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Results for “DIAZOXIDE”

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PubMed1982

Haemodynamic and metabolic effects of diazoxide during rest and forearm exercise.

The immediate haemodynamic and metabolic effects of acute dose of diazoxide 300 mg i.v. were studied in six healthy subjects at rest and during dynamic forearm exercise. Control periods of rest, exercise and recovery were compared with corresponding periods after drug administration. Resting forearm blood flow was almost doubled after diazoxide, and during forearm exercise it increased by about 24%. Systolic blood pressure did not change significantly, but diastolic blood pressure was moderately decreased (5-10 mm Hg). The mean heart rate increased from 57 to 92 beats/min immediately after diazoxide administration and remained about 20% higher throughout the study. There was a sustained increase in arterial blood glucose of almost 1 mmol/l. The arterial concentration of free fatty acids increased transiently just after diazoxide and then returned to the pre-drug level. The arterial concentration of triglycerides after diazoxide was decreased by about 15% throughout the study. Arterial blood lactate remained unchanged. Forearm uptake of oxygen and glucose tended to increase during the exercise and recovery periods, whereas lactate release remained unchanged.

Adult↗

PubMed2005

Effects of diazoxide treatments on electrophysiologyic properties in guinea pig papillary muscles undergoing ischemia/reperfusion.

The effects of diazoxide treatments on electrophysiologyic properties in guinea pig papillary muscles undergoing ischemia/reperfusion was studied using intracellular microelectrode technique. Twenty-four guinea pigs were randomly divided into three groups (n=8 in each group). In control group, St. Thomas solution was given. In experimental group, St. Thomas solution with diazoxide (100 mol/L) was given. In pretreatment group, the muscle was treated with diazoxide 20 min before arrested with St. Thomas cardioplegia. The results showed that the APD50 and APD90 in experimental and pretreatment groups were significantly shorter after 5 and 10 min reperfusion (P <0.01, P<0.05), but longer after 30 min reperfusion (P<0.01, P<0.05) than in control group. In experimental and pretreatment groups, APA, OS, Vmax recovered more quickly than those in control group. The time to re-systole after reperfusion in control group was longer than that in experimental and pretreatment groups. There was no significant difference in RP among three groups. The time of arrest in pretreatment group was longer than that in experimental and pretreatment group (P<0.05). This study indicates that protective effects of St. Thomas solution with diazoxide is better than that of pretreatment with diazoxide or St. Thomas solution alone.

Adenosine Triphosphate↗

PubMed1982

Beneficial hemodynamic effects of intravenous diazoxide in refractory congestive heart failure.

Despite the growing popularity of vasodilator therapy for acute and chronic congestive heart failure (CHF), no single agent has been uniformly effective and well tolerated. Therefore, we investigated the acute hemodynamic response to diazoxide, a potent and long-acting arteriolar dilator, in nine patients with severe CHF refractory to conventional treatment and, in seven of nine, other vasodilators. Diazoxide was administered intravenously in successive 300 mg infusions, each over 10 minutes, until a satisfactory response in cardiac and output occurred or a fall in arterial blood pressure or increase in heart rate was noted. The mean dose of diazoxide was 670 mg (range 450 to 900 mg). Systemic vascular resistance fell immediately, by a maximum of 44%. Arterial pressure was not changed significantly, but cardiac and stroke volume indices rose by 64% and 49%, respectively, from 2.0 +/- 0.5 to 3.3 +/- 0.6 L/min/m2 and from 24 +/- 10 to 36 +/- 9 ml/m2 (each p less than 0.001). Pulmonary capillary wedge pressure declined more gradually, by a mean of 8 mm at 4 and 6 hours after drug infusion. This hemodynamic improvement was sustained for a mean of 9.7 hours (range 6 to 12 hours). Our findings indicate that intravenous diazoxide may be useful in the management of acute heart failure and that a trial of oral diazoxide in chronic normotensive CHF is warranted.

Adult↗

PubMed1989

Effects of tolbutamide, glibenclamide and diazoxide upon action potentials recorded from rat ventricular muscle.

Drugs which influence the electrical activity of insulin-secreting B cells of mammalian islets of Langerhans by closing (tolbutamide and glibenclamide) or opening (diazoxide) ATP-sensitive potassium channels were applied to the ventricular muscle of the rat. Action potentials were recorded from ventricular epicardium of perfused intact rat hearts. Tolbutamide (0.5-2.0 mM), glibenclamide (0.01-0.1 mM) and diazoxide (0.5 mM) each evoked a dose-dependent increase (7-33%) in the duration of the ventricular action potential measured at 50% of repolarization. These drugs were without effect upon the resting membrane potential or the peak of the action potential. Single-channel recordings of ATP-sensitive K+ channels were obtained from excised membrane patches of enzymatically isolated rat ventricular myocytes. Tolbutamide and diazoxide inhibited openings of ATP-sensitive K+ channels. Diazoxide inhibited ATP-sensitive K+ channel openings in the presence of ATP. Diazoxide did not evoke opening of ATP-sensitive K+ channels. It is concluded that these drugs could act to increase the duration of the cardiac action potential by inhibiting openings of ATP-sensitive K+ channels.

Action Potentials↗

PubMedDate not supplied

Evidence for the involvement of alpha-adrenoceptor blockade in the antihypertensive action of diazoxide in the renal hypertensive rat.

The effects of diazoxide on the blood pressure and heart rate of conscious renal hypertensive rats have been investigated. The antihypertensive action of diazoxide has been studied in relation to the effects of diazoxide pretreatment on pressor responses to stimulation of the complete sympathetic outflow and to injections of noradrenaline, phenylephrine, angiotensin and serotonin in pithed rats. In pithed preparations, pressor responses to sympathetic nerve stimulation, and to injected noradrenaline and phenylephrine were significantly reduced by diazoxide pretreatment, at a time corresponding to maximal reduction of blood pressure in conscious animals. At this time there was no significant reduction of pressor responses to injected angiotensin or serotonin. These findings suggest a contribution of alpha-adrenoceptor blockade to the antihypertensive activity of diazoxide.

Adrenergic alpha-Antagonists↗

PubMed1989

Protein phosphorylation is required for diazoxide to open ATP-sensitive potassium channels in insulin (RINm5F) secreting cells.

The patch-clamp open-cell recording configuration has been used to investigate the effects of non-hydrolyzable analogues of ATP on the diazoxide-activation of KATP channels in the insulin-secreting cell line RINm5F. K+ channels inhibited by 0.1, 0.5 and 1.0 mM ATP were consistently activated by 200 microM diazoxide. During sustained activation of channels, exchange of ATP for either AMP-PNP, AMP-PCP or ATP gamma S abolished the effects of diazoxide. If diazoxide was added to the membrane in the continued presence of AMP-PNP, AMP-PCP or ATP gamma S either no effects were observed or alternatively a small transient activation of channels occurred. This study suggests that protein phosphorylation is necessary for diazoxide to activate ATP-sensitive potassium channels in insulin-secreting cells.

Adenosine Triphosphate↗

PubMed1992

Diazoxide infusion at excess but not at basal hyperglycemia enhances beta-cell sensitivity to glucose in vitro in neonatally streptozotocin-diabetic rats.

The influence of chronic and moderate hyperglycemia vis-à-vis a 48-hour further elevation of blood glucose on beta-cell sensitivity to glucose was compared in an animal model of non-insulin-dependent diabetes. Neonatally streptozotocin-diabetic (n-STZ) rats infused with saline for 48 hours displayed moderate nonfasting hyperglycemia (mean, 11.5 +/- 1.5 mmol/L/48 h) and plasma insulin levels similar to those seen in normoglycemic, nondiabetic rats. In perfused pancreas, the insulin response to 27 mmol/L glucose was severely reduced to 1.60 +/- 0.45 pmol/min, ie, approximately 15% of the response in nondiabetic rats. A continuous infusion of diazoxide (5 mg/kg/h), which normally blocks glucose-induced insulin secretion, did not affect glucose and insulin levels in vivo, nor did it significantly affect the insulin response to glucose in vitro. In other experiments, "basal" hyperglycemia in n-STZ rats was doubled by glucose infusions for 48 hours to reach a mean of 23.8 +/- 0.6 mmol/L. Plasma insulin increased 3.2-fold. The in vitro insulin response to 27 mmol/L glucose was totally abolished, and the pancreatic insulin content was decreased by 81% relative to the content after saline. Addition of a diazoxide infusion inhibited the increase in plasma insulin by 93%. After the combined glucose and diazoxide infusion, the subsequent in vitro response to 27 mmol/L glucose was dramatically enhanced to 9.55 +/- 3.25 pmol/min, ie, the response was sixfold higher than after saline alone. This aftereffect of the diazoxide infusion was not significantly altered by an insulin infusion (2 U/d) added to the hyperglycemia plus diazoxide protocol to compensate for the insulin-lowering effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

The effects of topical diazoxide on hair follicular growth and physiology of the stumptailed macaque.

Diazoxide, an anti-hypertensive agent, has diverse pharmacologic effects; hypertrichosis, hyperglycemia associated with suppression of insulin release, and elevation of serum levels of androgens. Taking advantage of the hypertrichotic side effects of diazoxide, we examined the effect of topical application of the drug on hair regrowth in the bald frontal scalp of stumptailed macaques (Macaca arctoides); we also monitored systemic side effects. Using 7 adult stumptails, we applied diazoxide (5% solution in a vehicle) topically on the bald frontal scalp, once a day, 5 days per week. Two of seven macaques had vehicle alone applied. Hair growth was monitored by photographic recording (once every month) and by sequential analysis of folliculograms from biopsied skin (once every 4 months). We also examined body weight, hematology, blood pressure, heart rate, serum levels of testosterone and dihydrotestosterone, and glucose tolerance for a 4-month period. All 5 diazoxide-treated animals showed thickening and maintenance of the frontal hair during the entire treatment period (16 months). Analysis of folliculograms showed progressive enlargement of hair follicular size and acceleration of its cyclic growth from telogen to anagen phase and prolongation of anagen phase in all treated animals. Controls showed no consistent progressive changes of follicular growth. None of the animals treated with diazoxide showed abnormal changes in physical growth, cardiovascular function, serum levels of androgens, glucose tolerance (including insulin levels), or hematology.

Alopecia↗

PubMed2004

Effect of classic preconditioning and diazoxide on endothelial function and O2- and NO generation in the post-ischemic guinea-pig heart.

OBJECTIVES: A hypothesis was tested that a reaction product between superoxide (O2-) and nitric oxide (NO) mediates post-ischemic coronary endothelial dysfunction that ischemic preconditioning (IPC) protects the endothelium by preventing post-ischemic cardiac O2- and/or NO formation, and that the opening of the mitochondrial ATP-dependent potassium channel (mKATP) plays a role in the mechanism of IPC. METHODS: Langendorff-perfused guinea-pig hearts were subjected either to 30 min global ischemia/30 min reperfusion (IR) or were preconditioned prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min infusion/5 min wash-out of mKATP opener, diazoxide (0.5 microM). Coronary flow responses to acetylcholine (ACh) and nitroprusside were used as measures of endothelium-dependent and -independent vascular function, respectively. Myocardial outflow of O2- and NO, and functional recoveries were followed during reperfusion. RESULTS: IR impaired the ACh response by approximately 60% and augmented cardiac O2- and NO outflow. Superoxide dismutase (150 U/ml) and NO synthase inhibitor, l-NMMA (100 microM) inhibited the burst of O2- and NO, respectively, and afforded partial preservation of the ACh response in IR hearts. NO scavenger, oxyhemoglobin (25 microM), afforded similar endothelial protection. IPC and diazoxide preconditioning attenuated post-ischemic burst of O2-, but not of NO, and afforded a complete endothelial protection. Diazoxide given after 30-min ischemia increased the O2- burst and was not protective. The effects of IPC and diazoxide preconditioning were not affected by HMR-1098 (25 microM), a selective blocker of plasmalemmal KATP, and were abolished by glibenclamide (0.6 microM) and 5-hydroxydecanoate (100 microM), a nonselective and selective mK(ATP) blocker, respectively. 5-Hydroxydecanoate produced similar effects, whether it was given as a continuous treatment or was washed out prior to IR. CONCLUSION: The results suggest that in guinea-pig heart: (i) a reaction product between O2- and NO mediates the post-ischemic endothelial dysfunction; (ii) the mK(ATP) opening serves as a trigger of the IPC and diazoxide protection; and (iii) the mK(ATP) opening protects the endothelium in the mechanism that involves the attenuation of the O2- burst at reperfusion.

Animals↗

PubMed2004

Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain.

Aging and dementia are accompanied by cerebral white matter (WM) injury, which is considered to be of ischemic origin. A causal link between cerebral ischemia and WM damage has been demonstrated in rats; however, few attempts appear to have been made to test potential drugs for the alleviation of ischemia-related WM injury. We induced cerebral hypoperfusion via permanent, bilateral occlusion of the common carotid arteries of rats. A mitochondrial ATP-sensitive potassium channel opener diazoxide (5 mg/kg) or its solvent dimethyl sulphoxide (DMSO) was administered i.p. (0.25 ml) on 5 consecutive days after surgery. Sham-operated animals served as control for surgery, and non-treated rats as controls for treatments. Thirteen weeks after surgery, the animals were sacrificed and astrocytes and microglia were labeled immunocytochemically in the internal capsule, the corpus callosum and the optic tract. The astrocytic proliferation was enhanced by cerebral hypoperfusion in the optic tract, and reduced by diazoxide in DMSO, but not by DMSO alone in the corpus callosum. After carotid artery occlusion, microglial activation was enhanced two-fold in the corpus callosum and four-fold in the optic tract. DMSO decreased microglial activation in the optic tract, while diazoxide in DMSO, but not DMSO alone, restored microglial activation to the control level in the corpus callosum. In summary, the rat optic tract appeared to be particularly vulnerable to ischemia, while the effect of diazoxide was restricted to the corpus callosum. We conclude that diazoxide dissolved in DMSO can moderate ischemia-related neuroinflammation by suppressing glial reaction in selective cerebral WM areas.

Animals↗

PubMed2002

Diazoxide amelioration of myocardial injury and mitochondrial damage during cardiac surgery.

BACKGROUND: Recently, we have shown that the selective opening of mitochondrial ATP-sensitive potassium channels with diazoxide significantly decreases myocardial injury. The purpose of this study was to determine the effects of diazoxide on apoptosis and the mechanisms modulating apoptosis and myocardial injury in a blood-perfused model of acute myocardial infarction. METHODS: Pigs (32 to 42 kg) undergoing total cardiopulmonary bypass underwent left anterior descending coronary artery occlusion for 30 minutes. The aorta was cross-clamped and magnesium-supplemented potassium cold-blood cardioplegia (DSA; n = 6) or magnesium-supplemented potassium cardioplegia containing 50 micromol/L diazoxide (DZX; n = 6) was administered, followed by 30 minutes of global ischemia and 120 minutes of reperfusion. Left ventricular tissue samples from DSA and DZX hearts were obtained after reperfusion. Apoptosis was determined by TUNEL, caspase-3 and PARP cleavage, and caspase-3 activity. Bax and bcl-2 levels were determined and tissue morphology was examined by light and transmission electron microscopy. RESULTS: Apoptosis, as estimated by TUNEL-positive nuclei/3,000 myocardial cells, was 120.3 +/- 48.8 in DSA hearts and was significantly decreased to 21.4 +/- 5.3 in DZX hearts (p < 0.05 vs control). Caspase-3 and poly-ADP-ribose polymerase cleavage and pro-apoptotic bax protein levels were significantly decreased with diazoxide (p < 0.05 vs DSA). Light and transmission electron microscopy indicated severe disruption of tissue with capillary dilatation, mitochondrial cristae damage, and evidence of increased presence of mitochondrial granules in DSA as compared with DZX hearts. CONCLUSIONS: The addition of diazoxide (50 micromol/L) to cardioplegia significantly decreases regional myocardial apoptosis and mitochondrial damage, and provides an additional modality for achieving myocardial protection.

Animals↗

PubMed1975

Drug interaction: diazoxide and diphenylhydantoin.

In two children treated for hypoglycemia and convulsions with diazoxide and diphenylhydantoin, therapeutic serum diphenylhydantoin levels were not achieved despite doses of diphenylhydantoin of 17 and 29 mg/kg/day, respectively. After diazoxide was discontinued, serum diphenylhydantoin levels were within the therapeutic range in each patient with doses of 6.6 and 10 mg/kg/day, respectively. Serum diphenylhydantoin fell to undetectable levels within four days after experimental reinitiation of diazoxide administration in one patient. Although the mechanism for the effect of diazoxide on serum concentrations of diphenylhydantoin is uncertain, an increased rate of metabolism of diphenylhydantoin is suggested by our findings. Decreased plasma protein binding of diphenylhydantoin, induced by diazoxide, was observed and may play a role.

Administration, Oral↗

PubMed2003

Novel pharmacological preconditioning with diazoxide attenuates myocardial stunning in coronary artery bypass grafting.

OBJECTIVE: To investigate whether novel pharmacological preconditioning with diazoxide could protect the myocardial function and decrease myocardial injury in patients undergoing coronary artery bypass grafting (CABG). METHODS: Forty patients with stable angina who were scheduled for isolated elective CABG operations were randomized into control group (n=20) and diazoxide (DZX) group (n=20). In the DZX group, 1.5 mg/kg diazoxide was infused intravenously within 5 min followed by a 5-min washout before commencing the cardiopulmonary bypass (CPB). In the control group, a time-matched period of placebo infusion was given. Hemodynamic data and biochemical markers of myocardial injury were measured perioperatively. RESULTS: There were no adverse effects related to diazoxide. Cardiac index (CI) increased postoperatively as compared with baseline. In the DZX group, the improvement of CI was better than that in the control group (p=0.001). Left and right ventricular stroke work indexes decreased postoperatively, and recovered much faster in the DZX group (p=0.027 and p=0.049, respectively). There were no statistically significant differences in the other hemodynamic parameters. The creatine kinase cardiac isoenzyme (CK-MB) was highest in both groups on the first postoperative day (control 28.8+/-23.8 and DZX 27.3+/-19.4, N.S.). The cumulative release of CK-MB postoperatively was lower in the DZX patients as compared with the controls, but the difference remained not significant (p=0.09). CONCLUSIONS: Pharmacological preconditioning of the human heart with diazoxide is feasible; it confers additional myocardial protection beyond that provided by the cardioplegia alone by attenuating myocardial stunning after CABG operations.

Aged↗

PubMed1998

Regulation by tolbutamide and diazoxide of the electrical activity in mouse pancreatic beta-cells recorded in vivo.

1. The glucose-dependence of beta-cell electrical activity and the effects of tolbutamide and diazoxide were studied in anaesthetized mice. 2. In untreated animals there was a direct relationship between glycaemia and the burst pattern of electrical activity. Animals with high glucose concentration showed continuous electrical activity. The application of insulin led to a steady decrease in blood glucose concentration and a transition from continuous to oscillatory activity at 7.7+/-0.1 mM glucose (mean+/-s.d.) and a subsequent transition from oscillatory to silent at 4.7+/-0.6 mM glucose. 3. At physiological blood glucose concentrations the electrical activity was oscillatory. The injection of tolbutamide (1800 mg kg[-1]) transformed this oscillatory pattern into one of continuous electrical activity. The increased electrical activity was associated with a decrease in blood glucose concentration from 7.1+/-0.9 (control) to 5.5+/-1.0 mM (10 min after tolbutamide injection). The effects of tolbutamide are consistent with a direct blocking effect on the K(ATP) channel that leads to membrane depolarization. 4. The injection of diazoxide (6000 mg kg[-1]) hyperpolarized the cells and transformed the oscillatory pattern into a silent one. This is consistent with a direct stimulant effect by diazoxide on the K(ATP) channel. The use of tolbutamide or diazoxide correspondingly led to the lengthening or shortening of the active phase of electrical activity, respectively. This indicates that in vivo, such activity can be modulated by the relative degree of activation or inhibition of the K(ATP) channel. 5. These results indicate that under physiological conditions, tolbutamide and diazoxide have direct and opposite effects on the electrical activity of pancreatic beta-cells, most likely through their action on K(ATP) channels. This is consistent with previous work carried out on in vitro models and explains the drugs hypo- and hyperglycaemic effects.

Animals↗

PubMed2001

Diazoxide, a K(ATP) opener, accelerates restitution of ethanol or indomethacin-induced gastric ulceration in rats independent of polyamines.

BACKGROUND AND AIMS: Experimental acute gastric ulcerations (EAGU) are healed very rapidly. This healing process has two steps; mucosal restitution and delayed repair. Adenosine 5'-triphosphate (ATP)-dependent potassium channels (K(ATP)) have a regulatory role in the gastrointestinal physiology. In the present study, the effects of K(ATP) channel modulators; diazoxide (channel opener) and glibenclamide (channel antagonist) on the healing of EAGU were investigated. The effect of polyamine (mediators presumably responsible for restitution) biosynthesis by difluoromethylornithine (DFMO) on diazoxide-induced alterations, and the effects of acid secretion inhibitors (cimetidine, omeprazole and atropine) on the mucosal restitution of EAGU were also studied. METHODS: Groups of 10 male rats were starved for 24 h and EAGU was induced by oral administration of 1 mL 60% ethanol or a subcutaneous injection of 30 mg/kg indomethacin. Different groups were subjected to various doses of diazoxide (5, 15, 45 mg/kg) and/or glibenclamide (2, 6, 18 mg/kg) administered intraperitoneally (i.p.) after EAGU induction. Polyamine biosynthesis was inhibited by a single i.p. injection of DFMO (500 mg/kg), administered 10 min before EAGU induction. Cimetidine, omeprazole or atropine were administered intraperitoneally at doses of 200, 5 and 1 mg/kg, respectively, after EAGU induction. Animals were killed and their gastric mucosa was examined for ulcerations. RESULTS: Diazoxide accelerated the healing of EAGU, whereas glibenclamide aggravated EAGU. The concomitant administration of glibenclamide antagonized the diaoxide effect. Diazoxide-induced acceleration of mucosal restitution was not abolished by DFMO. Cimetidine, omeprazole and atropine had no effect on the healing of EAGU. CONCLUSION: The K(ATP) channels may play an important role in the gastric mucosal restitution independent of polyamines. Acid inhibition cannot reverse EAGU.

Acute Disease↗

PubMed2000

Metabolic, cationic and secretory response to D-glucose in depolarized and Ca(2+)-deprived rat islets exposed to diazoxide.

D-glucose stimulates insulin release from islets exposed to both diazoxide, to activate ATP-responsive K+ channels, and a high concentration of K+, to cause depolarization of the B-cell plasma membrane. Under these conditions, the insulinotropic action of D-glucose is claimed to occur despite unaltered cytosolic Ca2+ concentration, but no information is so far available on the changes in Ca2+ fluxes possibly caused by the hexose. In the present experiments, we investigated the effect of D-glucose upon 45Ca efflux from islets exposed to both diazoxide and high K+ concentrations. In the presence of diazoxide and at normal extracellular Ca2+ concentration, D-glucose (16.7 mmol/l) inhibited insulin release at 5 mmol/l K+, but stimulated insulin release of 90 mmol/l K+. In both cases, the hexose inhibited 45Ca outflow. In the presence of diazoxide, but absence of Ca2+, D-glucose (8.3 to 25.0 mmol/l) first caused a rapid decrease in insulin output followed by a progressive increase in secretory rate. This phenomenon was observed both at 5 mmol/l or higher concentrations (30, 60 and 90 mmol/l) of extracellular K+. It coincided with a monophasic decrease in 45Ca efflux and either a transient (at 5 mmol/l K+) or sustained (at 90 mmol/l K+) decrease in overall cytosolic Ca2+ concentration. The decrease in 45Ca efflux could be due to inhibition of Na(+)-Ca2+ countertransport with resulting localized Ca2+ accumulation in the cell web of insulin-producing cells. A comparable process may be involved in the secretory response to D-glucose in islets exposed to diazoxide and a high concentration of K+ in the presence of extracellular Ca2+.

Animals↗

PubMed2001

Diazoxide protects mitochondria from anoxic injury: implications for myopreservation.

BACKGROUND: Heart muscle primarily relies on adenosine triphosphate produced by oxidative phosphorylation and is highly vulnerable to anoxic insult. Although a number of strategies aimed at improving myopreservation are available, no effective means of preserving mitochondrial energetics under conditions of anoxic injury have been developed. Openers of mitochondrial adenosine triphosphate-sensitive potassium channels have emerged as powerful cardioprotective agents presumably capable of maintaining mitochondrial function under metabolic stress. Here, we evaluated the ability of a prototype mitochondrial adenosine triphosphate-sensitive potassium channel opener, diazoxide, to preserve oxidative phosphorylation in mitochondria subjected to anoxia and reoxygenation. METHODS: Mitochondria were isolated from rat hearts and subjected to 20 minutes of anoxia, followed by reoxygenation. Mitochondrial respiration and oxidative phosphorylation, as well as mitochondrial integrity, were assessed by means of ion-selective minielectrodes, high-performance liquid chromatography, fluorometry, and electron microscopy. RESULTS: Anoxia-reoxygenation decreased the rate of adenosine diphosphate-stimulated oxygen consumption, inhibited adenosine triphosphate production, and disrupted mitochondrial integrity. On average, anoxic stress reduced adenosine diphosphate-stimulated respiration from 291 +/- 14 to 141 +/- 15 ng-atoms O(2). min(-1). mg(-1) protein and decreased the rate of adenosine triphosphate production from 752 +/- 14 to 414 +/- 34 nmol adenosine triphosphate. min(-1). mg(-1) protein. After anoxia, the majority (88%) of mitochondria was damaged or swollen and released adenylate kinase, a marker of mitochondrial integrity. Diazoxide (100 micromol/L), present throughout anoxia, preserved adenosine diphosphate-stimulated respiration at 255 +/- 7 ng-atoms O(2). min(-1). mg(-1) protein and adenosine triphosphate production at 640 +/- 39 nmol adenosine triphosphate. min(-1). mg(-1) protein. Diazoxide also protected mitochondrial structure from anoxia-mediated damage, so that after anoxic stress, 67% of mitochondria remained intact and adenylate kinase was confined to the mitochondria. CONCLUSIONS: The present study demonstrates that diazoxide diminishes anoxia-induced functional and structural deterioration of cardiac mitochondria. By protecting mitochondria and preserving myocardial energetics, diazoxide may be useful under conditions of reduced oxygen availability, including global surgical ischemia or storage of donor heart.

Adenosine Diphosphate↗

PubMed1994

An extrapancreatic action of diazoxide to inhibit glucose transport activity on adipocytes.

The effect of diazoxide on 3-O-methylglucose (3-O-MG) transport was studied in isolated rat adipocytes to elucidate its extrapancreatic action. Diazoxide (0.3-3 mmol/L) significantly inhibited 3-O-MG uptake into adipocytes in a basal state or an insulin-stimulated state. The inhibitory effect was mainly due to the inhibition of insulin responsiveness for 3-O-MG uptake. The insulin responsiveness is determined by the capacity in the process of insulin action and in the final glucose transport activity, and diazoxide mainly inhibited the 3-O-MG transport activity itself. Based on these findings, this extrapancreatic action of diazoxide is considered to contribute partially to raising the blood glucose level in children receiving the drug. Diazoxide, as a glucose transport inhibitor, may be a useful tool for studying the issues related to glucose transport or insulin action.

3-O-Methylglucose↗