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PubMed1975

The stimulation of renin secretion by diazoxide in the isolated rat kidney.

The intrarenal effect of diazoxide on renin secretion was examined in the isolated perfused rat kidney. Mean renin secretion measured at 2 min intervals during the continuous infusion of diazoxide for 6 min was consistently higher than the corresponding control values, although this was significantly different at the end of the infusion only. Since renal perfusion pressure during diazoxide infusion and control studies decreased to a similar extent, it is suggested that diazoxide stimulates renin secretion by a direct effect on the juxtaglomerular cell.

Animals↗

PubMed1977

Effect of diazoxide, verapamil and compound D600 on isoproterenol and calcium-mediated dose-response relationships in isolated rabbit atrium.

The effect of diazoxide, verapamil and compound D600 on calcium and isoproterenol dose-response relationships was investigated in isolated rabbit atrial preparations. All three agents shifted calcium dose-force relationships parallel and to the right. D600 acted as a competitive antagonist of calcium, as a plot of log (x - 1) vs. -log B resulted in a straight line with a slope of approximately -1.0. Diazoxide, verapamil and D600 also antagonized isoproterenol but in a non-competitive manner. A reduction of calcium in the bathing fluid produced a qualitatively similar non-competitive antagonism of isoproterenol and markedly potentiated diazoxide antagonism of isoproterenol. We conclude that: (1) diazoxide has calcium antagonistic properties similar to the "calcium antagonists" verapamil and D600; (2) these agents act as competitive antagonists of calcium through a specific site that is beyond the beta-adrenergic receptor and in the series of events between the beta-adrenergic receptors and inotropic response in myocardial tissue.

Adrenergic beta-Antagonists↗

PubMed1984

Systemic vasodilatation and renal sodium excretion: effects of hydralazine and diazoxide.

The effects on renal sodium excretion of two systemic vasodilators, hydralazine and diazoxide, were investigated in volume expanded, anesthetized rats with unilaterally denervated kidneys. Urinary sodium excretion and fractional excretion of filtered sodium increased following hydralazine but decreased following diazoxide. Changes in renal hemodynamics were dissimilar as well: renal plasma flow was increased following hydralazine, but unchanged with diazoxide. All changes in renal sodium excretion and renal hemodynamics following hydralazine were prevented by pretreatment with indomethacin. Renal denervation accentuated the increases in fractional sodium excretion and renal blood flow that occurred following hydralazine. Hydralazine and diazoxide differ substantially in their effects on renal sodium excretion, apparently due to the stimulation of renal prostaglandins by the former agent. Although renal innervation attenuates the natriuretic effect of hydralazine, stimulation of the sympathetic nervous system does not account for differences in the renal effects of these two drugs.

Animals↗

PubMed2005

Alterations of insulin secretion following long-term manipulation of ATP-sensitive potassium channels by diazoxide and nateglinide.

Previous studies have shown that prolonged exposure to drugs, which act via blocking KATP channels, can desensitize the insulinotropic effects of drugs and nutrients acting via KATP channels. In this study, effects of prolonged exposure to diazoxide, a KATP channel opener, on beta cell function were examined using clonal BRIN-BD11 cells. The findings were compared to the long-term effects of KATP channel blockers nateglinide and tolbutamide. Following 18 h exposure to 200 microM diazoxide, the amounts of insulin secreted in response to glucose, amino acids and insulinotropic drugs were increased. Secretory responsiveness to a variety of agents acting via KATP channels was retained following prolonged diazoxide exposure. In contrast, 18 h exposure to 100 microM nateglinide significantly attenuated the insulin secretory responses to tolbutamide, nateglinide and BTS 67 582. Glucose- and L-alanine-stimulated insulin release were unaffected by prolonged nateglinide exposure, however responsiveness to L-leucine and L-arginine was diminished. Prolonged exposure to nateglinide had no effect on forskolin- and PMA-stimulated insulin release, and the overall pattern of desensitization was similar to that induced by 100 microM tolbutamide. We conclude that in contrast to chronic long-term KATP channel blockade, long-term diazoxide treatment is not harmful to KATP channel mediated insulin secretion and may have beneficial protective effects on beta cell function.

Adenosine Triphosphate↗

PubMed2004

Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion.

Chronic cerebral hypoperfusion, a mild ischemic condition is associated with advancing age and severity of dementia; however, no unanimous therapy has been established to alleviate related neurological symptoms. We imposed a permanent, bilateral occlusion of the common carotid arteries of rats (n=18) to create cerebral hypoperfusion. A mitochondrial ATP-sensitive K+ channel opener diazoxide (DZ, 5 mg/kg) or its solvent dimethyl sulphoxide (DMSO) were administered i.p. (0.25 ml) on five consecutive days after surgery. Sham-operated animals (n=18) served as control for the surgery, while nontreated rats were used as control for the treatments. Three months after the onset of cerebral hypoperfusion, the rats were tested in a hippocampus-related learning paradigm, the Morris water maze. Subsequently, the animals were sacrificed and neurons, astrocytes and microglia were labeled with immunocytochemistry in the dorsal hippocampus. DMSO and diazoxide dissolved in DMSO restored cerebral hypoperfusion-related learning dysfunction and prevented cyclooxygenase-2-positive neuron loss in the dentate gyrus. Cerebral hypoperfusion led to reduced astrocyte proliferation, which was not clearly affected by the treatment. Microglia activation was considerably enhanced by cerebral hypoperfusion, which was completely prevented by diazoxide dissolved in DMSO, but not by DMSO alone. We conclude that diazoxide can moderate ischemia-related neuroinflammation by suppressing microglial activation. Furthermore, we suggest that DMSO is a neuroprotective chemical in ischemic conditions, and it must be considerately used as a solvent for water-insoluble compounds in experimental animal models.

Animals↗

PubMed2004

Inhibition of phenylephrine induced hypertrophy in rat neonatal cardiomyocytes by the mitochondrial KATP channel opener diazoxide.

The effect of the putative mitochondrial K(ATP) channel opener diazoxide (100 microM) was studied in terms of its ability to modulate the hypertrophic effect of 24 h treatment with the alpha(1) adrenoceptor agonist phenylephrine (PE; 10 microM) in cultured neonatal rat ventricular myocytes. PE on its own significantly increased cell size by 40%, (3)H leucine incorporation by 37% and produced more than a threefold elevation in both atrial natriuretic peptide and myosin light chain-2 expression. These effects were nearly completely prevented by diazoxide although the inhibitory effect of this agent was generally mitigated by the mitochondrial K(ATP) channel antagonists 5-hydroxydecanoic acid (100 microM) and glibenclamide (50 microM). Although PE produced an early threefold elevation in MAP kinase activation this was generally unaffected by diazoxide. PE also produced a greater than threefold increase in Na-H exchanger isoform 1 (NHE-1) expression which, was prevented by diazoxide treatment. Our study therefore, demonstrates a potential antihypertrophic influence of mitochondrial K(ATP) channel activation which, is related to diminished NHE-1 expression. Mitochondrial K(ATP) channel activation could represent an effective approach to minimize the myocardial hypertrophic process.

Adrenergic alpha-1 Receptor Agonists↗

PubMed1975

Intravenous diazoxide in acute poststreptococcal glomerulonephritis.

Twenty-six patients with hypertension secondary to acute poststreptococcal glomerulonephritis were treated by the rapid intravenous infusion of diazoxide. The average pretreatment systolic pressure was 159 mm Hg. Five minutes after administration, the average systolic pressure was 122 mm Hg (a 23% reduction). The average initial diastolic pressure was 104 mm Hg, which fell 5 minutes after diazoxide injection to 71 mm Hg (a 32% reduction). No hypotensive episodes were noted. Occasional episodes of nausea occurred. Concentrations of blood glucose increased after administration of diazoxide; however, no values were above 155 mg/dl. Diazoxide appears to be a safe antihypertensive drug that is effective in the treatment of hypertension secondary to acute poststreptococcal glomerulonephritis.

Acute Disease↗

PubMed1998

4H-1,2,4-Pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4H-1,2, 4-pyridothiadiazine 1,1-dioxides chemically related to diazoxide and cyclothiazide as powerful positive allosteric modulators of (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors: design, synthesis, pharmacology, and structure-activity relationships.

A series of 4H-1,2,4-pyridothiadiazine 1,1-dioxides and 2, 3-dihydro-4H-1,2,4-pyridothiadiazine 1,1-dioxides bearing various alkyl and aryl substituents on the 2-, 3-, and 4-positions was synthesized and tested as possible positive allosteric modulators of the (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. Many compounds were found to be more potent than the reference compounds diazoxide and aniracetam as potentiators of the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most active compound, 4-ethyl-2,3-dihydro-4H-pyrido[3,2-e]-1,2, 4-thiadiazine 1,1-dioxide (31b), revealed an in vitro activity on Xenopus oocytes not far from that of cyclothiazide, the most potent allosteric modulator of AMPA receptors reported to date. Moreover, 31b, but not cyclothiazide, was found to potentiate the duration and the amplitude of the excitatory postsynaptic field potentials induced by electric stimulation in rat hippocampal slices. Such an effect could indicate, for 31b, but not for cyclothiazide, a possible interaction with postsynaptic AMPA receptor binding sites located on hippocampal CA1 neurons. Structure-activity relationships indicated that the structural requirements responsible for a biological activity on AMPA receptors are different from those responsible for an inhibitory activity on the insulin releasing process (putative ATP-sensitive K+-channel openers). For instance, 31b and other related dihydropyridothiadiazines were found to be ineffective as inhibitors of insulin release from rat pancreatic B-cells, in contrast to diazoxide and known pyridothiadiazines reported as ATP-sensitive K+-channel openers. Conversely, the pyridothiadiazines active on B-cells were found to be ineffective as potentiators of the AMPA currents in Xenopus oocytes. Thus, 31b appeared to be more specific than diazoxide as an AMPA receptor modulator. This compound may be considered as a new pharmacological tool, different from diazoxide and cyclothiazide, for studying AMPA receptors. Moreover, 31b can also constitute a new therapeutic agent for the treatment of cognitive disorders.

Adenosine Triphosphate↗

PubMed1986

Post-receptor insulin resistance after diazoxide in non-insulin dependent diabetes.

Insulin binding to monocytes and the counterregulatory hormone response to intravenous insulin was determined in six normal subjects and eight patients with non-insulin dependent diabetes mellitus (NIDDM), before and after seven days treatment with oral diazoxide. In the normal subjects diazoxide had no effect on insulin binding or sensitivity. In the patients with NIDDM diazoxide caused resistance to intravenous insulin with no change in the counterregulatory hormone response or in insulin binding to account for this. Diazoxide appears to cause post-receptor insulin resistance in NIDDM, and it may be a useful tool for studying post-receptor binding events.

Adult↗

PubMedDate not supplied

Diazoxide in the management of chlorpropamide overdose.

Three cases of chlorpropamide overdose are reported. Plasma levels of chlorpropamide, diazoxide, glucose, and insulin are presented for each patient during treatment. The simultaneous analysis of chlorpropamide, hydrochlorothiazide, and diazoxide in plasma by high pressure liquid chromatography (HPLC) is also reported. Although all three cases presented at hospital with potentially lethal plasma levels of chlorpropamide, each was successfully treated with intravenous diazoxide and glucose. Plasma diazoxide concentrations between 50-100 microgram/mL appear to be optimal in achieving therapeutic control of chlorpropamide induced hypoglycemia.

Adolescent↗

PubMed2006

Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy.

BACKGROUND: Antihypertensive drugs such as clonidine, diazoxide, hydralazine and furosemide are used in the hypertensive disorders of pregnancy to control blood pressure, but it is not clear if they modulate the production of placental or circulating cytokines. OBJECTIVE: To examine the effect of pharmaceutical doses of well known antihypertensive drugs used for blood pressure control on the production of the cytokines interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-alpha in placental tissue and peripheral blood mononuclear cells (PBMCs) in normal pregnancy. DESIGN: Placental biopsies were taken from the decidual surface of placentas after delivery of normal pregnancies (n = 6) and PBMCs were separated from the whole blood of normal term pregnant women (n = 7). Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs. The dose effect of drugs on the production of placental and circulating cytokines (IL-6, IL-10 and TNF-alpha) were examined by enzyme-linked immunosorbent assay. RESULTS: Placental production of IL-10 was not affected by clonidine, but decreased significantly after incubation of the tissue with diazoxide, hydralazine or furosemide. Production of IL-10 by PBMCs increased significantly: by from 3.4 +/- 2.7% [16.3 pg/ml (range 6.1-21.5 pg/ml)] to 24.5 +/- 3.3% [30.4 pg/ml (range 16.9-34.8 pg/ml)] with increasing concentrations of clonidine (0.08-1.3 microg/ml), and by 8.8 +/- 3.5% [4.1 pg/ml (range 3.0-17.8 pg/ml)] and 17.2 +/- 1.9% [22.6 pg/ml (range 13.2-23.2 pg/ml)] with lower doses of hydralazine (6.3 and 12.5 microg/ml) (all P values < 0.05). There was a stepwise reduction in production of TNF-alpha and IL-6 with increasing doses of diazoxide, hydralazine and furosemide by placentas and PBMCs from these women with normal pregnancies. CONCLUSION: Our data suggest that the antihypertensive drugs clonidine and hydralazine can stimulate production of the circulating anti-inflammatory cytokine IL-10, whereas furosemide and diazoxide inhibit the production of this cytokine and the proinflammatory cytokines TNF-alpha and IL-6 by placentas and PBMCs.

Antihypertensive Agents↗

PubMed1983

Effect of diazoxide-induced hypotension on cerebral blood flow in hypertensive rats.

The effect on cerebral blood flow of acute diazoxide-induced hypotension was studied in rats with renal and spontaneous hypertension. Diazoxide (5 mg/kg, i.v. bolus), caused arterial pressure to fall rapidly to that of normotensive rats, i.e. c. 75 mmHg. There was a concomitant fall in cerebral blood flow of about 35% (P less than 0.01) in renal hypertensive rats and 25% (P less than 0.05) in spontaneously hypertensive rats; the greater fall in flow in the former corresponded to a greater drop in pressure. Flow remained at these reduced levels during a 2 h observation period. Histological examination revealed small areas of ischaemic damage in the brains of five of the twelve animals. In control hypertensive rats not given diazoxide, cerebral blood flow and blood pressure were stable during a 2 1/2 h period and there was no evidence of ischaemic damage to the brains. The diazoxide-induced reduction in cerebral blood flow was interpreted as being secondary to a blood pressure fall to below the lower limit of cerebral blood flow autoregulation. No evidence was found of direct effects on the cerebral circulation such as seen with ganglionic blockers, alpha-blockers and cerebral vasodilators.

Animals↗

PubMed1994

Inhibitory effects of diazoxide or polymyxin B on glucose transport by isolated rat erythrocytes or adipocytes.

The inhibitory effects of diazoxide or polymyxin B on 3-O-methylglucose uptake were studied in isolated rat erythrocytes or adipocytes to elucidate the mechanisms of the actions of these agents. One to three mmol/L diazoxide significantly inhibited 3-O-methylglucose uptake into erythrocytes by 11-33% without altering the equilibrium space, while 0.3 mmol/L diazoxide did not. The inhibitory effect was exerted in a dose-dependent manner in this concentration range. To test whether polymyxin B affects the process of insulin action or the glucose transport activity recruited by insulin, adipocytes prestimulated with insulin and exposed to 2 mmol/L potassium cyanide (KCN) were employed since the cells, on which glucose transporters recruited by insulin were located quiescently, were useful to estimate the effect of an agent on glucose transport activity per se. Polymyxin B (100 micrograms/mL) inhibited the insulin-stimulated uptake activity in this transport system by 22.5% while it inhibited the insulin-stimulated uptake activity in intact adipocytes which were not exposed to KCN by 32.2%. These results suggest that diazoxide inhibits the function of the erythrocyte glucose transporter, GLUT1 (classified by Bell et al.), and indicate that the inhibition of the glucose transport activity recruited by insulin is the major effect of polymyxin B (100 micrograms/mL) and the inhibition of the process of insulin action is rather small.

3-O-Methylglucose↗

PubMed1973

Effect of single dose administration of diuretics on the blood sugar of alloxan-diabetic mice or mice made hyperglycaemic by the acute administration of diazoxide.

1. Frusemide produced hyperglycaemia in mice when administered together with diazoxide. The interaction between the drugs in elevating the blood sugar was shown to be additive.2. The diuretic, natriuretic and kaliuretic effects of frusemide were very markedly attenuated by diazoxide.3. Neither ethacrynic acid nor hydrochlorothiazide exerted any effect upon blood sugar when administered together with diazoxide.4. Bilateral nephrectomy completely prevented the hyperglycaemic effect of frusemide in normal mice and in mice treated with diazoxide. Diazoxide itself still produced hyperglycaemia in nephrectomized mice.5. Frusemide, ethacrynic acid and diazoxide, but not hydrochlorothiazide, each produced hyperglycaemia in alloxan-diabetic mice, this being prevented by bilateral nephrectomy.

Animals↗

PubMed1981

Effect of diazoxide on the antepartum cardiotocograph in severe pregnancy-associated hypertension.

Intravenous diazoxide was given to 8 patients with severe pregnancy-associated hypertension (diastolic pressure greater than or equal to 110) in the antepartum period. Maternal hypertension was rapidly controlled in all patients; the diastolic blood pressure fell to less than or equal to 100 in all patients and to less than or equal to 85 in 7. Diazoxide had no significant effect on the basal fetal heart rate (FHR) or on the latency period or amplitude of late decelerations in the 3 patients with abnormal (positive) stress cardiotocographs (SCTG) and abnormal (unreactive) non-stress cardiotocographs (NSCTG). In the 5 patients with reactive NSCTGs, diazoxide had no significant effect on the basal FHR or on the frequency of fetal movement-induced FHR accelerations. Thus, diazoxide did not adversely affect fetal well-being in these patients with severe pregnancy-associated hypertension as assessed by cardiotocography.

Blood Pressure↗

PubMed1989

Effect of diazoxide and hydralazine on intestinal transit and blood pressure in the rat.

This study examines the effects of diazoxide and hydralazine on gastrointestinal and vascular smooth muscle. The effect of the drugs administered individually and in combination was determined on small intestinal transit and blood pressure in adult male Sprague-Dawley rats. Both diazoxide and hydralazine produced dose-dependent decreases in the ratio of intestinal transit to total length. Additionally, combinations of various doses of hydralazine and diazoxide produced a greater than simple summation of the inhibitory effects on intestinal transit. The combination of diazoxide and hydralazine produced only a simple additive effect on mean arterial pressure.

Animals↗

PubMed1996

The sulphonylurea receptor confers diazoxide sensitivity on the inwardly rectifying K+ channel Kir6.1 expressed in human embryonic kidney cells.

1. We have examined the effects of diazoxide and intracellular ATP (ATPi) on whole-cell currents in HEK293 cells transfected transiently with the inwardly rectifying K+ channel Kir6.1 (uKATP1) or cotransfected with Kir6.1 and the sulphonylurea receptor (SUR1). 2. Kir6.1 currents were unaffected by the K+ channel opener diazoxide or by dialysis with 0.3 mM ATPi. 3. Kir6.1-SUR1 currents increased in amplitude when cells were dialysed with 0.3 mM ATP, but not with 5 mM ATP. This activation may be explained by the loss of endogenous ATP from the cell when the intracellular solution contains 0.3 mM ATP. Kir6.1-SUR1 currents were also activated by diazoxide; this activation was greater with 0.3 mM ATP1 than with 5 mM ATP1. 4. We conclude that SUR1 is required to confer both diazoxide and ATP sensitivity on Kir6.1.

Adenosine Triphosphate↗

PubMed1999

Diazoxide-induced insulin deficiency greatly reduced muscle protein synthesis in rats: involvement of eIF4E.

We have investigated the effect of a postprandial acute insulin deficiency induced by diazoxide injection on rat skeletal muscle protein synthesis. Diazoxide administration lowered plasma insulin >85% within 3 h after injection, whereas other hormones (insulin-like growth factor I, glucagon, corticosterone) involved in the regulation of muscle protein synthesis were not altered significantly compared with control animals. The fractional rate of muscle protein synthesis, measured in vivo, was reduced significantly (P < 0.05) in epitrochlearis (-46%), gastrocnemius (-41%), and soleus (-35%). The reduction in protein synthesis did not result from a reduced total RNA content but was associated with diminished translation efficiency. Analysis of ribosomal subunits revealed that the decreased translation efficiency resulted from an impairment in the initiation phase of protein synthesis. Diazoxide-induced insulin deficiency was associated with a dramatic decrease in eukaryotic initiation factor (eIF) 4G bound to eIF4E and a 2.5-fold increase in the amount of the eIF4E. 4E-binding protein 1 (BP1) complex. In contrast, diazoxide injection did not change either the relative amount of eIF4E present in gastrocnemius or its phosphorylation state. These results indicate that an acute insulin deficiency significantly decreases postprandial muscle protein synthesis by modulating the interaction between 4E-BP1, eIF4G, and eIF4E to control translation initiation.

Animals↗