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Results for “DIAZOXIDE”

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PubMed1995

Evidence that diazoxide promotes calcium influx in mouse keratinocyte cultures by membrane hyperpolarization.

We have used fura-2/AM to investigate the effect of diazoxide on the cytosolic calcium concentration (Cai) in primary mouse keratinocyte cultures. Treatment of keratinocytes with 100 microM diazoxide induced a transient peak in Cai, followed by a sustained elevation. Depletion of medium calcium by addition of EGTA abolished the diazoxide-induced Cai response, indicating that the agent promoted calcium influx without release of calcium from intracellular stores. The diazoxide-induced rise in Cai was inhibited both by addition of 60 mM KCl to the assay buffer and by preincubation with glibenclamide, a specific K+ channel blocker. In addition, studies with the membrane potential-sensitive fluorescent probe bis-oxonol demonstrated that diazoxide hyperpolarized keratinocyte membranes. These findings suggest that keratinocytes possess K+ channels, and that the previously reported proliferation effects of K+ channel openers such as diazoxide on keratinocytes may result from hyperpolarization-induced elevation of Cai.

Animals↗

PubMed2005

Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice.

Protection by ischemic preconditioning is lost in cardiomyocytes and hearts of heterozygous connexin 43 deficient (Cx43+/-) mice. Because connexin 43 (Cx43) is localized in cardiomyocyte mitochondria and mitochondrial Cx43 content is increased with ischemic preconditioning, we now tried to identify a functional defect at the level of the mitochondria in Cx43+/- mice by use of diazoxide and menadione. Diazoxide stimulates the mitochondrial formation of reactive oxygen species (ROS) and menadione generates superoxide at multiple intracellular sites; both substances elicit cardioprotection through increased ROS formation. ROS formation in response to the potassium ionophore valinomycin was also measured for comparison. Menadione (2 micromol/L) and valinomycin (10 nmol/L) induced similar ROS formation in wild-type (WT) and Cx43+/- cardiomyocytes. In contrast, diazoxide (200 micromol/L) increased ROS formation by 43+/-10% versus vehicle in WT, but only by 18+/-4% in Cx43+/- cardiomyoctes (P<0.05). Two hour-simulated ischemia and oxygenated, hypo-osmolar reperfusion reduced viability as compared with normoxia (WT: 7+/-1% versus 39+/-2%, (Cx43+/-): 8+/-1% versus 40+/-3%, P<0.01). Although menadione protected WT and Cx43+/- cardiomyocytes, diazoxide increased viability (17+/-2%, P<0.01) in WT, but not in Cx43+/- (9+/-1%). Menadione (37 microg/kg i.v.) before 30 minutes coronary occlusion and 2 hour reperfusion reduced infarct size in WT and Cx43+/- mice (24+/-4% versus 24+/-5%). In contrast, diazoxide (5 mg/kg i.v.) reduced infarct size in WT (35+/-4% versus 55+/-3% of area at risk, P<0.01), but not in Cx43+/- mice (56+/-2% versus 54+/-3%). Cardiomyocytes of Cx43+/- mice have a specific functional deficit in ROS formation in response to diazoxide and accordingly less protection.

Animals↗

PubMedDate not supplied

In vivo and In vitro studies on the cerebrovascular dilatation induced by diazoxide in normotensive and renal hypertensive goats.

We studied the in vivo and in vitro effects of diazoxide on the cerebral circulation of 8 normotensive (mean arterial pressure = 100 mm Hg) and 5 renal hypertensive (mean arterial pressure = 146 mm Hg) goats. Injections of diazoxide (0.3-27 mg) into the internal maxillary artery of unanesthetized goats produced dose-dependent increases in cerebral blood flow (electromagnetic flowmeter), this effect being significantly higher in hypertensive goats. Intravenous injection of 5 mg/kg of diazoxide into normotensive goats increased cerebral blood flow 40 ml/min/100 g and mean arterial pressure dropped 22 mm Hg whereas in hypertensive goats cerebral blood flow was unchanged and mean arterial pressure decreased 50 mm Hg. The increase in heart rate due to intravenous diazoxide was similar in normotensive and hypertensive goats (35 beats/min). Cumulative applications of diazoxide (10(-5) to 10(-3)M) on isolated middle cerebral arteries produced dilatory responses both under resting conditions and after previous tonic contraction by serotonin. This relaxation was significantly greater in arterial segments from hypertensive goats. The results indicate that diazoxide exerts powerful dilatatory effects on cerebral vessels, both in vivo and in vitro, and that these effects are particularly evident in hypertensive animals.

Animals↗

PubMed1983

Treatment of chlorpropamide overdose with diazoxide.

A patient who took a chlorpropamide overdose was treated for several hours with concentrated glucose solutions, with little success in maintaining adequate serum glucose concentrations. Intravenous diazoxide administration was begun with the hope of decreasing pancreatic insulin release. After diazoxide was begun, glucose requirements decreased dramatically, and serum glucose was supranormal for most of the period of diazoxide administration. The case was complicated by the fact that the patient had taken three agents that can cause hypoglycemia--chlorpropamide, alcohol, and aspirin. Drug interactions potentiating the hypoglycemic effect of the chlorpropamide were also possible. Glucose infusion is the mainstay of therapy for a sulfonylurea overdose. However, glucose acts as a further stimulus of insulin release from a sulfonylurea-primed pancreas. Administration of concentrated glucose solutions is technically difficult because of damage to veins. Metabolic consequences of high rates of glucose infusion to hyperinsulinemic patients include hypokalemia and hypophosphatemia. Diazoxide appeared to decrease the glucose requirement in this patient, as it did in three other reported cases. Diazoxide is approved for certain hypoglycemic, hyperinsulinemic conditions. Sulfonylurea overdose represents a hypoglycemic, hyperinsulinemic condition; diazoxide appears to be an effective treatment.

Adolescent↗

PubMed1982

Idiopathic leucine-sensitive hypoglycemia syndrome: insulin and glucagon responses and effects of diazoxide.

Four children, treated with diazoxide for idiopathic leucine-sensitive (ILS) hypoglycemia of infancy, had follow-up studies at 2 to 10 yr of age to assess: (1) persistence of leucine sensitivity in later childhood. (2) pancreatic glucagon responses, and (3) the hormonal and glycemic effects of diazoxide therapy. On the third day after diazoxide therapy was stopped, the mean +/- S.E. baseline plasma glucose level (65.3 +/- 3.4 mg/dl) was significantly (P less than 0.005) lower than that of the controls (80.1 +/- 3.1 mg/dl). Corresponding mean plasma immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) values were higher than control values but the differences were not significant. After the oral administration of leucine (50 mg/kg) in the ILS children, the mean plasma IRI level rose from 15.2 +/- 4.1 to 59 +/- micro U/ml, the mean plasma glucose concentration fell to 36.0 +/- 3.3 mg/dl and the mean plasma IRG level rose from 196 +/- 16 to 261 +/- 41 pg/ml. These responses were significantly greater (P less than 0.05 to 0.005) than those of control children who received 150 mg/kg of leucine. Intravenous arginine administration caused similar changes in mean plasma glucose, IRI and IRG values in the ILS and control children. During diazoxide therapy in the ILS children, the baseline mean plasma glucose level (89.5 +/- 4.2 mg/dl) was significantly (P greater than 0.005) higher than without therapy. Corresponding mean plasma IRI and IRG values decreased with therapy but the differences were not significant. Diazoxide therapy blunted the changes induced by leucine administration in the ILS children but did not significantly change their response to arginine infusion. Our results indicate that marked sensitivity to leucine persists after infancy in the ILS children. Their IRG responses are appropriate to the stimuli, indicating that their pancreatic alpha cells do not share the abnormality of the beta cells. Diazoxide therapy increases baseline plasma glucose levels and inhibits IRI responses to leucine in ILS children, but it has little if any effect on IRG responses.

Arginine↗

PubMed2006

Diazoxide prevents diabetes through inhibiting pancreatic beta-cells from apoptosis via Bcl-2/Bax rate and p38-beta mitogen-activated protein kinase.

Increased apoptosis of pancreatic beta-cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic beta-cell apoptosis and its potential mechanism in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes, at the prediabetic and diabetic stages. We found a significant increase with age in the frequency of apoptosis, the sequential enlargement of islets, and the proliferation of the connective tissue surrounding islets, accompanied with defective insulin secretory capacity and increased blood glucose in untreated OLETF rats. In contrast, diazoxide treatment (25 mg.kg(-1).d(-1), administered ip) inhibited beta-cell apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet beta-cells whether diazoxide was used at the prediabetic or diabetic stage. Linear regression showed the close correlation between the frequency of apoptosis and hyperglycemia (r = 0.913; P < 0.0001). Further study demonstrated that diazoxide up-regulated Bcl-2 expression and p38beta MAPK, which expressed at very low levels due to the high glucose, but not c-jun N-terminal kinase and ERK. Hence, diazoxide may play a critical role in protection from apoptosis. In this study, we demonstrate that diazoxide prevents the onset and development of diabetes in OLETF rats by inhibiting beta-cell apoptosis via increasing p38beta MAPK, elevating Bcl-2/Bax ratio, and ameliorating insulin secretory capacity and action.

Animals↗

PubMed2006

Comparative proteomics analysis of differentially expressed phosphoproteins in adult rat ventricular myocytes subjected to diazoxide preconditioning.

Mitochondrial ATP sensitive potassium channels (mitoK(ATP) channels) are involved in the cardioprotection afforded by ischemic preconditioning (IPC) and diazoxide, a selective mitoK(ATP) channel opener. The activation of some kinases, including phoshoprotein kinase (PKC)-epsilon and mitogen-activating protein kinases (MAPK), is involved in signal conduction of preconditioning downstream from mitoK(ATP) channel opening. Diazoxide can open mitoK(ATP) channels and activate PKC-epsilon, which will phosphorylate some substrate proteins. These proteins that exhibit altered post-translational modification via phosphorylation due to diazoxide pretreatment may be the target molecules and play an important role in cellular protection after mitoK(ATP) channel opening. To analyze and identify the phosphoproteins associated with diazoxide preconditioning, phosphoprotein enrichment and comparative two-dimensional gel electrophoresis (2D-GE) were used. Cultured adult rat ventricular myocytes were pretreated in the presence and absence of 100 micronol/1l diazoxide for 10 min and enriched phosphoproteins from control myocytes and those pretreated with 100 micromol/l diazoxide were separated by 2D-GE and stained with a silver staining kit. Phosphoproteins of interest were further identified by matrix-assisted laser desorption ionization tandem mass spectrometry (MALDI-TOF MS). Eight protein spots with different abundance were found, of which six differentially expressed proteins were identified by MALDI-TOF MS. They included 94 kDa glucose-regulated protein, calpactin I heavy chain, chaperonin containing TCP-1 zeta subunit, hypothetical protein XP_346548, ferritin light chain and ferritin light chain 2. These findings provide new clues to understanding the mechanism of ischemic preconditioning in cardiomyocytes downstream from mitoK(ATP) channel opening.

Animals↗

PubMed1984

Effects of diazoxide on maternal and fetal circulations in normotensive and hypertensive pregnant sheep.

Diazoxide is a potent antihypertensive agent due to its peripheral vasodilator action. For this reason it is used in the management of hypertensive crises in pregnancy. To assess the effects of an intravenous bolus injection of diazoxide on maternal and fetal hemodynamics an experimental study was performed in 11 chronically instrumented pregnant sheep. In six ewes hypertension was induced by surgical removal of one kidney and reduction of arterial blood flow to the remaining kidney (one-kidney renovascular hypertension). The other five ewes remained normotensive. In a second operation, one week after the first one, the animals were equipped with electromagnetic flow transducers and catheters for monitoring of blood flow in a renal, a uterine, and an umbilical artery and for measurement of maternal and fetal arterial blood pressures, and blood sampling. Maternal heart rate was derived from the arterial pressure curve, fetal heart rate from a fetal ECG. Experiments were begun on the third day after the second operation. In each experiment a bolus of 300 mg of diazoxide was administered intravenously, with or without rapid simultaneous infusion of 500 ml of a plasma expander. A total of 17 experiments were performed in the one-kidney hypertensive ewes (Group H), nine with and eight without plasma expander. In the five normotensive animals (Group NH) 10 experiments were done, four with and six without plasma expansion. During the control periods maternal arterial pressure was approximately 30 mm Hg higher in Group H than in Group NH. In Group H also maternal heart rate, and renal and uterine vascular resistances were significantly elevated. All fetal variables were equal in both groups. Administration of diazoxide without simultaneous plasma expansion resulted in both groups in a significant fall in maternal arterial pressure, a rise in maternal heart rate, and a fall in uterine and renal blood flows with a rise in vascular resistance. Fetal arterial pressure and umbilical blood flow showed no significant changes, but fetal heart rate showed a transient fall together with a drop in fetal pO2 and pH, although acidosis did not occur. When diazoxide was combined with a plasma expander maternal blood pressure did not change significantly in Group NH, but fell in Group H. Maternal heart rate rose significantly in both groups. The decrease in uterine and renal blood flows which occurred when diazoxide was given without plasma expansion was not observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1977

On the mechanism of diazoxide-induced hyperglycemia.

Infusion of diazoxide (16.5 mg./kg. in 10 minutes) into normal unanesthetized dogs resulted in a prompt hyperglycemia due to increased hepatic glucose production as measured with a 3-3H-glucose primer-infusion technique. Plasma insulin and glucagon were decreased. Glucose uptake failed to increase. Diazoxide administration during period of alpha adrenergic receptor blockade with phentolamine still caused hyperglycemia and increased glucose production. Glucose uptake was inhibited despite adequate plasma insulin. Infusion of somatostatin along with insulin prevented the effects of diazoxide on plasma glucose and glucose production. It is concluded that diazoxide hyperglycemia is not due solely to decreased insulin secretion or increased epinephrine secretion and that glucagon is not a contributory factor. Diazoxide may act directly to increase glucose production and inhibit glucose uptake. Somatostatin appears capable of blocking the effect of diazoxide on glucose production by an unknown mechanism.

Animals↗

PubMed2002

Glucagon is paradoxically secreted at high concentrations of glucose in rat pancreas perfused with diazoxide.

To study the role of B-cells in the regulation of glucagon secretion by glucose, the rat pancreas was perfused with 0.4 mmol/l diazoxide. Perfusate glucose was 5 mmol/l of a basal concentration, and then was decreased to 1 mmol/l, or was increased to 15 mmol/l. Insulin secretion was suppressed by diazoxide below the detectable level at each glucose concentration. Glucagon secretion was increased two-fold during the glucopenic perfusion without diazoxide, but was not changed at a low glucose concentration in the presence of diazoxide. During the glucose-excessive perfusion for 15 min, glucagon secretion was lowered from 0.69 +/- 0.17 pmol at 5 mmol/l glucose to 0.36 +/- 0.10 pmol at 15 mmol/l glucose (p < 0.05) without diazoxide, whereas that was inversely increased from 0.55 +/- 0.14 at 5 mmol/l glucose to 0.85 +/- 0.13 pmol at 15 mmol/l glucose (p < 0.05) in the presence of diazoxide. These results suggest that appropriate insulin secretion is necessary for the normal responses of glucagon secretion to hypoglycemia and hyperglycemia in the non-diabetic rat pancreas.

Animals↗

PubMed2003

Protective effects of the potassium channel opener-diazoxide against injury in neonatal rat ventricular myocytes.

The mitochondrial ATP-regulated potassium channel is present in the inner membrane of heart mitochondria. Similarly to plasma membrane K(ATP), the mitochondrial channel is inhibited by antidiabetic sulfonylureas and activated by potassium channel openers, such as diazoxide. In the present work, the cytoprotective properties of diazoxide on the H9c2 cardiac myoblast cell line and neonatal rat ventricular cardiomyocytes were analysed. It was observed that 100 micromol/l diazoxide protected neonatal rat ventricular cardiomyocytes, but not H9c2 myoblasts, against injury induced by hydrogen peroxide or simulated ischemia. Moreover, diazoxide prevented hydrogen peroxide-induced mitochondrial potential depolarisation in neonatal rat ventricular cardiomyocytes. Diazoxide, at the same time, did not affect the expression level of the anti-apoptotic protein bcl-2 in these cells. The protective effects of diazoxide were suppressed by 5-hydroxydecanoic acid, a potassium channel blocker. These observations suggest that activation of the mitochondrial ATP-regulated potassium channel plays an important role in protection of neonatal cardiomyocytes against injury.

Animals↗

PubMed1989

Similarities between the effects of pinacidil and diazoxide on ionic and secretory events in rat pancreatic islets.

The present study aimed at comparing the effects of pinacidil, a putative K+ channel opener, and diazoxide on ionic and secretory events in rat pancreatic islets. Pinacidil and diazoxide provoked a dose-dependent increase in 86Rb outflow from pancreatic islets perifused in the presence of glucose. Both drugs inhibited the glucose- and tolbutamide-induced increase in 45Ca outflow and insulin release whereas failing to affect the ionic and secretory responses to K+ depolarization. Pinacidil and diazoxide, in contrast to quinine, failed to affect 86Rb outflow from pancreatic islets stimulated by the Ca++-ionophore A23187. Pinacidil as well as diazoxide abolished the glucose-induced increase in [Ca++]i but did not modify the rise in [Ca++]i provoked by KCl. Lastly, both drugs were shown to stimulate an ouabain-resistant modality of 86Rb inflow into the islet cells. The close similarities between the ionic and secretory events mediated by pinacidil and diazoxide suggest that pinacidil could interfere with the same target site as diazoxide; namely the beta-cell ATP-sensitive K+ channel.

Animals↗

PubMed1993

Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus.

Among the non-NMDA (non-N-methyl-D-aspartic acid) glutamate receptors, the AMPA (alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid) selective receptors are characterized by a fast occurring desensitization. We and others have searched for specific modifiers of the rapid desensitization of AMPA responses in hippocampal slices using the patch-clamp technique. Aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone) and diazoxide (7-chloro-3-methyl-2H-1,2,4-benzo-thiadiazine 1,1-dioxide) (1 mM) increased glutamate-activated currents recorded from voltage-clamped CA1 pyramidal neurons in presence of 5 microM MK-801 (dizocilpine; 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine) by 2.5 fold. Cyclothiazide (3-bicyclo[2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzoth ia diazine-7-sulfonamide 1,1-dioxide) (100 microM), a chemical congener of diazoxide, completely removed the desensitization of the AMPA response measured with fast application in excised outside-out patches. At this concentration cyclothiazide produced an 18 fold enhancement of the glutamate current. Eighteen diazoxide analogues (2H-1,2,4-benzothiadizines: IDRA 2-19) were then tested but none of them was as effective as diazoxide. Three analogues of cyclothiazide (3,4-dihydro-2H-1,2,4-benzothiadiazines: IDRA 20-22) were also tested and none of them were as potent as the parent compound. However, IDRA 21 produced a response 3 times larger than diazoxide. Moreover, while cyclothiazide and diazoxide potentiated kainate responses for all the doses that decreased AMPA receptor desensitization, IDRA 21, similarly to aniracetam, inhibited AMPA receptor desensitization preferentially. These results suggest that similarly to NMDA receptors the structure of AMPA receptors may include a center that regulates desensitization.

Action Potentials↗

PubMed1996

Oedema formation with the vasodilators nifedipine and diazoxide: direct local effect or sodium retention?

OBJECTIVE: To determine whether the common side effect of ankle oedema with arteriolar vasodilators such as the calcium entry blocker (CEB) nifedipine and the potassium channel opener (PCO) diazoxide is the direct result of peripheral vasodilation or merely a consequence of renal sodium retention. DESIGN: In 12 healthy sitting volunteers we studied for 3 h the effects of 20 mg nifedipine, 150 mg diazoxide intravenously, 25 mg captopril and placebo on oedema formation and sodium excretion. CONCLUSIONS: Foot swelling was determined with a new accurate device (coefficient of variation 0.30%), which uses Archimedes principle to measure water displacement induced by immersion of the foot. Blood pressures were recorded with a Hawksley random-zero sphygmomanometer. RESULTS: All of the active drugs decreased diastolic blood pressure (captopril by 9 +/- 2%, nifedipine by 4 +/- 3% and diazoxide by 2 +/- 2%, compared with an increase of 5 +/- 2% with placebo). Foot volume increased acutely after administration of nifedipine (by 2.6 +/- 0.4%), whereas it remained stable with placebo and the other drugs. Administration of captopril and nifedipine induced increases of fractional sodium excretion (by 20 +/- 9% and 40 +/- 20%, respectively) in contrast to the decreases with placebo and diazoxide (by 13 +/- 11% and 24 +/- 10%, respectively). Only administration of nifedipine induced significant, albeit small, increases in haemoglobin and serum albumin levels. CONCLUSIONS: Administration of nifedipine increased foot volume and natriuresis simultaneously, thereby supporting the hypothesis that development of ankle oedema with CEB is a local phenomenon at the site of vasodilation. The absence of a similar increase in foot volume with diazoxide administration should be interpreted with caution because of the rather minor effect of this dose of diazoxide on blood pressure. However, it could be indicative of a different mechanism of oedema formation with PCO.

Adult↗

PubMed2004

Diazoxide preconditioning protects against neuronal cell death by attenuation of oxidative stress upon glutamate stimulation.

We examined the effects of diazoxide, the putative mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channel opener, against glutamate excitotoxicity in primary cultures of rat cortical neurons. Cells were treated with diazoxide for 24 hr and then exposed to 200 microM glutamate. Cell viability was measured 24 hr after glutamate exposure. We found that treatment 24 hr before glutamate exposure with 250 and 500 microM diazoxide but not with another mitoK(ATP) channel opener, nicorandil, increased neuronal viability from 54 +/- 2% to 84 +/- 2% and 92 +/- 3%, respectively (n = 25-40). These effects were not inhibited by the putative mitoK(ATP) channel blocker 5-hydroxydecanoic acid. Diazoxide application increased production of reactive oxygen species (ROS) and coapplication of M40401, a superoxide dismutase mimetic, prevented delayed preconditioning. The 24 hr preconditioned neurons showed significantly reduced ROS production upon glutamate stimulation compared to that in untreated cells. These results suggest that diazoxide induces delayed preconditioning in cultured cortical neurons via increased ROS production and attenuation of oxidative stress upon glutamate stimulation.

Analysis of Variance↗

PubMed1994

Effect of diazoxide on serum and tissue electrolyte levels in rats with deoxycorticosterone acetate-induced hypertension.

Effects of diazoxide, a benzothiadiazine derivative, on the blood pressure, excretion of Na+, K+, and Ca2+, and the levels of these electrolytes in serum, kidney, and aorta were studied in rats with deoxycorticosterone acetate (DOCA)-induced hypertension in comparison with rats treated with hydrochlorothiazide. After a lateral nephrectomy, 5 mg kg-1 of DOCA was injected subcutaneously three times a week. Drinking water for the rats injected with DOCA contained 1% NaCl. Systolic blood pressure in the DOCA-induced hypertensive rats became about 170 mmHg, with associated elevation of serum level of Na+ 7 weeks after the treatment, whereas that in the normotensive rats was about 100 mmHg. In the DOCA-hypertensive rats, urinary output, and renal excretion of Na+ and Ca2+ increased, and aortic tissue level of Ca2+ decreased as compared with those in the normotensive rats. After 7 weeks of the treatment, diazoxide (10 mg kg-1) or hydrochlorothiazide (10 mg kg-1) was injected intravenously. Diazoxide decreased the blood pressure in both DOCA-hypertensive and normotensive rats, whereas hydrochlorothiazide decreased it only in the DOCA-hypertensive rats. Diazoxide recovered the tissue aortic Ca2+ level that had been decreased by hypertension to that in the normotensive rats. Diazoxide may improve Ca2+ perturbation in the vascular smooth muscle due to DOCA-induced hypertension.

Animals↗

PubMed1994

Effects of diazoxide on KCl- and norepinephrine-induced contraction in isolated rat aorta.

Diazoxide produced endothelium-independent relaxations of the rat aorta contracted by either low concentrations of KCl or norepinephrine (NE). However, contraction with a high concentration of KCl was not altered by diazoxide. Hydrochlorothiazide did not affect the contraction induced by either KCI or NE. Tetraethylammonium and glibenclamide inhibited the relaxations of the aorta induced by diazoxide. Diazoxide significantly reduced the phasic and tonic contractions under Ca2+-free conditions induced by NE and CaCl2 following NE addition, respectively. These results suggest that diazoxide dilates vascular smooth muscle by opening the ATP-sensitive K+ channels and inhibiting receptor-operated Ca2+ movements from either the intracellular store sites or extracellular space to the cytoplasm, but not antagonizing voltage-dependent Ca2+ channels directly.

Animals↗

PubMed1994

The countering of diazoxide-induced vasodilatation by tenoxicam in normal volunteers.

The effect of the nonsteroidal anti-inflammatory drug, tenoxicam, on diazoxide-induced lowering of standing diastolic blood pressure was explored in 10 normal volunteers. With diazoxide there was a significant fall in the 5-min standing diastolic pressure, i.e. a median drop of 15.5, 11.0, 9.5 and 7.0 mm Hg at 10, 35, 75 and 105 min, respectively, but with the tenoxicam-diazoxide regimen this pressure did not differ significantly from baseline at any time point. Tenoxicam did not modify the diazoxide-induced changes in blood glucose and plasma insulin. It may be that prostaglandins normally contribute to the lowering of peripheral vascular resistance, or that acutely-administered diazoxide enhances the release of vasodilatory prostaglandins.

Adult↗