP-sensitive K(+) channels (mK(ATP)), protects neurons against hypoxic/ischemic stress in vivo, however, direct evidence showing mitochondrial effects of DIAZ in postischemic neurons is lacking. We investigated if DIAZ affects mitochondrial alterations after global ischemia/reperfusion (I/R) in CA1 pyramidal neurons by using oxalate-pyroantimonate electron cytochemistry. Anesthetized piglets were either non-treated, or treated with DIAZ (3 mg/kg, iv), I/R, DIAZ+I/R, or 5-hydroxy-decanoate (5HD)+DIAZ+I/R (n=6, 6, 11, 5, 7, respectively). Ischemia (10 min) was induced by intracranial pressure (ICP) elevation. After 5-30 min of reperfusion, the brains were fixed for ultrastructural studies. Relative volumes of Ca(2+)-containing deposits and mitochondria in CA1 pyramidal cells were determined by point counting on electron micrographs. I/R resulted in maximal increases in mitochondrial volume (from 7.14+/-0.63% to 9.74+/-0.57%*), and Ca(2+) levels (from 5.86+/-1.11% to 11.39+/-1.35%*; mean+/-S.E.M., *p<0.05) at 10-15-min reperfusion time. In this interval, pretreatment with DIAZ virtually abolished mitochondrial swelling (6.88+/-0.49%) and Ca(2+) accumulation (5.15+/-0.82%) evoked by I/R. The protective effect of DIAZ was reduced by 5HD, an inhibitor of mK(ATP), resulting in a calcium accumulation similar to that after IR (10.44+/-1.98%). Thus, DIAZ might preserve mitochondrial integrity in CA1 pyramidal cells after I/R, at least in part mediated by mK(ATP).

Animals↗

PubMed2004

Effect of diazoxide on regulation of vesicular and plasma membrane GABA transporter genes and proteins in hippocampus of rats subjected to picrotoxin-induced kindling.

Epileptiform discharges and behavioral seizures may be the consequences of excess excitation from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). GABA is taken up and accumulated in synaptic vesicles by the action of vesicular GABA transporter (VGAT) before its release into the synaptic cleft, and removed from synaptic regions by the action of transporter proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, the effects of diazoxide (DIZ) on the VGAT, GAT-1 and GAT-3 mRNA and protein levels in hippocampus, and on the seizure activities of picrotoxin (PTX)-induced kindling rats were observed. DIZ caused increase in the quantity of VGAT mRNAs and proteins, and down regulation of GABA transporters GAT-1 and GAT-3 mRNAs and proteins after the PTX re-kindling. Furthermore, DIZ produced not only a prompt but also a later suppression of PTX-induced seizures. Although DIZ has effects on ATP-sensitive potassium (K(ATP)) channels when measured in vitro, our study suggests that additional mechanisms of action may involve the regulation of GABA transporters, which may aid in understanding epileptogenesis and inform investigators about future design and development of K(ATP) channel openers to treat epilepsy.

Animals↗

PubMed1996

Antiobesity effect of diazoxide in obese Zucker rats.

Hyperinsulinism and insulin resistance are characteristic findings in obese subjects. Obesity in both humans and experimental animals is associated with a reduced number of insulin receptors and a decreased insulin-mediated glucose disposal, whereas sensitivity to insulin's antilipolytic action is unaltered. To evaluate the antiobesity effect of diazoxide (DZ), an inhibitor of glucose-stimulated insulin release, 7-week-old Zucker obese and lean rats were studied. Obese and lean rats were grouped into DZ-treated (150 mg/kg/d) and control (C) groups. DZ-treated obese rats consumed similar amounts of calories per kilogram body weight (BW) compared with C obese animals, but gained less weight (P<.01). Postabsorptive plasma free fatty acids (FFA), cholesterol, and triglycerides were significantly higher in obese versus lean animals (P<.01). DZ treatment reduced plasma triglyceride levels in obese animals (P<.001), but had no significant effect on FFA or cholesterol concentrations. Plasma glucose concentrations in the postabsorptive state and during glucose tolerance tests (GTTs) were significantly lower in DZ obese versus C obese rats (P<.01) despite a decrease in plasma insulin concentrations in DZ-treated animals (P<.01). In contrast, DZ lean rats developed glucose intolerance (P<.05). Sensitivity and responsiveness to the antilipolytic effect of insulin in isolated adipocytes were significantly decreased in DZ obese as compared with C obese rats (P<.01). Moreover, adipocyte specific insulin receptor binding was increased in both DZ lean and DZ obese animals (P<.01). This was accompanied by increased basal and insulin-stimulated glucose transport in both genotypes (P<.01). In conclusion, DZ increased insulin receptor binding and glucose transport while decreasing hyperinsulinemia and insulin sensitivity to the antilipolytic action of insulin. This combined effect resulted in improved glucose tolerance and a decrease in weight gain in obese rats, implying that pharmacologic modification of the disturbed insulin metabolism of obesity may be therapeutically beneficial.

Adipocytes↗

PubMed2001

Diazoxide effects on hypothalamic and extra-hypothalamic NPY content in Zucker rats.

To determine if the anorectic effects of the insulin antagonist diazoxide (DZ) are mediated by reduced central neuropeptide Y (NPY), female Zucker rats, given DZ (150 mg/kg/day) or placebo for about four weeks, were sacrificed following overnight fasting or free feeding. Several hypothalamic and extra-hypothalamic nuclei were extracted for NPY content. DZ reduced weight gain in obese rats and lowered glucose of lean and obese rats without affecting insulin. Contrary to the hypothesis, DZ increased NPY in hypothalamic nuclei of free fed lean and obese rats. DZ elevated hypothalamic NPY levels in fasted obese rats and had more diverse effects in extra-hypothalamic nuclei of lean rats.

Analysis of Variance↗

PubMed2000

Modulation of kainate--activated currents by diazoxide and cyclothiazide analogues (IDRA) in cerebellar granule neurons.

1. Patch-clamp technique was used in primary cultures of cerebellar granule neurons to study the modulation of the cyclothiazide analogue (IDRA21) and of the diazoxide derivative (IDRA 5) on KA-evoked currents. 2. The dose-response of kainic acid (KA) reveals an EC50=90 microM and an Hill coefficient of 1.3. IDRA 21 and cyclothiazide potentiate KA-evoked current in a dose dependent way, being cyclothiazide more potent but less efficacious than IDRA 21. Conversely IDRA 5 acts as a negative modulator of KA evoked -current. 3. Application of IDRA 21 and cyclothiazide results in a current potentiation of 125+/-18% and 80+/-12% respectively, while IDRA 5 decreases KA-current (-21+/-5%). Coapplication of cyclothiazide and IDRA 21 produces a potentiation of 110+/-17%, suggesting a competition of the two drugs for the same site. 4. In the same experimental model we studied the ability of IDRA compounds of promoting toxicity through AMPA-receptor activation. Under basal conditions AMPA treatment (50 microM for 1 hour) results in a negligible excitotoxicity. 5. In contrast similar treatment with AMPA + IDRA 21 (1 mM) or + IDRA 5 (1 mM) or + cyclothiazide (100 microM) induces citotoxicity. The neurotoxic damage induced by IDRA 21 and cyclothiazide is blocked by GYKI 53655 (50 microM) and by NBQX (10 microM). Interestingly GYKI and NBQX are ineffective in reducing IDRA 5 toxicity.

Action Potentials↗

PubMed2004

[Hyperinsulinism-hyperammonemia syndrome due to a de novo mutation in exon 7 (G979A) of the glutamate dehydrogenase gene with excellent response to diazoxide].

Hyperinsulinism-hyperammonemia syndrome is characterized by recurrent and symptomatic hypoglycemias in childhood, secondary to hyperinsulinism associated with mild and asymptomatic hyperammonemia. This syndrome is caused by dominantly expressed mutations of the glutamate dehydrogenase gene (10q23.3). These mutations modify control of enzyme activity and represent the second cause of congenital hyperinsulinism of known genetic etiology. Moreover, this syndrome is the first genetic disorder due to an increase of function in an enzyme of intermediary metabolism to have been identified. We present the case of a 16-month-old boy with symptomatic recurrent hypoglycemias from the end of the first year of life, caused by a de novo mutation in exon 7 (G979A) of the GDH gene, with excellent outcome after diazoxide treatment.

Diazoxide↗

PubMed1991

Attenuated anomeric difference of glucose-induced insulin release in the perfused pancreas of diazoxide-treated rats.

Mild hyperglycemia was induced in normal rats by oral administration of both diazoxide and D-glucose. After 48 hours of such a treatment, the insulin and glucagon secretory responses of the perfused pancreas to alpha- and beta-D-glucose (3.3 mM) were examined in the presence of 10.0 mM L-leucine. The output of insulin, but not that of glucagon, and the perfusion pressure were higher in treated than control rats. The alpha-anomer of D-glucose was a more potent insulin secretagogue than beta-D-glucose in both control and treated rats. However, the alpha/beta ratio in insulin output was twice higher in control than treated rats. By analogy with other experimental models of diabetes, the attenuation in the anomeric difference of glucose-stimulated insulin output in the treated rats could reflect an altered secretory response to alpha- rather than beta-D-glucose. These findings suggest that hyperglycemia provokes, as a function of its severity and duration, first attenuation and then suppression, if not inversion, of the anomeric preference for alpha-D-glucose in insulin release. They are also compatible with the hypothesis that the anomeric malaise, associated with B-cell glucotoxicity, is caused by a progressive accumulation of glycogen in this cell.

Administration, Oral↗

PubMed1993

Diazoxide suppresses slowly-inactivating outward and inward currents in CA1 hippocampal neurones.

Diazoxide (DZX) opens ATP-sensitive K (KATP) channels in muscle and other cells. In whole-cell voltage-clamp recordings in slices, in the presence of kynurenate and bicuculline to minimize indirect effects, DZX (0.65 mM) did not increase input conductance; but it sharply reduced persistent inward and outward currents. An inward current (peak near -20 mV) was especially clear in the presence of K channel blockers; was fully evident in Ca-channel blocking medium; but was abolished by tetrodotoxin. The main direct effects of DZX on these neurones are thus mediated not by activation of KATP channels, but rather by modulation of voltage-dependent channels, including a TTX-sensitive persistent NA current and possibly a Ca current.

Animals↗

PubMed2004

Diazoxide and N omega-nitro-L-arginine counteracted A beta 1-42-induced cytotoxicity.

K(+) channel openers can activate K channels and have been shown to protect cultured neurons against excitotoxicity. Our study showed that diazoxide, a K(+) channel opener, could counteract the effects of A beta(1-42) and protect cells from A beta(1-42)-induced the increasing of mitochondrial membrane potential and the associated increase in intracellular reactive oxygen species levels; an inducible nitric oxide synthase inhibitor, N omega-nitro-L-arginine could protect cells from A beta(1-42)-induced the increasing of both mitochondrial membrane potential and intracellular reactive oxygen species levels. A 24 h exposure to A beta(1-42) did not result in apoptosis, suggesting that the increase in both mitochondrial membrane potential and reactive oxygen species levels preceded cell apoptosis or death.

Amyloid beta-Peptides↗

PubMed1975

Hypertrichosis due to diazoxide.

Two cases of hypertrichosis due to diazoxide are described. The mechanism is unknown bu may be due either to increased cutaneous perfusion or to increased levels of cyclic AMP.

Aged↗

PubMed1976

Diazoxide-induced renin release in diagnosis of remediable renovascular hypertension.

In hypertensive patients with unilateral renal artery stenosis, intravenous diazoide increased renal vein renin activity more on the involved side than on the contralateral side, whereas, in a group with predominantly unilateral renal parenchymal disease, the increase in renal vein was similar for both kidneys. In patients with bilateral renal artery stenosis, the use of diazoxide was helpful in lateralizing the dominant ischaemic lesion. Diazoide administration appears to be a safe, rapid and convenient method of increasing the sensitivity of the renal vein renin test used in predicting the outcome of surgical treatment of renovascular hypertension. Bilateral renal vein renin determination of established value in the diagnosis of functional renal ischaemia. 1-4 However, in the use of this procedure to predict the efficacy of corrective surgery, false positive and false negative results still occur. Thus, various manoeuvres which stimulate renin release have been employed to improve the sensitivity of the test. 5-7 We report a new application the practical approach to of this procedure in the diagnosis of renal hypertension, which both basal and stimulated levels of renal venous renin activitity can be measured during a brief period of bilateral renal vein catherization.

Adolescent↗