SEARCH · PubMed Health

Results for “DIAZOXIDE”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 991 records · Page 55Linked to original sources

PubMed1994

Effects of sulphonylureas on cAMP-stimulated Cl- transport via the cystic fibrosis gene product in human epithelial cells.

The cystic fibrosis gene product (CFTR) is a Cl- channel that possesses specific binding sites for cytosolic adenosine triphosphate (ATP) and is activated by cyclic adenosine monophosphate (cAMP)-dependent protein kinases. We explored the possibility that CFTR shares a common pharmacology with another ATP-regulated channel protein, the ATP-sensitive K+ channel that is blocked by sulphonylureas and activated by diazoxide. cAMP-stimulated Cl- effluxes were measured with 36Cl- in the epithelial cell line T84 which stably expresses CFTR. Neither glibenclamide (30 microM), tolbutamide (1 mM) nor diazoxide (100 microM) significantly affected forskolin-activated 36Cl- effluxes in T84 cells. In patch-clamp experiments, glibenclamide exerted only weak inhibitory effects on the whole-cell currents through CFTR with an IC50 of around 0.1 mM. Tolbutamide at 1 mM, but not at 0.1 mM, blocked a current of small amplitude which reversed near the equilibrium potential for K+ ions. We conclude that sulphonylureas and diazoxide are not effective antagonists of endogenous CFTR Cl- channels.

Adenosine Triphosphate↗

PubMed1983

Transient lactic acidosis and hyperalaninaemia associated with neonatal hyperinsulinaemic hypoglycaemia: the effects of dichloroacetate (DCA).

Soon after birth a 36-week-gestational age, appropriate for dates, newborn infant developed hyperinsulinaemic hypoglycaemia which responded to diazoxide and glucose infusion. While normoglycaemic, he became increasingly ill with high lactate, pyruvate, and alanine levels. Provocation tests suggested a defect in lactate handling. Dichloroacetate (DCA) was given and resulted in the prompt normalisation of his metabolic profile with no recurrence after discontinuation of the drug. A second episode of hyperinsulinaemic hypoglycaemia followed and this was controlled satisfactorily by short term diazoxide treatment. Diazoxide treatment could be stopped at the age of 1 month. Although at the age of 1.5 years the infant is retarded developmentally, there has been no recurrence of lactic acidosis nor hyperinsulinaemic hypoglycaemia. The association of lactic acidosis and hyperinsulinism, and the use of DCA in this circumstance have not been reported previously.

Acetates↗

PubMed2003

Protection of rat pancreatic islets by potassium channel openers against alloxan, sodium nitroprusside and interleukin-1beta mediated suppression--possible involvement of the mitochondrial membrane potential.

AIMS/HYPOTHESIS: We aimed to study the effects of two K(ATP) channel openers (KCO), diazoxide and the more potent compound NNC 55-0118, on beta-cell suppression and/or toxicity induced by alloxan, sodium nitroprusside and IL-1beta. METHODS: Islets from rats were exposed to 0.3 mmol/l diazoxide or NNC 55-0118 for 30 min and either alloxan (0.5 mmol/l), sodium nitroprusside (0.5 mmol/l) or IL-1beta (12.5 or 25 U/ml) were added and the incubation continued for 30 min. Islets were then washed and incubated for 24 h before examination. RESULTS: After exposure to alloxan, islets showed reduced glucose oxidation rate and impaired glucose-stimulated insulin release. NNC 55-0118 counteracted the effects of alloxan, while diazoxide was less effective. After treatment with sodium nitroprusside, islet glucose oxidation rates were reduced and this was prevented by pretreatment with NNC 55-0118. In short-term experiments the potassium channel openers (KCOs) did not influence the IL-1beta effect on insulin secretion. However, long-term addition (24 h) of NNC 55-0118 counteracted IL-1beta induced inhibition of the glucose oxidation rate. It was shown, using the fluorescent probe JC-1, that the mitochondrial membrane potential was reduced by the potassium channel openers (KCOs), most strongly by NNC 55-0118. Nevertheless culture with KCOs for 72 h did not cause irreversible damage to the islets. CONCLUSION/INTERPRETATION: Potassium channel openers (KCOs), in particular NNC 55-0118, prevented the toxic effects of alloxan and sodium nitroprusside. IL-1beta mediated suppression was reduced by NNC 55-0118 provided the long-term addition of the potassium channel opener (KCO). The protective mechanism of potassium channel openers (KCOs) might involve a decrease of the mitochondrial membrane potential.

Alloxan↗

PubMed2000

Characterization of ATP-sensitive potassium channels functionally expressed in pituitary GH3 cells.

ATP-sensitive K+ (KATP) channels have been characterized in pituitary GH3 cells with the aid of the patch-clamp technique. In the cell-attached configuration, the presence of diazoxide (100 microM) revealed the presence of glibenclamide-sensitive KATP channel exhibiting a unitary conductance of 74 pS. Metabolic inhibition induced by 2,4-dinitrophenol (1 mM) or sodium cyanide (300 microM) increased KATP channel activity, while nicorandil (100 microM) had no effect on it. In the inside-out configuration, Mg-ATP applied intracellularly suppressed the activity of KATP channels in a concentration-dependent manner with an IC50 value of 30 microM. The activation of phospholipase A2 caused by mellitin (1 microM) was found to enhance KATP channel activity and further application of aristolochic acid (30 microM) reduced the mellitin-induced increase in channel activity. The challenging of cells with 4,4'-dithiodipyridine (100 microM) also induced KATP channel activity. Diazoxide, mellitin and 4,4'-dithiodipyridine activated the KATP channels that exhibited similar channel-opening kinetics. In addition, under current-clamp conditions, the application of diazoxide (100 microM) hyperpolarized the membrane potential and reduced the firing rate of spontaneous action potentials. The present study clearly indicates that KATP channels similar to those seen in pancreatic beta cells are functionally expressed in GH3 cells. In addition to the presence of Ca(2+)-activated K+ channels, KATP channels found in these cells could thus play an important role in controlling hormonal release by regulating the membrane potential.

2,4-Dinitrophenol↗

PubMed2003

Ischaemic preconditioning and a mitochondrial KATP channel opener both produce cardioprotection accompanied by F1F0-ATPase inhibition in early ischaemia.

Ischaemic preconditioning gives powerful protection against prolonged ischaemia affecting several intracellular regulatory and messenger pathways, although their mutual importance is far from established. Protective, preconditioning-like effects have been reported for K(ATP) channel openers, and most of the evidence points to the mitochondrial K(ATP) channels. We show here that the K(ATP) channel opener diazoxide, which acts selectively on the mitochondrial channel, causes potentiation of ischaemic inhibition of mitochondrial ATP synthase (F(1)F(0)-ATPase) along with cardioprotection. These effects are comparable with that of ischaemic preconditioning. The administration of diazoxide did not affect the cellular energy state as monitored with (31)P NMR. The actions of both diazoxide and ischaemic preconditioning were prevented by 5-hydroxydecanoate, a specific inhibitor of the mitochondrial K(ATP) channel. Thus mitochondrial K(ATP) channel opening and ischaemic preconditioning must share common mechanisms of action involving mitochondrial F(1)F(0)-ATPase, although involvement of the energy state in protection could not be proved.

Adenosine Diphosphate↗

PubMed2006

Total cellular calcium and magnesium content of cultured human peripheral blood mononuclear cells following exposure to antidiabetic drugs.

Drugs modulating the ATP-sensitive potassium (K(ATP)) channel activity are widely used for the treatment of diabetes mellitus, the target being pancreatic beta-cells. However, any cell type possessing K(ATP) channels might be concomitantly affected. We investigated the metabolic effect of glibenclamide, a K(ATP) channel closer, and/or diazoxide, a K(ATP) channel opener, on total intracellular content of calcium (Ca) and magnesium (Mg) of cultured peripheral blood mononuclear cells (PBMC). Metformin and rosiglitazone, acting via cellular mechanisms other than K(ATP) channels, were also tested. Ca and Mg were assessed in PBMC from healthy subjects following 72 h in vitro treatment with the respective drugs. Ca content increased significantly in PBMC treated with glibenclamide or rosiglitazone, however apparently via different intracellular pathways. Mg increased only following treatment with rosiglitazone. Metformin had no effect on intracellular Ca or Mg. Pretreatment with diazoxide resulted in a significant intracellular Ca and Mg loss in each experimental situation. If verified clinically, rosiglitazone-induced increase in Mg content of PBMC might prove beneficial beyond hypoglycaemic control. On the other hand, loss of intracellular Ca/Mg content following K(ATP) channel opening by diazoxide might eventually result in significant intracellular Ca and/or Mg depletion.

Adult↗

PubMed1992

Effectors of ATP-sensitive K+ channels inhibit the regulatory effects of somatostatin and GH-releasing factor on growth hormone secretion.

Somatostatin inhibition of growth hormone (GH) secretion from adenohypophysis cells in culture was antagonized by the antidiabetic sulfonylurea glipizide (K0.5 = 10 +/- 5 nM). Although all cells that hyperpolarize with somatostatin have ATP-sensitive K+ channels, the antagonistic actions of the hormone and of the antidiabetic drug are due to effects on different types of K+ channels. Diazoxide, an opener of ATP-sensitive K+ channels, abolished the increase of intracellular Ca2+ provoked by growth hormone releasing factor (GRF) and induced inhibition of GRF stimulated GH secretion (K0.5 = 138 microM). This inhibition by diazoxide was largely suppressed by glipizide which blocked the ATP-sensitive K+ channels opened by diazoxide. In summary, hormonal activation of GH secretion is inhibited by openers of ATP-sensitive K+ channels, while hormonal inhibition of GH secretion is suppressed by blockers of ATP-sensitive K+ channels.

Adenosine Triphosphate↗

PubMed1994

In vitro stimulation of insulin release by SL 84.0418, a new alpha 2-adrenoceptor antagonist.

SL 84.0418 (2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2-propyl-pyrrolo[3, 2,1- hi]-indole hydrocholoride) is a novel alpha 2-adrenoceptor antagonist which possesses anti-hyperglycaemic properties in vitro study, we tested its effects on insulin release from isolated mouse islets. In the presence of 15 mM glucose, SL 84.0418 produced a concentration-dependent (0.1-100 microM) increase of insulin release with a slightly higher potency than tolbutamide. SL 84.0418 antagonized the inhibition of glucose-induced insulin release caused either by the alpha 2-adrenoceptor agonist clonidine or by diazoxide, a selective opener of ATP-sensitive K+ channels in the beta-cell membrane. Its potency was greater on the inhibition by clonidine than on that by diazoxide, complete antagonism of the inhibition being achieved by 0.9 microM and 6 microM SL 84.0418 respectively. When alpha 2-adrenoceptors were blocked by the antagonist idazoxan, the low concentrations of SL 84.0418 (0.1-0.3 microM) no longer increased insulin release, whereas the effect of higher concentrations (> or = 1 microM) was not affected. SL 84.0418 (> or = 1 microM) inhibited 86Rb efflux from islets perifused with a medium containing 3 mM glucose, i.e. under conditions where many ATP-sensitive K+ channels are open. It also reduced the acceleration of 86Rb efflux that diazoxide caused in the presence of 6 mM glucose. Moreover, SL 84.0418 directly inhibited ATP-sensitive K+ currents measured in single beta-cells by the whole-cell mode of the patch-clamp technique.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1994

Potassium channel activators counteract anoxic hyperexcitability but not 4-aminopyridine-induced epileptiform activity in the rat hippocampal slice.

The K+ channel activators diazoxide and cromakalim were investigated for effects on 4-aminopyridine (4AP)-induced epileptiform activity in adult rat hippocampal slices maintained in vitro. Under normal conditions of oxygenation, 4AP (50 microM) induced two types of field potentials in extracellular recordings from the CA3 stratum radiatum (apical dendritic region): epileptiform interictal discharge-like events occurring at a frequency of 0.75 +/- 0.36 Hz and long-lasting negative-going potentials mediated by GABA receptor activation that occurred at 0.03 +/- 0.01 Hz (n = 36 slices). Neither diazoxide (0.65-1.3 mM, n = 21 slices) nor cromakalim (50-200 microM, n = 6 slices) altered these two types of discharge. Brief periods of anoxia (4-6 min) reduced the frequency of the 4AP-induced interictal-like events (from 0.75 +/- 0.36 Hz to 0.19 +/- 0.15 Hz, n = 20 slices). In 45% of the experiments, the depressant effect of anoxia was preceded by a period of hyperexcitability consisting of a transient (36.1 +/- 12.9 sec) increase in the frequency of interictal-like events riding on a negative-going DC shift (n = 9 slices). Both responses to anoxia were reversible upon reoxygenation. In contrast, the rate of occurrence of the GABA-mediated potentials was unaffected by the anoxic episodes. Perfusion with cromakalim (n = 4 slices) or diazoxide (n = 5 slices) abolished the initial period of hyperexcitability produced by O2 deprivation but did not alter the subsequent depression of activity. Our experiments indicate that the K+ channel activators can prevent the initial hyperexcitability produced by anoxia, but do not influence 4AP-induced epileptiform activity in normoxic conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗

PubMed2006

Role of the sarcolemmal adenosine triphosphate-sensitive potassium channel in hyperkalemic cardioplegia-induced myocyte swelling and reduced contractility.

BACKGROUND: Hyperkalemic cardioplegia (Plegisol) has been shown to result in myocyte swelling and reduced contractility. We have demonstrated the elimination of these detrimental effects by the addition of an adenosine triphosphate-sensitive K+ (KATP) channel opener. To examine whether the mitochondrial or sarcolemmal KATP channel might be involved, volume and contractility in isolated myocytes from wild-type mice and mice lacking the sarcolemmal KATP channel (Kir6.2-/-) were evaluated. METHODS: Myocytes were perfused for 20 minutes each with control 37 degrees C Tyrode's solution, test solution, and then control solution. Test solutions were (n = 10 per group) either 9 degrees C Plegisol or 9 degrees C Plegisol with 100 micromol/L of diazoxide, a putative mitochondrial-specific KATP channel opener. Cell volume and contractility were measured by digital video microscopy at baseline and during the test solution and reexposure periods. RESULTS: Myocytes from wild-type mice, perfused with 9 degrees C Plegisol, demonstrated significant cell swelling (11.2% +/- 0.4%; p < 0.01) and diminished contractility (32.5% +/- 9.6% reduction in percent shortening, 47.2% +/- 10.1% reduction in peak velocity of shortening, and 52.0% +/- 8.8% reduction in peak velocity of relengthening; p < 0.05) versus baseline. Cell swelling and diminished contractility were significantly reduced by the addition of diazoxide. In Kir6.2-/- myocytes, Plegisol caused a greatly reduced level of cell swelling (3.2% +/- 0.1%; p < 0.01), and this was unaffected by diazoxide. Contractility was unchanged in Kir6.2-/- myocytes after Plegisol. CONCLUSIONS: The sarcolemmal KATP channel appears necessary for exaggerated cell swelling and reduced contractility to occur after hyperkalemic cardioplegia in mouse myocytes.

Animals↗

PubMed2005

Mitochondrial K(ATP) channels in respiratory neurons and their role in the hypoxic facilitation of rhythmic activity.

Hypoxia is damaging in neurons, but it can also produce beneficial effects by consolidating the activity of neural networks such as facilitation of respiratory activity [T.L. Baker-Herman, D.D. Fuller, R.W. Bavis, A.G. Zabka, F.J. Golder, N.J. Doperalski, R.A. Johnson, J.J. Watters, G.S. Mitchell, Nature Neuroscience 7 (2004) 48-55; J.L. Feldman, G.S. Mitchell, E.E. Nattie, Ann. Rev. Neurosci. 26 (2003) 239-266; D.M. Blitz, J.M. Ramirez, J. Neurophysiol. 87 (2002) 2964-2971]. The underlying mechanisms are unknown, and we hypothesized they may be similar to ischemic preconditioning in the heart, involving mitochondrial K(ATP) (mK(ATP)) channels. By measuring the mitochondrial potential (Psi(m)) and Ca2+ ([Ca2+]m) in neurons of pre-Botzinger complex (pBC), we examined the functional expression of mK(ATP) channels in the respiratory network. The opener of mK(ATP) channels diazoxide decreased Psi(m) and [Ca2+]m both in pBC neurons and in isolated immobilized mitochondria. 5-Hydroxydecanoate (5-HD), the blocker of mK(ATP) channels, increased both Psi(m) and [Ca2+]m. Phorbol 12-myristate-13-acetate (PMA) mimicked the effects of diazoxide. Protein kinase C (PKC) was stimulated during hypoxia that occurred mostly at the mitochondria. Brief hypoxia induced facilitation of the respiratory activity, which was prevented after blockade of mK(ATP) channels with 5-HD and PKC with staurosporine. Diazoxide potentiated the motor output and subsequent application of hypoxia was ineffective. We propose that a PKC-induced stimulation of K(ATP) channels in the mitochondria of respiratory neurons is responsible for the hypoxic facilitation of rhythmic activity.

Animals↗

PubMed2004

Influence of central administration ATP-dependent K+ channel on morphine state-dependent memory of passive avoidance.

Pre-training injection of a moderate dose of morphine (5-10 mg/kg) in a step-down passive avoidance task induced state-dependent learning with impaired memory retrieval on the test day. The impairment of memory was restored after the pre-test administration of the same dose of the drug. We have studied the effect of intracerebroventricular administration of naloxone and K(ATP) channel modulators (glibenclamide and diazoxide) on the test day on restoration of memory by morphine in mice. The effect of scopolamine on restoration of memory on the test-day by glibenclamide was studied as well. Naloxone pretreatment (0.006, 0.025 and 0.1 microg/mouse) reversed the effect of pre-test morphine administration. The K(ATP) channel blocker, glibenclamide (0.1, 0.5 and 1 microg/mouse), showed effects similar to those of pre-test administration of morphine. Glibenclamide tended to potentiate the morphine response. Scopolamine (0.15 and 0.30 microg/mouse) prevented the effect of glibenclamide on the restoration of memory. The pre-test administration of different doses of diazoxide (1.7, 5 and 15 microg/mouse), a K(ATP) channel opener, showed no effect on restoration of memory when used alone but decreased morphine state-dependence. Diazoxide blocked the effects of glibenclamide on memory restoration. It is concluded that K(ATP) channel modulators may be involved, at least in part, in morphine state dependence through a cholinergic system mechanism.

ATP-Binding Cassette Transporters↗

PubMed2006

LPS from Escherichia coli protects against indomethacin-induced gastropathy in rats--role of ATP-sensitive potassium channels.

The effect of lipopolysaccharide (LPS) in gastric protection has not been elucidated, but ATP-sensitive potassium (K(ATP)) channels are known to be involved in gastric defense. We evaluated the effect of LPS administration on indomethacin-induced gastropathy, and the role of K(ATP) channels in this event. Rats received intravenous (i.v.) LPS administration. After 1/2, 6, 24 or 48 h, indomethacin was injected. 3H later, gastric damage and myeloperoxidase activity were determined. Another group received LPS and 5 h later, glibenclamide, diazoxide or glibenclamide plus diazoxide. After 1 h, the rats received indomethacin and 3 h later, gastric damage and myeloperoxidase activity were evaluated. LPS reduced dose dependently gastric damage and myeloperoxidase activity induced by indomethacin. Glibenclamide reversed this LPS effect on indomethacin-induced gastropathy. Glibenclamide plus diazoxide administration did not change this LPS effect. Thus LPS has a protective effect against indomethacin-induced gastropathy, probably through activation of K(ATP) channels.

Analysis of Variance↗

PubMed2001

Opening of mitochondrial ATP-sensitive potassium channels enhances cardioplegic protection.

BACKGROUND: Mitochondrial and sarcolemmal ATP-sensitive potassium channels have been implicated in cardioprotection; however, the role of these channels in magnesium-supplemented potassium (K/Mg) cardioplegia during ischemia or reperfusion is unknown. METHODS: Rabbit hearts (n = 76) were used for Langendorff perfusion. Sham hearts were perfused for 180 minutes. Global ischemia hearts received 30 minutes of global ischemia and 120 minutes of reperfusion. K/Mg hearts received cardioplegia before ischemia. The role of ATP-sensitive potassium channels in K/Mg cardioprotection during ischemia and reperfusion was investigated, separately using the selective mitochondrial ATP sensitive potassium and channel blocker, 5-hydroxydecanoate, and the selective sarcolemmal ATP-sensitive potassium channel blocker HMR1883. Separate studies were performed using the selective mitochondrial ATP-sensitive potassium channel opener, diazoxide, and the nonselective ATP-sensitive potassium channel opener pinacidil. RESULTS: Infarct size was 1.9%+/-0.4% in sham, 3.7%+/-0.5% in K/Mg, and 27.8%+/-2.4% in global ischemia hearts (p < 0.05 versus K/Mg). Left ventricular peak-developed pressure (percent of equilibrium) at the end of 120 minutes of reperfusion was 91%+/-6% in sham, 92% +/-2% in K/Mg, and 47%+/-6% in global ischemia (p < 0.05 versus K/Mg). Blockade of sarcolemmal ATP-sensitive potassium channels in K/Mg hearts had no effect on infarct size or left ventricular peak-developed pressure. However, blockade of mitochondrial ATP-sensitive potassium channels before ischemia significantly increased infarct size to 23%+/-2% in K/Mg hearts (p < 0.05 versus K/Mg; no statistical significance [NS] as compared to global ischemia) and significantly decreased left ventricular peak-developed pressure to 69%+/-4% (p < 0.05 versus K/Mg). Diazoxide when added to K/Mg cardioplegia significantly decreased infarct size to 1.5%+/-0.4% (p < 0.05 versus K/Mg). CONCLUSIONS: The cardioprotection afforded by K/Mg cardioplegia is modulated by mitochondrial ATP-sensitive potassium channels. Diazoxide when added to K/Mg cardioplegia significantly reduces infarct size, suggesting that the opening of mitochondrial ATP-sensitive potassium channels with K/Mg cardioplegic protection would allow for enhanced myocardial protection in cardiac operations.

Adenosine Triphosphate↗

PubMed2002

Opening of potassium channels modulates mitochondrial function in rat skeletal muscle.

We have investigated the presence of diazoxide- and nicorandil-activated K+ channels in rat skeletal muscle. Activation of potassium transport in the rat skeletal muscle myoblast cell line L6 caused a stimulation of cellular oxygen consumption, implying a mitochondrial effect. Working with isolated rat skeletal muscle mitochondria, both potassium channel openers (KCOs) stimulate respiration, depolarize the mitochondrial inner membrane and lead to oxidation of the mitochondrial NAD-system in a strict potassium-dependent manner. This is a strong indication for KCO-mediated stimulation of potassium transport at the mitochondrial inner membrane. Moreover, the potassium-specific effects of both diazoxide and nicorandil on oxidative phosphorylation in skeletal muscle mitochondria were completely abolished by the antidiabetic sulfonylurea derivative glibenclamide, a well-known inhibitor of ATP-regulated potassium channels (K(ATP) channels). Since both diazoxide and nicorandil facilitated swelling of de-energised mitochondria in KSCN buffer at the same concentrations, our results implicate the presence of a mitochondrial ATP-regulated potassium channel (mitoK(ATP) channel) in rat skeletal muscle which can modulate mitochondrial oxidative phosphorylation.

Animals↗

PubMed2002

Effects of mitochondrial K(ATP) modulators on cardioprotection induced by chronic high altitude hypoxia in rats.

OBJECTIVES: Adaptation of rats to intermittent high altitude hypoxia increases the tolerance of their hearts to acute ischemia/reperfusion injury. Our aim was to examine the role of mitochondrial ATP-sensitive potassium channels (K(ATP)) in this form of protection. METHODS: Adult male Wistar rats were exposed to hypoxia of 5000 m in a barochamber for 8 h/day, 5 days a week; the total number of exposures was 24-32. A control group was kept under normoxic conditions (200 m). Infarct size (tetrazolium staining) was measured in anesthetized open-chest animals subjected to 20-min regional ischemia (coronary artery occlusion) and 4-h reperfusion. Isolated perfused hearts were used to assess the recovery of contractile function following 20-min global ischemia and 40-min reperfusion. In the open-chest study, a selective mitochondrial K(ATP) blocker, 5-hydroxydecanoate (5 mg/kg), or openers, diazoxide (10 mg/kg) or BMS-191095 (10 mg/kg), were administered into the jugular vein 5 and 10 min before occlusion, respectively. In the isolated heart study, 5-hydroxydecanoate (250 micromol/l) or diazoxide (50 micromol/l) were added to the perfusion medium 5 or 10 min before ischemia, respectively. RESULTS: In the control normoxic group, infarct size occupied 62.2+/-2.0% of the area at risk as compared with 52.7+/-2.5% in the chronically hypoxic group (P<0.05). Post-ischemic recovery of contractile function (dP/dt) reached 60.0+/-3.9% of the pre-ischemic value and it was improved to 72.4+/-1.2% by adaptation to hypoxia (P<0.05). While 5-hydroxydecanoate completely abolished these protective effects of chronic hypoxia, it had no appreciable influence in normoxic groups. In contrast, diazoxide significantly increased the recovery of contractile function and reduced infarct size in normoxic groups only. The later effect was also observed following treatment with BMS-191095. CONCLUSION: The results suggest that opening of mitochondrial K(ATP) channels is involved in the cardioprotective mechanism conferred by long-term adaptation to intermittent high altitude hypoxia.

Altitude↗

PubMed2002

Alterations of purine and pyrimidine nucleotide contents in rat corticoencephalic cell cultures following metabolic damage and treatment with openers and blockers of ATP-sensitive potassium channels.

Rat corticoencephalic cell cultures were investigated by high performance liquid chromatography for changes in the levels of adenosine 5'-triphosphate (ATP), guanosine 5'-triphosphate (GTP), uridine 5'-triphosphate (UTP), cytidine 5'-triphosphate (CTP), and the respective nucleoside diphosphates. Hypoxia was induced by gassing the incubation medium for 30 min with 100% argon. Removal of glucose was caused by washing the cultures in glucose-free medium at the beginning of the 30 min incubation period. Whereas hypoxia or glucose-deficiency alone failed to alter the nucleotide levels, the combination of these two manipulations was clearly inhibitory. Diazoxide (300 microM) an opener of ATP-dependent potassium channels (K(ATP)) did not alter the nucleotide contents either in a normoxic and glucose-containing medium, or a hypoxic and glucose-free medium. By contrast, the K(ATP) channel antagonist tolbutamide (300 microM) aggravated the hypoxic decrease of nucleotide levels in a glucose-free medium, although it was ineffective in a normoxic and glucose-containing medium. Hypoxia and glucose-deficiency decreased the ATP/ADP and UTP/UDP ratios, but failed to change the GTP/GDP ratio. Diazoxide and tolbutamide (300 microM each) had no effect on the nucleoside triphosphate/diphosphate ratios either during normoxic or during hypoxic conditions. In conclusion, corticoencephalic cultures are rather resistant to in vitro ischemia. Although they clearly respond to the blockade of plasmalemmal K(ATP) channels (plasmaK(ATP)) by tolbutamide, these channels appear to be maximally open as a consequence of the fall in intracellular nucleotides and, therefore, diazoxide has no further effect.

Animals↗

PubMed2002

Selective opening of mitochondrial ATP-sensitive potassium channels during surgically induced myocardial ischemia decreases necrosis and apoptosis.

OBJECTIVE: Mitochondrial ATP-sensitive potassium channels have been proposed to be myoprotective. The relevance and specificity of this mechanism in cardiac surgery was unknown. The purpose of this study was to examine the effects of the mitochondrial potassium ATP-sensitive channel opener diazoxide on regional and global myocardial protection using a model of acute myocardial infarction. METHODS: Pigs (n=19) were placed on total cardiopulmonary bypass and then subjected to 30 min normothermic regional ischemia by snaring the left anterior descending coronary artery (LAD). The aorta was then crossclamped and cold blood Deaconess Surgical Associates cardioplegia (DSA; n=6) or DSA containing 50 microM diazoxide (DZX; n=6) was delivered via the aortic root and the hearts subjected to 30 min hypothermic global ischemia. The crossclamp and snare were removed and the hearts reperfused for 120 min. RESULTS: No significant differences in preload recruitable stroke work relationship, Tau, proximal, distal or proximal/distal coronary flow, regional or global segmental shortening, systolic bulging or post-systolic shortening were observed within or between DSA and DZX hearts during reperfusion. Infarct was present only in the region of LAD occlusion in both DSA and DZX hearts. Infarct size (% of area at risk) was 33.6+/-2.9% in DSA and was 16.8+/-2.4% in DZX hearts (P<0.01 versus DSA). Apoptosis as estimated by TUNEL positive nuclei was 120.3+/-48.8 in DSA and was significantly decreased to 21.4+/-5.3 in DZX hearts. Myocardial infarct was located centrally within the area at risk in both DSA and DZX hearts but was significantly increased at borderline zones within the area at risk in DSA hearts. CONCLUSIONS: The addition of diazoxide to cardioplegia significantly decreases regional myocardial cell necrosis and apoptosis in a model of acute myocardial infarction and represents an additional modality for achieving myocardial protection.

Animals↗