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At least 217 records · Page 12Linked to original sources

PubMed1976

Prolonged infusion of diazoxide in the management of premature labor in the baboon.

The management of premature labor by the prolonged infusion of diazoxide was evaluated in 33 pregnant baboons. The drug was administered intravenously to the mother with an average rate of 0.065 mg/kg/min for 4 hours. Mild to moderate spontaneous labors were significantly inhibited by diazoxide without jeopardizing the fetus. Diazoxide produced a significant increase in maternal heart rate, but its effect on fetal circulation was minimal. Fetal acid-base state and arterial oxygenation remained essentially unchanged throughout the period of observation. Intravenous administration of this drug to the fetuses caused only mild cardiovascular changes irrespective of its preexisting conditions. Thus, a slow intravenous infusion of diazoxide to the mother in a low dosage appears to be of value for inhibiting the uterine activity in early labor, without interfering with the fetal well-being.

Amniotic Fluid↗

PubMed1979

Use of a simulation model to study the acute haemodynamic effects of diazoxide in man.

The acute haemodynamic effects of injected diazoxide (Hyperstat Schering) have been studied in 8 hypertensive subjects. Aortic blood pressure was measured and cardiac output and peripheral conductance were assessed continuously using a simulation model. In six of the patients pulmonary artery end-diastolic pressure was also measured. Blood pressure fell in all subjects 5-10 min after injection of the drug cardiac output increased in all patients studied. however, the initial change in cardiac output differed, as it decreased in two subjects and did not change in one. The largest initial increases in cardiac output were seen in the subjects with the highest pulmonary artery end-diastolic pressure. Patients with an initial decrease in cardiac output were those with the least compliant (stiffest) aortas. We consider that the responsiveness of the baroreceptors determines the size of the increase in cardiac output immediately after reduction of blood pressure by diazoxide. Thus in a patient with a stiff aorta, particularly at low cardiac filling pressure, diazoxide might cause a fall in blood pressure to an unacceptable level.

Adult↗

PubMed1983

Antihypertensive effect of diazoxide given intravenously in small repeated doses.

Seven patients with acutely elevated diastolic blood pressure (DBP greater than or equal to 135 mmHg) were treated with repeated injections of diazoxide 1 mg/kg body weight i.v. at 10-min intervals. If the DBP was not reduced to 110 mmHg or less after 5 injections, a dose of 5 mg/kg was given. Serum diazoxide (total and unbound) was determined by high pressure liquid chromatography. In all the patients it was possible to reduce the blood pressure to a satisfactory level (i.e. DBP less than 110 mmHg). The individual plasma diazoxide concentrations necessary to achieve the desired response ranged from 20 to 85 micrograms/ml. A significant correlation was found between the initial venous concentration and the initial reduction in blood pressure (p less than 0.02). A high initial concentration in venous blood was associated with high protein binding ("transport function", p less than 0.05), and so were the elimination half-lives, which ranged from 14.7 to 61.3 h ("depot function", p less than 0.05). It is concluded that the previously recommended therapy of injection of 5 mg/kg as a bolus should be given only to patients who do not respond to small repeated doses.

Adult↗

PubMed1990

Antineoplastic efficacy of melphalan and N-(2-chloroethyl)-N-nitrosocarbamoyl-omega-lysine, in combination with diazoxide or insulin in autochthonous mammary carcinoma of the Sprague-Dawley rat.

The anticancer activity of melphalan and N-(2-chloroethyl)-N-nitrosocarbamoyl-omega-lysine (CNC-omega-Lys), was compared in the autochthonous, methylnitrosourea-induced mammary carcinoma of the Sprague-Dawley rat. In addition, the influence on the therapeutic efficacy of the combination with diazoxide, causing a mild, reversible diabetes, and with insulin was investigated. The comparison of melphalan and CNC-omega-Lys clearly showed the superiority of melphalan. Both compounds displayed a significant tumour inhibition in their medium and the highest dosages in comparison to the untreated control. The combination with diazoxide resulted for almost all groups in an increased tumour inhibition. Only the lowest dose of CNC-omega-Lys + diazoxide did not reduce the tumour volume significantly versus the control group. The combination with insulin, however, resulted in a loss of tumour inhibition compared to the effect of the cytotoxic drug alone, although in these groups, too, a significant decrease of tumour volumes versus controls could be observed. Mortality was within tolerable limits (less than 20%) through the treatment period for all experimental groups. Median lifespans were increased in all therapy groups, but no additional benefit could be observed in the combination treatment groups.

Animals↗

PubMed1990

Effects of cromakalim, RP49356, diazoxide, glibenclamide and galanin in rat portal vein.

The study investigated the possible involvement of an ATP-sensitive potassium (K) channel in the relaxant actions of K channel openers in rat portal vein. The effects of glibenclamide on the relaxant responses and rises in 86Rb efflux evoked by cromakalim, RP49356 and diazoxide were studied. The effects of galanin and depletion of intracellular ATP concentrations [( ATP]i) were also examined. Galanin increased mechanical activity and 86Rb efflux, effects most likely mediated via galanin receptors rather than a direct action on a K channel. Glibenclamide inhibited the relaxant responses and rises in 86Rb efflux evoked by cromakalim, RP49356 and diazoxide. Reduction of [ATP]i caused relaxation and this effect was partially reversed by glibenclamide. The restored activity was abolished by cromakalim. These results suggest that an ATP-sensitive K channel is present on rat portal vein and that it may be involved in the relaxant actions of cromakalim, RP49356 and diazoxide.

Adenosine Triphosphate↗

PubMed1995

Diazoxide blocks the morphine induced lengthening of action potential duration on guinea-pig papillary muscle.

1. Intracellular microelectrodes were used to evaluate the possible involvement of potassium currents in the action potential prolongation induced by morphine. To this purpose we investigated the electrophysiological effect of morphine on the isolated guinea pig right ventricular papillary muscle in the presence of the potassium channel opener and inhibitor diazoxide and glibenclamide respectively. 2. Diazoxide (1 microM), which is devoid of effect on its own, blocks the lengthening of action potential duration (APD) induced by morphine (5 mM). 3. However, in the presence of glibenclamide (1 microM), morphine (5 mM) prolonged APD in approximately the same proportion as that observed when used alone. 4. These results suggest that diazoxide but not glibenclamide sensitive potassium channels could mediate the APD prolongation induced by morphine.

Action Potentials↗

PubMed1997

Pre-synaptic effect of the ATP-sensitive potassium channel opener diazoxide on rat substantia nigra pars reticulata neurons.

Spontaneous synaptic currents were recorded from visually identified substantia nigra pars reticulata (SNR) neurons in the rat brain slice preparation by whole-cell patch clamp technique. GABA neurons were distinguished from dopamine neurons by their electrophysiological characteristics. In the presence of 20 microM AP5 and CNQX, the spontaneous synaptic currents recorded from GABA neurons were sensitive to bicuculline and reversed polarity at a potential close to the equilibrium potential of Cl-, indicating that they were mediated by GABA(A) receptors. TTX at 1 microM eliminated action potential-dependent release of GABA from nerve terminals, revealing the miniature inhibitory post-synaptic currents (mIPSCs). The ATP-sensitive potassium channel (K(ATP) channel) opener diazoxide (30-300 microM) significantly reduced the frequency of the mIPSCs in a dose-dependent manner. However, diazoxide did not affect the average value and the distribution of the mIPSC amplitudes. Thus, this effect of diazoxide was pre-synaptic in nature. The K(ATP) channel blocker glibenclamide (300 microM) was able to restore the frequency of the mIPSCs. These data suggest that the striatonigral projection, which represents the major inhibitory input controlling SNR GABA neuron activities, possesses presynaptic K(ATP) channels on the nerve terminals.

Adenosine Triphosphate↗

PubMed1999

Role of nitric oxide in the cerebral circulation during hypotension after hemorrhage, ganglionic blockade and diazoxide in awake goats.

The role of nitric oxide in cerebrovascular response to hypotension was analyzed by evaluating the changes in cerebrovascular resistance after inhibition of nitric oxide synthesis with Nw-nitro-L-arginine methyl ester (L-NAME) during three types of hypotension in conscious goats. Blood flow to one brain hemisphere was electromagnetically measured, hypotension was induced by controlled bleeding, and by i.v. administration of hexametonium (ganglionic blocker) or of diazoxide (vasodilator drug), and L-NAME was injected by i.v. route (35 mg kg-1). Under control conditions (13 goats), L-NAME increased arterial pressure from 98 +/- 3 to 123 +/- 4 mmHg and decreased cerebral blood flow from 65 +/- 3 to 40 +/- 3 ml min-1 (all P < 0.001); cerebrovascular resistance increased from 1.52 +/- 0.04 to 3.09 +/- 0.013 mmHg ml-1 min-1 (P < 0.01) (delta = 1.59 +/- 0.12 mmHg ml-1 min-1). After bleeding (five goats), mean arterial pressure decreased to 60 +/- 4 mmHg and cerebral blood flow decreased to 37 +/- 4 ml min-1 (all P < 0.01); cerebrovascular resistance did not change (1.56 +/- 0.14 vs. 1.54 +/- 0.12 mmHg ml-1 min-1, P > 0.05). During this hypotension, L-NAME increased arterial pressure to reach the normotensive values an did not affect the hypotensive values for cerebral blood flow; cerebrovascular resistance increased from the hypotensive values to 2.91 +/- 0.19 mmHg ml-1 min-1 (P < 0.01) (delta = 1.37 +/- 0.16 mmHg ml-1 min-1), and this increment is comparable to that under control conditions (P > 0.05). Ganglionic blockade (six goats) decreased arterial pressure to 67 +/- 2 mmHg) and did not affect significantly cerebral blood flow; cerebrovascular resistance decreased from 1.71 +/- 0.11 to 1.05 +/- 0.09 mmHg ml-1 min-1 (P < 0.01). During this hypotension, L-NAME increased arterial pressure to 103 +/- 6 mmHg (P < 0.001), and did not affect cerebral blood flow; cerebrovascular resistance increased from the hypotensive values to 1.68 +/- 0.18 mmHg ml-1 min-1 (P < 0.01) (delta = 0.63 +/- 0.10 mmHg ml-1 min-1), and this increment was lower than under control conditions (P < 0.01). Diazoxide (six goats) decreased arterial pressure to 69 +/- 5 mmHg (P < 0.01) without changing cerebral blood flow; cerebrovascular resistance decreased from 1.89 +/- 0.11 to 1.16 +/- 0.14 mmHg ml-1 min-1 (P < 0.01). During this hypotension, L-NAME increased arterial pressure to 87 +/- 6 mmHg (P < 0.05) and did not affect the hypotensive values for cerebral blood flow (P > 0.05); cerebrovascular resistance increased from the hypotensive values to 1.53 +/- 0.13 mmHg ml-1 min-1 (P < 0.05) (delta = 0.36 +/- 0.06 mmHg-1 ml-1 min-1), and this increment was lower than under control conditions (P < 0.01). Therefore, the role of nitric oxide in cerebrovascular response to hypotension may differ in each type of hypotension, as this role during hemorrhagic hypotension may not change and during hypotension by ganglionic blockade or diazoxide may decrease. These differences may be related to changes in nitric oxide release as stimuli on the endothelium (shear stress and sympathetic activity) may vary in each type of hypotension.

Animals↗

PubMed1976

Improvement in insulin secretion in diabetes after diazoxide.

Diazoxide 5 mg/kg/day was administered to four normal subjects for five days and, together with insulin, to ten diabetic subjects for seven days. In every case there was a substantial increase in the insulin response to combined stimulation of the pancreatic beta cells with 1 mg of glucagon and 2 g of tolbutamide given intravenously. Similar increases were not seen in four diabetics who received placebo with insulin. It is likely that the observed improvements reflected increased insulin stores which resulted from diazoxide inhibition of insulin release. These findings suggest that poor insulin responses in diabetics may be due, at least in part, to chronic overstimulation of the beta cells. Pharmacological agents such as diazoxide, which inhibit glucose-induced insulin release, may have a place in preserving and restoring insulin secretion in diabetes.

Administration, Oral↗

PubMed1998

Verapamil- and cadmium-resistant stimulation of calcium uptake and insulin release by D-glucose in depolarised pancreatic islets exposed to diazoxide.

The possible activation by D-glucose of voltage-insensitive Ca2+ channels in rat pancreatic islets was investigated by measuring the release of insulin, as well as the net uptake and efflux of 45Ca, in islets incubated in the presence of 30 mM K+, 0.25 mM diazoxide and either 0.05 mM verapamil or 0.04 mM Cd2+. In the presence of verapamil, D-glucose (16.7 mM) stimulated, over 90-min incubation, both 45Ca net uptake and insulin release. Likewise, in prelabelled perifused islets, a rise in D-glucose concentration from 2.8 to 16.7 mM augmented both 45Ca outflow and insulin output. When the concentration of the hexose was raised from zero to 8.3 mM, in which case the glucose-induced stimulation of Ca2+ influx is thought to occur mainly at the intervention of voltage-insensitive Ca2+ channels, and when Cd2+ was used to selectively block L-type Ca2+ channels, a stimulation of both 45Ca efflux and insulin release was again observed in islets perifused, at high extracellular K+ concentration, in the presence of diazoxide. These findings support the view that, in depolarised islets in which the ATP-sensitive K+ channels are fully activated by diazoxide, the stimulation of insulin release by D-glucose might involve the gating of voltage-insensitive Ca2+ channels.

Animals↗

PubMed2002

Diazoxide and pinacidil uncouple pyruvate-malate-induced mitochondrial respiration.

We investigated the effects of K(ATP) channel openers diazoxide and pinacidil on the respiration rate and membrane potential (deltapsi) of rat heart mitochondria, oxidizing pyruvate and malate. Diazoxide and pinacidil (58.8-1348.3 microM) increased the V2 (-ADP) respiration rate accordingly by 13-208% and 30-273% and decreased the deltapsi by 2-17% and 6-55%. These effects were also similar in the respiration medium without K+. Moreover, carboxyatractyloside completely abolished diazoxide- and pinacidil-induced uncoupling, indicating a role for the mitochondrial adenine nucleotide translocase in this process.

Animals↗

PubMed2002

Diazoxide protects the rabbit heart following cardioplegic ischemia.

K(ATP) channels are present in sarcolemmal and mitochondrial membranes. This study tests the hypothesis that opening mitochondrial K(ATP) channels with Diazoxide (DZ) improves tolerance to cardioplegic ischemia during surgery. Twenty-two rabbit hearts were perfused with Krebs-Henseleit buffer (KHB) on a Langendorff apparatus and underwent 50 min of 37 degrees C global ischemia with St Thomas' cardioplegia (STCP). Hearts were divided into three groups. Ten (control) received no pretreatment. Seven (DZ) received 10 min of 30 microM DZ, a selective mitochondrial K(ATP) opener, in KHB before arrest with STCP containing 30 microM DZ. Five (5-HD + DZ) received 10 min of 100 microM sodium 5-hydroxydecanoate (5-HD), a selective mitochondrial K(ATP) channel blocker, followed by 10 min of 30 microM DZ and 100 microM 5-HD in KHB before arrest with STCP + 30 microM DZ + 100 microM 5-HD. LV developed pressure (LVDP), dP/dt and coronary flow (CF) were measured after 60 min of reperfusion. Diazoxide pretreatment significantly improved the recovery of LV function and coronary flow compared to control (LVDP: 49 +/- 5* vs. 31 +/- 4; +dP/dtmax 927 +/- 93 vs. 507 +/- 85 mmHg/sec*; CF 33 +/- 4 vs. 22 +/- 2 ml/min, *p < 0.05). Mitochondria K(ATP) channel blockade with 5-HD prevented DZ's salutary effect on the recovery of LV and vascular function. Diazoxide pretreatment protects the rabbit heart during cardioplegic ischemia by opening mitochondrial K(ATP) channels. Opening mitochondrial K(ATP) channels may be a new strategy for improving myocardial protection during cardiac surgery.

Animals↗

PubMed1975

Effect of diazoxide on renal handling of sodium in the rat.

1. To assess whether diazoxide-induced sodium retention is due to a direct renal action of the durg, independent of its systemic haemodynamic effects, diazoxide was infused directly into one renal artery of hydropenic rats. During the infusion period there was a small fall in mean systemic arterial blood pressure. There were no significant changes in the clearances of inulin or p-aminohippurate by either kidney. 2. Absolute and fractional excretion of sodium were unchanged on the non-infused side. On the side of infusion, there was a significant increase in absolute and in fractional sodium excretion. 3. Thus natriuresis rather than sodium retention seems to be the direct renal effect of diazoxide and may be related to its vasodilator properties.

Aminohippuric Acids↗

PubMed1976

Stimulation of renin secretion by frusemide and diazoxide in the isolated rat kidney.

1. The effect of diazoxide (17-3 micronmol min-1 g-1) and frusemide (0-12 micronmol min-1 g-1) on renin secretion was examined in the isolated perfused rat kidney. These substances are potential renal vasodilators with opposite effects on urine sodium excretion. 2. Both agents significantly increased renin secretion rate above control values. In the case of frusemide this was not altered by ureteric occlusion and presumed absence of urine flow. 3. Mean renal perfusion pressure decreased to the same extent with diazoxide and frusemide infusion as in the control experiments and no additional vasodilatory effect was observed on the basis of changes in flow rate of perfusate. 4. These observations identify an intrarenal site of action for diazoxide and frusemide on renin secretion. The apparent independence of this stimulatory action on renal vasodilation and urine flow suggests a direct effect on the renin-producing cell.

Animals↗

PubMed1976

Diazoxide-induced stimulation of renin release in renal vein renin sampling.

1. The acute effect of diazoxide (150-300 mg, intravenously) on renal venous renin has been evaluated in forty-four patients with suspected renal hypertension. 2. In twenty-seven studies which showed no lateralization, diazoxide raised the mean peripheral renin to 175% of control (P less than 0-05) but the renal vein renin ratio showed an insignificant change (1-15 to 1-21). 3. In seventeen studies which showed lateralization the increase in peripheral renin was similar, but mean renal vein renin ratio increased from 1-90 to 3-52 (P less than 0-005), and the mean ratio of contralateral renal vein to peripheral renin showed no change (1-05 to 1-07), indicating persistence of contralateral suppression. 4. Diazoxide accentuates the distinction between lateralizing and non-lateralizing renal vein renin studies.

Adult↗

PubMed1982

A comparative study of two insulin secretion inhibitors: somatostatin and diazoxide.

We studied the effect of the ionophere A 23187 and of phosphodiesterase inhibitors and activators (Theophylline, Pentoxiphylline and Imidazol) on insulin secretion and on the pool of free tubulin in rat pancreas in the presence of somatostatin and diazoxide. The results suggest that: 1. The inhibitory effect of somatostatin on insulin secretion does not seem to be related mainly to an inhibition of cAMP production. The decrease in calcium translocation induced by somatostatin could inhibit the cAMP participation in the mechanism of hormonal secretion. 2. Somatostatin seems to inhibit the movement of calcium towards the cytoplasm from outside and from within the cell. Diazoxide seems to inhibit only the entrance of calcium from outside the cell but does not seem to inhibit the entrance determined by theophylline and pentoxiphylline from intracellular compartments. 3. Arginine glucose stimulation in the presence of A 23187-induced calcium translocation is able to determine insulin secretion although cAMP degradation is increased by imidazol. 4. Somatostatin and diazoxide inhibit pancreatic tubulin polimerization; however, the effect seem to be indirect and related to the inhibition of calcium translocation determined by both substances.

Animals↗

PubMed2002

Protection of cardiac mitochondria by diazoxide and protein kinase C: implications for ischemic preconditioning.

Mitochondrial ATP-sensitive K (mitoK(ATP)) channels play a central role in protecting the heart from injury in ischemic preconditioning. In isolated mitochondria exposed to elevated extramitochondrial Ca, P(i), and anoxia to simulate ischemic conditions, the selective mitoK(ATP) channel agonist diazoxide (25-50 microM) potently reduced mitochondrial injury by preventing both the mitochondrial permeability transition (MPT) and cytochrome c loss from the intermembrane space. Both effects were blocked completely by the selective mitoK(ATP) antagonist 5-hydroxydecanoate. The protective effect against Ca-induced MPT was most evident under conditions in which the ability of electron transport to support membrane potential (Deltapsi(m)) was decreased and inner membrane leakiness was increased moderately. Under these conditions, mitoK(ATP) channel activity strongly regulated Deltapsi(m), and diazoxide prevented MPT by inhibiting the driving force for Ca uptake. Phorbol 12-myristate 13-acetate mimicked the protective effects of diazoxide, unless 5-hydroxydecanoate was present, indicating that protein kinase C activation also protects mitochondria by activating mitoK(ATP) channels. Because Deltapsi(m) recovery ultimately is required for heart functional recovery, these results may explain how mitoK(ATP) channel activation mimics ischemic preconditioning by protecting mitochondria as they pass through a critical vulnerability window during ischemia/reperfusion.

Animals↗

PubMed2000

Diazoxide down-regulates leptin and lipid metabolizing enzymes in adipose tissue of Zucker rats.

We have previously reported that attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, increased insulin sensitivity and reduced body weight in obese Zucker rats. These findings prompted us to investigate the effects of DZ on key insulin-sensitive enzymes regulating adipose tissue metabolism, fatty acid synthase (FAS), and lipoprotein lipase (LPL), as well as on circulating levels of leptin. We also determined the direct effects of diazoxide on FAS in 3T3-L1 adipocytes. Seven-week-old female obese and lean Zucker rats were treated with DZ (150 mg/kg/d) or vehicle (C, control) for a period of 6 wk. Changes in plasma parameters by DZ include significant decreases in triglycerides, free fatty acids, glucose, and insulin, consistent with our previous reports. DZ obese rats exhibited lower plasma leptin levels (P<0.03) compared to their C animals. DZ significantly reduced adipose tissue FAS activity in both lean (P<0.0001) and obese (P<0.01) animals. LPL mRNA content was also decreased significantly in DZ-treated obese animals (P<0.009) as compared to their respective controls without a significant effect on lean animals. The possibility that DZ exerted a direct effect on adipocytes was further tested in cultured 3T3-L1 adipocytes. Although diazoxide (5 microM) alone did not change FAS activity in cultured 3T3-L1 adipocytes, it significantly attenuated insulin's effect on FAS activity (P<0.001). We demonstrate that DZ regulates key insulin-sensitive enzymes involved in regulation of adipose tissue metabolism. These findings suggest that modification of insulin-sensitive pathways can be therapeutically beneficial in obesity management.

3T3 Cells↗