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 1,009 records · Page 56Linked to original sources

PubMed2003

Adenine nucleotide translocase mediates the K(ATP)-channel-openers-induced proton and potassium flux to the mitochondrial matrix.

KATP channel openers have been shown to protect ischemic-reperfused myocardium by mimicking ischemic preconditioning, although their mechanisms of action have not been fully clarified. In this study we investigated the influence of the adenine nucleotide translocase (ANT) inhibitors--carboxyatractyloside (CAT) and bongkrekic acid (BA)--on the diazoxide- and pinacidil-induced uncoupling of isolated rat heart mitochondria respiring on pyruvate and malate (6 + 6 mM). We found that both CAT (1.3 microM) and BA (20 microM) markedly reduced the uncoupling of mitochondrial oxidative phosphorylation induced by the K(ATP) channel openers. Thus, the uncoupling effect of diazoxide and pinacidil is evident only when ANT is not fixed by inhibitors in neither the C- nor the M-conformation. Moreover, the uncoupling effect of diazoxide and pinacidil was diminished in the presence of ADP or ATP, indicating a competition of K(ATP) channel openers with adenine nucleotides. CAT also abolished K+-dependent mitochondrial respiratory changes. Thus ANT could also be involved in the regulation of K(ATP)-channel-openers-induced K+ flux through the inner mitochondrial membrane.

Animals↗

PubMedDate not supplied

Subcellular heterogeneity in mitochondrial red-ox responses to KATP channel agonists in freshly isolated rabbit cardiomyocytes.

We have used the technique of fluorescent microscopy imaging supplemented with the refined analysis of temporal cartography of the cell fluorescence to investigate the mechanisms of regulation of mitochondrial function and its red-ox state in cardiac cells in vivo. Autofluorescence of flavoproteins of the respiratory chain in the isolated rabbit cardiomyocytes was registered before and after application of mitochondrial KATP channel opener diazoxide (100 and 400 microM). Diazoxide addition resulted in oxidation of flavoproteins. Detailed analysis of these responses showed that they were heterogeneous over space and time. The local responses show rapid jumps. In a few cells, metabolic oscillations developed and could be recorded for tens of minutes. Under these conditions the cells appeared divided into a small number of regions in which mitochondria function synchronously. Local pattern of oxidation switches again and again from a reduced state to the same level of oxidation. All these phenomena where absent when the cells were permeabilized by saponin giving a direct access to mitochondrial KATP channel opener. Cross-correlation analysis revealed a high degree of homogeneity for cells presenting metabolic oscillations, contrarily to those displaying a smooth increase in fluorescence in response to diazoxide. The results are consistent with the view that mitochondria form independent functional units whose behaviour can be synchronised by some unknown cellular factors or metabolites.

Animals↗

PubMed2000

Pharmacology of human sulphonylurea receptor SUR1 and inward rectifier K(+) channel Kir6.2 combination expressed in HEK-293 cells.

1. The pharmacological properties of K(ATP) channels generated by stable co-expression of the sulphonylurea receptor SUR1 and the inwardly rectifying K(+) channel Kir6.2 were characterized in HEK-293 cells. 2. [(3)H]-Glyburide (glibenclamide) bound to transfected cells with a B(max) value of 18.5 pmol mg(-1) protein and with a K(D) value of 0.7 nM. Specific binding was displaced by a series of sulphonylurea analogues with rank order potencies consistent with those observed in pancreatic RINm5F insulinoma and in the brain. 3. Functional activity of K(ATP) channels was assessed by whole cell patch clamp, cation efflux and membrane potential measurements. Whole cell currents were detected in transfected cells upon depletion of internal ATP or by exposure to 500 microM diazoxide. The currents showed weak inward rectification and were sensitive to inhibition by glyburide (IC(50)=0.92 nM). 4. Metabolic inhibition by 2-deoxyglucose and oligomycin treatment triggered (86)Rb(+) efflux from transfected cells that was sensitive to inhibition by glyburide (IC(50)=3.6 nM). 5. Diazoxide, but not levcromakalim, evoked concentration-dependen decreases in DiBAC(4)(3) fluorescence responses with an EC(50) value of 14.1 microM which were attenuated by the addition of glyburide. Diazoxide-evoked responses were inhibited by various sulphonylurea analogues with rank order potencies that correlated well with their binding affinities. 6. In summary, results from ligand binding and functional assays demonstrate that the pharmacological properties of SUR1 and Kir6.2 channels co-expressed in HEK-293 cells resemble those typical of native K(ATP) channels described in pancreatic and neuronal tissues.

ATP-Binding Cassette Transporters↗

PubMed1974

The pancreatic beta-cell recognition of insulin secretagogues. Effects of calcium and sodium on glucose metabolism and insulin release.

The transport and oxidation of glucose, the content of fructose 1,6-diphosphate, and the release of insulin were studied in microdissected pancreatic islets of ob/ob mice incubated in Krebs-Ringer bicarbonate medium. Under control conditions glucose oxidation and insulin release showed a similar dependence on glucose concentration with the steepest slope in the range 5-12mm. The omission of Ca(2+), or the substitution of choline ions for Na(+), or the addition of diazoxide had little if any effect on glucose transport. However, Ca(2+) or Na(+) deficiency as well as diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) or ouabain partially inhibited glucose oxidation. These alterations of medium composition also increased the islet content of fructose 1,6-diphosphate, as did the addition of adrenaline. Phentolamine [2-N-(3-hydroxyphenyl)-p-toluidinomethyl-2-imidazoline] counteracted the effects of adrenaline and Ca(2+) deficiency on islet fructose 1,6-diphosphate. After equilibration in Na(+)-deficient medium, the islets exhibited an increase in basal insulin release whereas the secretory response to glucose was inhibited. The inhibitory effects of Na(+) deficiency on the secretory responses to different concentrations of glucose correlated with those on (14)CO(2) production. When islets were incubated with 17mm-glucose, the sudden replacement of Na(+) by choline ions resulted in a marked but transient stimulation of insulin release that was not accompanied by a demonstrable increase of glucose oxidation. Galactose and 3-O-methylglucose had no effect on glucose oxidation or on insulin release. The results are consistent with a metabolic model of the beta-cell recognition of glucose as insulin secretagogue and with the assumption that Ca(2+) or Na(+) deficiency, or the addition of adrenaline or diazoxide, inhibit insulin release at some step distal to stimulus recognition. In addition the results suggest that these conditions create a partial metabolic block of glycolysis in the beta-cells. Hence the interrelationship between the processes of stimulus recognition and insulin discharge may involve a positive feedback of secretion on glucose metabolism.

Animals↗

PubMed1976

Vasodilating drugs: contrasting haemodynamic effects.

1. We investigated the haemodynamic effects of intravenously administered hydrallazine, diazoxide and nitroprusside and orally administered minoxidil to determine whether vasodilators (such as nitroprusside) which do not increase cardiac output might be better treatment for hypertensive complications associated with, or caused by, myocardial failure than those that do. 2. Hydrallazine and diazoxide caused increases in heart rate, cardiac output, cardiopulmonary blood volume, the ratio of cardiac output to cardiopulmonary volume, and pulmonary artery pressure. Nitroprusside, although decreasing pressure and vascular resistance, caused no significant change in the other functions except for reducing pulmonary artery pressure. Minoxidil, when given orally, had the potential for causing pulmonary hypertension. This seemed explained by increased flow (hyperdynamic type) in some but by congestive cardiac failure in others; the latter condition was probably intensified by the marked fluid retention that the drug can cause. 3. On the basis of these results a classification of vasodilators was constructed which depends on the presence or absence of a venodilating effect. Vasodilators which produce no (or little) venodilatation, increase heart rate, cardiac output, cardiopulmonary blood volume and pulmonary artery pressure. In this class are diazoxide, hydrallazine and minoxidil. Those that cause venodilatation do not stimulate the heart nor do they cause pulmonary hypertension. Nitroprusside and nitroglycerine are drugs of this type. 4. These results suggest that drugs producing both venodilatation and arteriolar dilatation may be more specific therapy for hypertensive complications associated with cardiac failure than those that cause only arteriolar dilatation.

Diazoxide↗

PubMed2001

Ten years' experience of persistent hyperinsulinaemic hypoglycaemia of infancy.

OBJECTIVE: To review the presentation, management and outcome of persistent hyperinsulinaemic hypoglycaemia of infancy seen at the Royal Alexandra Hospital for Children over a 10 year period. METHODOLOGY: A retrospective review of 20 subjects was performed. As well as laboratory data, data were collected on clinical presentation, medical and surgical management and developmental outcome. RESULTS: Twenty subjects (11 male) were identified with presentation at a median age of 1.5 months (range 0-10 months), with 10 (50%) presenting in the first week of life. Only 20% of patients were large for gestational age. Diagnosis was made on the basis of high glucose requirements and inappropriately high insulin levels at the time of hypoglycaemia. Eight (40%) responded well to diazoxide treatment alone, seven (35%) received diazoxide in combination with other short-term medical therapy initially and five (25%) required pancreatectomy (repeat surgery in three). Those who required surgery had a higher mean birth weight. Infants presenting in the first week of life were less likely to respond to diazoxide. At the time of last review, eight (40%) of those treated medically had ceased all treatment. Two of the five cases requiring pancreatectomy now require insulin treatment. Neurodevelopmental assessment was normal in 11 (55%), mild delay was found in six (30%) and moderate or severe delay was found in three (15%). CONCLUSIONS: Persistent hyperinsulinaemic hypoglycaemia of infancy remains a major diagnostic and management challenge. Early suspicion and recognition is critical with definitive investigation and medical therapy to avoid hypoglycaemia, with pancreatectomy in medically unresponsive cases. Normal neurodevelopmental outcome was found in only 55% of cases.

Adolescent↗

PubMed1998

Intracellular Ca2+ during metabolic activation of KATP channels in spontaneously active dorsal vagal neurons in medullary slices.

Intracellular Ca2+ ([Ca2+]i) and membrane properties were measured in fura-2 dialysed dorsal vagal neurons (DVN) spontaneously active at a frequency of 0.5-5 Hz. [Ca2+]i increased by about 30 nm upon rising spike frequency by more than 200% due to 20-50 pA current pulses or 10 micrometer serotonin. It fell by 30 nm upon block of spiking by current-injection, tetrodotoxin or Ni2+ and also during hyperpolarization due to gamma-aminobutyric acid or opening of adenosine triphosphate (ATP) -sensitive K+ (KATP) channels with diazoxide. KATP channel-mediated hyperpolarizations during anoxia or cyanide produced an initial [Ca2+]i decrease which reversed into a secondary Ca2+ rise by less than 100 nm. Similar moderate rises of [Ca2+]i were observed during block of aerobic metabolism under voltage-clamp as well as in intact cells, loaded with fura-2 AM. The magnitude of the metabolism-related [Ca2+]i transients did not correlate with the amplitude of the KATP channel-mediated outward current. [Ca2+]i did not change during diazoxide-induced or spontaneous activation of KATP outward current observed in 10% of cells after establishing whole-cell recording. Increasing [Ca2+]i with cyclopiazonic acid did not activate KATP channels. [Ca2+]i was not affected upon block of outward current with sulphonylureas, but these KATP channel blockers were effective to reverse inhibition of spike discharge and, thus, the initial [Ca2+]i fall upon spontaneous or diazoxide-, anoxia- and cyanide-induced KATP channel activation. A sulphonylurea-sensitive hyperpolarization and [Ca2+]i fall was also revealed in the early phase of iodoacetate-induced metabolic arrest, whereas after about 20 min, occurrence of a progressive depolarization led to an irreversible rise of [Ca2+]i to more than 1 micrometer. The results indicate that KATP channel activity in DVN is not affected by physiological changes of intracellular Ca2+ and the lack of a major perturbance of Ca2+ homeostasis contributes to their high tolerance to anoxia.

Action Potentials↗

PubMed1993

Insulin action in patients with insulinoma influenced by pharmacological and surgical therapy.

Organic hyperinsulinism due to insulinoma is accompanied by changes of insulin action on receptor and postreceptor levels. The influence of conservative and surgical treatment on insulin sensitivity was examined by euglycaemic hyperinsulinaemic clamps in ten patients with insulinoma. The "responders" (n = 5) and "non-responders" (n = 5) to diazoxide treatment were distinguished by using fasting plasma glucose and insulin concentrations. The index of insulin sensitivity was significantly decreased in pretreated "responders" as compared to healthy persons (19 +/- 3 vs 39 +/- 6 and 20 +/- 3 vs 37 +/- 5 mumol.kg-1.min-1 per mU.l-1 x 100, p < 0.01) and it was improved during diazoxide administration (27 +/- 4 vs 19 +/- 3 and 35 +/- 12 vs 20 +/- 3 mumol.kg-1.min-1 per mU.l-1 x 100, p < 0.05). Significantly decreased insulin sensitivity in pretreated "non-responders" (25 +/- 5 vs 39 +/- 6 and 28 +/- 6 vs 37 +/- 5 mumol.kg-1.min-1 per mU.l-1 x 100, p < 0.05) was not improved by diazoxide administration. Metabolic clearance rate of glucose was significantly higher in "non-responders" as compared to "responders" and healthy persons (12.7 +/- 3.4 vs 7.9 +/- 2.7 and 7.4 +/- 2.4 ml.min-1.kg-1, p < 0.05) already in pretreated state. An inverse relationship was found between metabolic clearance rate of glucose and of insulin (r = 0.72, p < 0.001). Plasma glucose, insulin concentration, index of insulin sensitivity, and metabolic clearance rate of glucose and of insulin were normalized after surgical removal of an insulinoma in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1997

Effect of potassium channel openers on the firing rate of hippocampal pyramidal cells and A10 dopaminergic neurons in vitro.

The effect of four KATP channel openers (KCOs) on the firing rate of CA1 pyramidal cells and A10 dopaminergic neurons was investigated using extracellular recording techniques in rat brain slices. Pinacidil, lemakalim, diazoxide and a new compound, BPDZ44, had an inhibitory effect on the electrical activity of CA1 pyramidal cells. They all had a similar potency. Only BPDZ44 and diazoxide inhibited the firing rate of A10 dopamine neurons. The sulfonylurea glipizide (1 microM) antagonized the effect of BPDZ44 and diazoxide on A10 neurons but failed to antagonize the effect of KCOs on CA1 pyramidal cells. These results show that differences exist among KCOs in their ability to decrease the electrical activity of various populations of central neurons.

Action Potentials↗

PubMed2001

Lidocaine and mexiletine inhibit mitochondrial oxidation in rat ventricular myocytes.

BACKGROUND: Accumulating evidence suggests that mitochondrial rather than sarcolemmal adenosine triphosphate-sensitive K+ (K(ATP)) channels may have an important role in the protection of myocardium during ischemia. Because both lidocaine and mexiletine are frequently used antiarrhythmic drugs during myocardial ischemia, it is important to investigate whether they affect mitochondrial K(ATP) channel activities. METHODS: Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. The authors measured flavoprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or mexiletine was applied after administration of diazoxide (25 microM), a selective mitochondrial K(ATP) channel opener. The redox signal was normalized to the baseline flavoprotein fluorescence obtained during exposure to 2,4-dinitrophenol, a protonophore that uncouples respiration from ATP synthesis and collapses the mitochondrial potential. RESULTS: Diazoxide-induced oxidation of flavoproteins and the redox changes were inhibited by 5-hydroxydecanoic acid, a selective mitochondrial K(ATP) channel blocker, suggesting that flavoprotein fluorescence can be used as an index of mitochondrial oxidation mediated by mitochondrial K(ATP) channels. Lidocaine (10(-3) to 10 mM) and mexiletine (10(-3) to 10 mM) reduced oxidation of the mitochondrial matrix in a dose-dependent manner with an EC50 of 98+/-63 microM for lidocaine and 107+/-89 microM for mexiletine. CONCLUSIONS: Both lidocaine and mexiletine reduced flavoprotein fluorescence induced by diazoxide in rat ventricular myocytes, indicating that these antiarrhythmic drugs may produce impairment of mitochondrial oxidation mediated by mitochondrial K(ATP) channels.

Adenosine Triphosphate↗

PubMed2002

Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways.

BACKGROUND: Volatile anesthetics induce pharmacological preconditioning in cardiac tissue. The purpose of this study was to test whether volatile anesthetics mediate this effect by activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) or sarcolemmal K(ATP) (sarcK(ATP)) channel in rat ventricular myocytes and to evaluate the signaling pathways involved. METHODS: A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to determine the effects of 5-hydroxydecanoate, a selective mitoK(ATP) channel blocker, HMR-1098, a selective sarcK(ATP) channel blocker, diazoxide, a preconditioning mimicking agent, and various modulators of putative signaling pathways on cardioprotection elicited by sevoflurane and isoflurane. Microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct index of mitoK(ATP) channel activity. RESULTS: Volatile anesthetics significantly enhanced diazoxide-mediated activation of mitoK(ATP) channels as assessed by autofluorescence of myocytes. Conversely, volatile anesthetics alone did not alter mitoK(ATP) channel activity, implying a priming effect of volatile anesthetics on mitoK(ATP) channels. Administration of the protein kinase C inhibitor chelerythrine completely blocked this effect. Also, pretreatment with volatile anesthetics potentiated diazoxide-mediated protection against ischemia, as indicated by a reduction in trypan blue-positive myocytes. Importantly, cardioprotection afforded by volatile anesthetics was unaffected by the sarcK(ATP) channel blocker HMR-1098 but sensitive to modulations of nitric oxide and adenosine-G(i) signaling pathways. CONCLUSIONS: Using autofluorescence in live cell imaging microscopy and a simulated model of ischemia, the authors present evidence that volatile anesthetics mediate their protection in cardiomyocytes by selectively priming mitoK(ATP) channels through multiple triggering protein kinase C-coupled signaling pathways. These observations provide important new insight into the mechanisms of anesthetic-induced preconditioning.

Adenosine Triphosphate↗

PubMed1993

Decreased ATP sensitivity of a K+ channel and enhanced vascular smooth muscle relaxation in genetically hypertensive rats.

OBJECTIVE: To characterize an ATP-sensitive K+ channel at the single-channel and tissue level in the vascular smooth muscle of normotensive and genetically hypertensive rats. METHODS: Age- and sex-matched Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) were used. Patch-clamp single-channel recording was used to measure K+ channel activity in dissociated tail artery cells. The effect of the K+ channel-opener diazoxide and the specific ATP-sensitive K+ channel antagonist glyburide on isometric force development in isolated tail artery strips was determined by a standard muscle bath technique. RESULTS: The concentration of ATP that caused half-maximal reduction in channel activity was greater in the SHRSP than in the WKY rats. Tail artery strips and cells from SHRSP were more sensitive to the effect of diazoxide on relaxation and channel activity, and less responsive to the effect of glyburide, than were those from WKY rats. CONCLUSIONS: The decreased ATP sensitivity of this K+ channel may partly compensate for the increased vascular reactivity in hypertension, and the change in this property of the channel may be responsible for the altered sensitivity to diazoxide and glyburide in SHRSP.

Adenosine Triphosphate↗

PubMed2004

NO donor-activated PKC-delta plays a pivotal role in ischemic myocardial protection through accelerated opening of mitochondrial K-ATP channels.

Nitric oxide (NO) can activate protein kinase C (PKC) and the activation of mitochondrial ATP-sensitive potassium (K-ATP) channels is cardioprotective. However, interactions among NO, PKC, and mitochondrial K-ATP channels remain vague. To clarify the cardioprotective mechanism induced by nicorandil, we compared its ability to activate PKC isoforms with that of the mitochondrial K-ATP channel opener, diazoxide. We induced myocardial infarction in rats by 30 minutes of ischemia followed by reperfusion, then assessed the infarct size 3 weeks later. We also examined the translocation of PKC isoforms in the isolated perfused rat heart. Nicorandil and diazoxide reduced infarct size, and the effect of nicorandil, but not of diazoxide attenuated by the PKC inhibitor, chelerythrine, or by the NO quencher, carboxy PTIO. Immunoblotting revealed that nicorandil translocated PKC-delta to the mitochondria, and that this was inhibited by carboxy PTIO. The protective effect of nicorandil against myocardial infarction partly depended on the translocation of PKC-delta to the mitochondria, which we attributed to the NO donor effect of nicorandil. The PKC-delta- dependent activation of mitochondrial K-ATP channel opening might be synergistic with its direct effect, making nicorandil an efficient opener of such channels.

Animals↗

PubMed2006

P-1075 exerts diverse modulatory effects on mitochondrial ATP-sensitive K+ channels in rabbit ventricular myocytes.

P-1075 was reported to be selective for sarcolemmal ATP-sensitive K (sarcKATP) channels because of its lack of mitochondria-oxidizing effect in isolated adult rabbit myocytes. Conflicting results however have been reported on the action of P-1075 on mitochondrial KATP (mitoKATP) channels. The aim of the present study was to reevaluate the effect of P-1075 on mitoKATP channels. Endogenous flavoprotein autofluorescence in isolated rabbit ventricular myocytes was measured to assay mitoKATP channel activity. The mitoKATP channel opener diazoxide (100 microM) oxidized the flavoprotein. P-1075 at a concentration of 30 microM significantly inhibited the oxidative effect of diazoxide from 48.6 +/- 7.1% to 28.2 +/- 5.2% of the maximum value induced by 2,4-dinitrophenol (DNP, 100 microM) (n = 4, P < 0.05). Additionally, P-1075 (30 microM) significantly inhibited the pinacidil (100 microM)-induced flavoprotein oxidation by 48.4 +/- 3.9% (n = 4, P < 0.05). The inhibitory effects of P-1075 on diazoxide-induced flavoprotein oxidation were observed in the micromolar range in a concentration dependent manner. P-1075 alone oxidized flavoprotein in the range 30 nM to 5 microM, and was nearly maximal at 150 nM (11.1 +/- 1.9% of the DN P value, n = 5). These results indicate that P-1075 exerts diverse effects on mitoKATP channel in rabbit ventricular myocytes: P-1075 has a partial agonist effect and weakly activates mitoKATP channels at low concentrations, whereas P-1075 rather inhibits the opening of mitoKATP channels in the micromolar concentration range.

2,4-Dinitrophenol↗

PubMed2006

ATP-sensitive potassium channels mediate the anti-ischemic properties of ischemic and pharmacologic preconditioning in rat random-pattern skin flap.

Ischemic preconditioning (IPC) and pharmacologic preconditioning by morphine and adenosine may significantly decrease the amount of necrosis in rat random pattern skin flaps. We examined the role of ATP-sensitive potassium channels (K(ATP) channels) in mediating these protective phenomenon by using glibenclamide a nonspecific blocker of these channels. We also investigated whether administration of diazoxide an opener of the K(ATP) channels could mimic the same protective effect. Ninety male Sprague-Dawley rats were randomly divided into either control or treatment groups (n = 6 each). Bipedicled dorsal skin flaps (2 x 8 cm) were elevated at the midline. In pharmacologic preconditioning groups, 1 mL of morphine (5 mg/flap), adenosine (0.5 mg/flap), or different doses of diazoxide (0.5, 1, 5, and 15 mg/flap) were administered locally in the cranial half of the flap, respectively. One milliliter of saline was locally injected in the control group. In the IPC group, 1 hour after local saline injection the cranial pedicle was clamped for 20 minutes, and then 40 minutes' reperfusion was performed. In another experiment, 0.3 mg/kg of glibenclamide was injected intraperitoneally 30 minutes before local administration of saline or drug in ischemic or pharmacologic preconditioning groups. Regardless of the group, all flaps were cut at the cranial side 2 hours after elevation and were sutured back. Flap survival area was evaluated on the seventh postoperative day. IPC and pharmacologic preconditioning with morphine, adenosine, and diazoxide (in higher doses; 1, 5, and 15 mg/flap) improved survival area compared with the control group. Glibenclamide abolished their protective effect. K(ATP) channels may have a key role in anti-ischemic properties of IPC and pharmacologic preconditioning.

Adenosine↗

PubMed2004

Activation of the ATP-dependent potassium channel attenuates norepinephrine-induced vasoconstriction in the human forearm.

Sepsis-induced vasodilation is characterized by an attenuated sensitivity to vasoconstrictor substances such as norepinephrine, possibly mediated by activation of vascular potassium channels. We determined whether vasodilation associated with potassium channel activation resulted in an attenuated vasoconstrictive response to norepinephrine in humans and whether the vasodilation associated with potassium channel activation could be inhibited by pharmacological potassium channel blockers. In 30 volunteers, the brachial artery was cannulated for infusion of drugs. Forearm blood flow (FBF) was measured in both arms using strain-gauge venous occlusion plethysmography. Forearm vascular resistance (FVR, mean arterial pressure/FBF) was calculated. The effects of vasodilation induced by sodium nitroprusside (SNP, nitric oxide donor) or diazoxide (activator of the ATP-dependent potassium channel) on norepinephrine-mediated vasoconstriction were examined. Also, the effects of potassium channel blockers on vasodilation associated with potassium channel activation were determined. Intraarterial SNP infusion (2 microg/min/dL) increased forearm blood flow by 235%, from (mean +/- SEM) 2.8 +/- 0.7 to 9.4 +/- 1.5 mL/min/dL (P < 0.0001). Subsequent norepinephrine infusion (10, 30, 100, 300, 1000 ng/min/dL) increased FVR dose-dependently from 13 +/- 4 AU to 249 +/- 45 AU at the highest norepinephrine infusion. Intraarterial diazoxide infusion (1 mg/min/dL) increased FBF by 209% from 2.2 +/- 0.3 to 6.8 +/- 1.0 mL/min/dL (P < 0.001). Subsequent norepinephrine infusion increased FVR from 18 +/- 5 to 51 +/- 6 AU at the highest norepinephrine infusion rate (n = 10), significantly different from the norepinephrine-induced effects during SNP coinfusion (P < 0.001). Diazoxide-induced fall in FVR in the infused forearm was inhibited by potassium channel blockers tetraethyl ammonium (1 mg/min/dL, n = 10, P = 0.004) and quinine (50 microg/min/dL, n = 10, P = 0.016). Vasodilation induced by vascular potassium channel activation is associated with an impressive reduction in the vasoconstrictor response to norepinephrine in humans. In accordance with animal experiments, this indicates that potassium channel activation could account for the diminished norepinephrine sensitivity in septic patients. Vasodilation associated with potassium channel activation can be inhibited by pharmacological potassium channel blockade. The possible role of potassium channel blockers during sepsis-induced potassium channel activation and vasodilation in humans needs further elucidation.

Adult↗

PubMed2005

Novel and established potassium channel openers stimulate hair growth in vitro: implications for their modes of action in hair follicles.

Although ATP-sensitive potassium (K(ATP)) channel openers, e.g., minoxidil and diazoxide, can induce hair growth, their mechanisms require clarification. Improved drugs are needed clinically. but the absence of a good bioassay hampers research. K(ATP) channels from various tissues contain subtypes of the regulatory sulfonylurea receptor, SUR, and pore-forming, K(+) inward rectifier subunits, Kir6.X, giving differing sensitivities to regulators. Therefore, the in vitro effects of established potassium channel openers and inhibitors (tolbutamide and glibenclamide), plus a novel, selective Kir6.2/SUR1 opener, NNC 55-0118, were assessed on deer hair follicle growth in serum-free median without streptomycin. Minoxidil (0.1-100 microM, p<0.001), NNC 55-0118 (1 mM, p<0.01; 0.1, 10, 100 microM, p<0.001), and diazoxide (10 microM, p<0.01) increased growth. Tolbutamide (1 mM) inhibited growth (p<0.001) and abolished the effect of 10 microM minoxidil, diazoxide and NNC 55-0118; glibenclamide (10 microM) had no effect, but prevented stimulation by 10 microM minoxidil. Phenol red stimulated growth (p<0.001), but channel modulator responses remained unaltered. Thus, deer follicles offer a practical, ethically advantageous in vitro bioassay that reflects clinical responses in vivo. The results indicate direct actions of K(ATP) channel modulators within hair follicles via two types of channels, with SUR 1 and SUR 2, probably SUR2B, sulfonylurea receptors.

Animals↗

PubMed2006

Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS).

OBJECTIVE: Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease. PATIENTS: Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests. RESULTS: All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation. CONCLUSIONS: Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.

Adult↗