UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cromakalim, an adenosine triphosphate-sensitive potassium channel opener, shows proarrhythmic activity at moderate doses (1-10 micromol/liter) in the ischemic and reperfused myocardium. We studied the effects of extracellular Mg++ ([Mg++]o) on the incidence of reperfusion-induced ventricular fibrillation and ventricular tachycardia in isolated working hearts (n = 12 in each group) subjected to 20 min of global ischemia followed by 30 min of reperfusion, a model eliciting a low incidence of reperfusion arrhythmias, obtained from 8-wk streptozotocin-induced diabetic rats. Cromakalim, at a concentration of 3 micromol/liter, perfused 5 min before the induction of ischemia and throughout reperfusion increased the incidence of ventricular fibrillation and ventricular tachycardia from their drug-free diabetic control values of 25 and 42% ([Mg++]o = 1.2 mmol/liter) to 92% (P < .05) and 100% (P < .05), respectively. Glibenclamide at a concentration of 3 micromol/liter prevented the proarrhythmiac activity of cromakalim. Increasing concentration of [Mg++]o to 2.4, 3.6 and 4.8 mmol/liter in the perfusion buffer, the arrhythmogenic effect of cromakalim was also abolished. Thus, with 2.4, 3.6 and 4.8 mmol/liter of [Mg++]o perfused before the administration of cromakalim and the onset of ischemia, the incidence of reperfusion-induced ventricular tachycardia was reduced from 92% (in cromakalim treated group) to 67%, 42% (P < .05), and 25% (P < .05), respectively. The incidence of reperfusion-induced ventricular tachycardia showed the same pattern. Elevated [Mg++]o prevented the cromakalim-induced cellular Na+ gain and K+ loss, measured by atomic absorption spectrophotometer. [Mg++]o could prevent the proarrhythmic activity of cromakalim, and the use of cromakalim as an antihypertensive or antiischemic agent may be of particular concern in the population of postischemic diabetic subjects who are known to be at high risk of sudden coronary death.
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PMID:Extracellular Mg++ manipulation prevents the proarrhythmic activity of cromakalim in ischemic/reperfused diabetic hearts. 922 69

Ischemic preconditioning is known to be mediated by several humoral factors, such as adenosine, norepinephrine, and bradykinin. We examined intracellular signal transduction of ischemic preconditioning following receptor stimulation. Alterations in the pH of the ischemic bed were monitored to assess the response of control and ischemic-preconditioned myocardium to glibenclamide and pertussis toxin. Pentobarbital-anesthetized open-chest dogs were subjected to 40 min of ligation of the left anterior descending coronary artery. Ischemic preconditioning was elicited by 25-min periods of coronary ligation followed by 5 min of reperfusion before a 40-min period of ligation. Glibenclamide (0.3 mg/kg)was given i.v. 20 min before the onset of ischemic preconditioning. Pertussis toxin (6-10 micrograms/kg) was given i.v. 3 days before the experiment. Tissue myocardial pH was measured by a glass micro-pH electrode. Ischemia for 5 min decreased myocardial pH and reperfusion returned it to the preischemic levels. Ischemia for 40 min decreased the myocardial pH from 7.43 +/- 0.06 to 6.43 +/- 0.08. Ischemic preconditioning significantly attenuated the decrease in myocardial pH (6.57 +/- 0.06) induced by 40 min of ischemia. Pretreatment with either glibenclamide or pertussis toxin completely abolished the effect of ischemic preconditioning on ischemic myocardial acidosis. Ischemic preconditioning can attenuate ischemia-induced myocardial acidosis in dogs, and this effect is mediated by activation of adenosine triphosphate-sensitive potassium channels and pertussis toxin-sensitive guanosine triphosphate-binding protein.
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PMID:Inhibitory effects of glibenclamide and pertussis toxin on the attenuation of ischemia-induced myocardial acidosis following ischemic preconditioning in dogs. 927 77

Heat shock protects against myocardial ischemia-reperfusion injury possibly via increased expression of heat shock proteins. The direct evidence of heat shock protein protection in vivo remains circumstantial, and no other new mechanism of protection has been proposed. Recent studies suggest that opening of ATP-sensitive K+ channels (KATP channels) plays an important role in ischemic preconditioning; however, it is not known whether this channel is also important in delayed protection conferred by heat shock. Anesthetized rabbits underwent heat shock treatment by raising core temperature to 42 degrees C for 15 min. Twenty-four hours later, the animals were reanesthetized and subjected to regional ischemia-reperfusion. The specific KATP channel blockers glibenclamide (0.3 mg/kg i.p.) and sodium 5-hydroxydecanoate (5HD; 5 mg/kg i.v.) were used to block the channel function. The drugs were administered at two different times, either pre-heat stress or preischemia. Infarct size was determined by triphenyltetrazolium chloride staining. The 72-kDa heat shock protein (HSP 72) was measured by Western blots. Our results show that heat shock produced a marked reduction in infarct size (39.4 +/- 8.1 to 14.3 +/- 2.5% of risk area, P < 0.05). Glibenclamide and 5HD completely abolished heat shock-induced reduction in infarct size (42.3 +/- 0.32 and 33.7 +/- 4.8%) when given before ischemia-reperfusion; however, these antagonists failed to block protection when administered before the onset of heat shock. Furthermore, the enhanced expression of HSP 72 in heat shock groups was not diminished by glibenclamide or 5HD, suggesting a lack of a direct role of this protein in conferring cardiac protection by heat shock. The complete blockade of cardiac protection by glibenclamide and 5HD strongly suggests that opening of this channel is a very important component of heat shock-induced ischemic protection in rabbit hearts.
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PMID:ATP-sensitive potassium channel mediates delayed ischemic protection by heat stress in rabbit heart. 937 85

Glibenclamide has been shown to prevent ischemia-induced shortening of action-potential duration (APD) and to prolong effective refractory period (ERP). Glibenclamide also has been shown to prolong APD under normal conditions. The aim of this study was to test the hypothesis that glibenclamide would prolong APD and ERP in the nonischemic heart by blocking adenosine triphosphate-sensitive K+ (K(ATP)) channels in myocardium, thus reducing defibrillation energy requirements. Hearts from 15 adult male New Zealand White rabbits, weight 3.1 +/- 0.1 kg, were perfused with a Krebs-Henseleit solution containing either no drugs (five hearts) or glibenclamide (10 hearts) at six concentrations ranging from 30 nM to 10 microM. Two 140-mm2 Pt-Ir mesh patch electrodes were sutured onto the ventricles. A 3.5/2.5-ms biphasic pulse (impedance, 95 +/- 16 omega) with randomly selected voltages of 20, 30, 50, 70, 90, or 110, defibrillated the heart after 10 s of fibrillation. The APD, ERP, fibrillation threshold (FT), and defibrillation threshold (DFT) were determined from monophasic action potentials, computer-controlled pacing, 50-Hz sinusoidal pacing, and multiple defibrillation shocks, respectively. Defibrillation thresholds were determined from a total of 180 fibrillation and defibrillation sequences, conducted in each preparation, and the results were fitted to a sigmoid dose-response curve by logistic regression analysis. Five repeated observations of APD, ERP, FT, and DFT showed no change over a 5-h period, whereas for DFT, there was a significant increase between first and next four determinations. With glibenclamide (100 and 300 nM, and 1 and 10 microM), a dose-dependent difference (p < 0.05) compared with controls was observed. There was an increase in APD, ERP, and FT and a decrease in DFT at 50% success (V50). The maximal effect for each parameter occurred at 300 nM. Glibenclamide dose-dependently reduced DFT and increased FT in an isolated nonischemic rabbit heart preparation. A probable mechanism is through APD and ERP prolongation by blocking ATP-sensitive K+ channels, suggesting that these channels may be important in modifying the APD and ERP during electrical defibrillation. This might be of particular interest in reducing electrical-defibrillation thresholds, thereby minimizing heart damage.
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PMID:Reducing electrical defibrillation thresholds with glibenclamide in an isolated rabbit heart preparation. 938 39

Evidence indicates that ATP-sensitive potassium channels (KATP) participate in the metabolic regulation of coronary flow and that this regulation is attenuated when endothelial production of nitric oxide (NO) is blocked. A hypothesis tested in this study was that, in hearts with the impaired NO-pathway, either with an inhibitor or as a result of ischemia/reperfusion, a coronary vasodilator response to KATP stimulation is impaired as well. In Langendorff perfused rat hearts, a blocker of NO synthesis (N omega-nitro-L-arginine, L-NOARG, 10 microM) and KATP inhibitor (glibenclamide, 0.6 microM) reduced the basal coronary flow by 44% and 29%, respectively. Glibenclamide caused a further 25% drop in the flow in L-NOARG perfused hearts. To determine the responsiveness of coronary resistance vessels to KATP stimulation and NO, dose-response curves (DRC) for KATP opener, pinacidil-, and NO-donor, 3-morpholino-syndomine-hydrochloride (SIN-1)-induced increase in coronary flow were constructed, respectively. The pinacidil DRC was shifted to the right by glibenclamide and L-NOARG and to the left by SIN-1 and adenosine. The L-NOARG-induced effect was reversed by L-arginine. The SIN-1 DRC was shifted to the right by glibenclamide and not affected by L-NOARG. Another NO synthesis blocker, L-NG-monomethylarginine (L-NMMA, 50 microM), caused a 43% drop in coronary flow in the untreated hearts and only 24% drop in the hearts subjected to 20 min global ischemia and 40 min reperfusion. The pinacidil DRC obtained at reperfusion showed a 2.3-fold rightward shift as compared to the DRC obtained before ischemia/reperfusion. Similar displacement of the pinacidil DRC was observed also in L-NMMA perfused hearts and in L-NMMA-perfused hearts which were subjected to ischemia/reperfusion. These results indicate that in the isolated rat heart: (1) NO and KATP, acting simultaneously, participate in the setting of the vasodilator component of the basal coronary flow; (2) The responsiveness of coronary microcirculation to KATP stimulation is attenuated when endothelial NO-pathway is impaired either pharmacologically or by ischemia/reperfusion.
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PMID:Inhibitors of nitric oxide synthesis and ischemia/reperfusion attenuate coronary vasodilator response to pinacidil in isolated rat heart. 944 21

The cardiac effects of KR-30450 ((-)-(2R)-2-([1,3]-dioxolan-2-yl)-2-methyl-4-(2-oxopyrrolidin++ +-1-yl)-6-nitro-2H-1-benzopyran), a newly synthesized potassium channel activator, and its major metabolite KR-30818 ((-)-(2R)-2-hydroxymethyl-2-methyl-4-(2-oxopyrrolidin-1-yl)-6-nitr o-2H-1-benzopyran) were compared with those of lemakalim, a prototype of this class, in isolated globally ischemic rat hearts. KR-30450 and KR-30818 significantly improved reperfusion cardiac function (LVDP, left ventricular developed pressure; double product, LVDP x heart rate/1000), their potency being 5.2-fold and 0.7-fold greater than lemakalim (ED50 for recovering predrug double product: 0.10, 0.80 and 0.54 microM, respectively). KR-30450 and KR-30818 significantly attenuated reperfusion contracture and lactate dehydrogenase release with potency greater than and equal to lemakalim, respectively. They significantly increased time to contracture (TTC) during ischemia in a dose-dependent manner with a greater potency than lemakalim (EC25 for increasing TTC: 1.2, 2.1 and 3.2 microM, respectively). The protective effects of three compounds on the measured parameters were reversed by glyburide, a selective K+(ATP) blocker. In non-ischemic hearts, KR-30450 and lemakalim exerted weak negative inotropism at high concentrations and KR-30818 had no effects, whereas the three compounds significantly increased coronary flow at doses studied. Glyburide completely reversed preischemic cardiodepressant effects of these compounds but not their effects on coronary flow. In conclusion, KR-30450, a recently developed K+(ATP) opener, exerted more potent cardioprotective effects than lemakalim, and its major metabolite KR-30818 may play a significant role in its action in vivo.
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PMID:Cardioprotective effects of KR-30450, a novel K+(ATP) opener, and its major metabolite KR-30818 on isolated rat hearts. 951 6

Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 +/- 3% (mean +/- SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 +/- 2, 17 +/- 2, and 12 +/- 3%, respectively (P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 +/- 4 and 41 +/- 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.
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PMID:KATP channels are common mediators of ischemic and calcium preconditioning in rabbits. 957 13

The possible ischemia-selective Class III anti-arrhythmic action (selective action potential widening in ischemia) of the IKATP blocker glibenclamide was assessed in anesthetized rabbits during ischemia induced by complete occlusion of a coronary artery. Coronary artery occlusion caused an initial prolongation in monophasic action potential (MAP) duration at 90% repolarization from 145 +/- 2.8 ms (mean +/- S.E.M., n = 14) to 162 +/- 4.5 ms (P < 0.05) 1 min after ischemia. This was followed by a rapid and sustained shortening to 104 +/- 4.9 ms 5 min after the onset of ischemia (P < 0.05 from both values). Glibenclamide (3, 6, 12 or 24 mg/kg, i.v.) caused a statistically significant, dose-related reduction in the rate of MAP shortening induced by ischemia, whereas 0.3 mg/kg was without effect. The effective dose for a 50% maximal effect (ED50) was 13 +/- 0.8 mg/kg (n = 28). Despite this, there was no effect on the final magnitude of MAP shortening. Five min after induction of ischemia, there were no longer any detectable effects of glibenclamide on MAP duration. Glibenclamide significantly reduced the incidence of ventricular fibrillation, although the effect was not dose related. No differences were found in the latency to ventricular fibrillation between groups. Ventricular fibrillation occurred 10.6 +/- 1.1 min (n = 19) after the start of ischemia. In a similar experiment, 0.3 mg/kg glibenclamide i.v. did not affect the rate of MAP shortening, the final magnitude of MAP shortening or the occurrence of arrhythmias caused by ischemia. Since the action potential widening effects of glibenclamide in ischemic tissue were not observed at the time when arrhythmias occurred, it is unlikely that an ischemia-selective Class III anti-arrhythmic action contributes to the limited antiarrhythmic actions of glibenclamide.
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PMID:Glibenclamide does not prevent action potential shortening induced by ischemia in anesthetized rabbits but reduces ischemia-induced arrhythmias. 961 40

The effect of opening and of blocking of ATP-sensitive potassium (K(ATP)) channels on the short-term capacity of neurons to resist ischemia-reperfusion-induced cell injury, was studied in a model of primary rat neuronal cultures, subjected to metabolic poisoning by iodoacetic acid (150 microM, 150 min), followed by reperfusion (1 h). The metabolic poisoning resulted in a marked decrease in cellular ATP content (from 65.3 +/- 13.4 to 21.6 +/- 11.7 nmole/mg protein), simulating an ischemia, or hypoxia-induced condition of energy crisis. The degree of neuronal damage was assessed by the trypan blue exclusion test. Exposure of the neurons to the channel-opener cromakalim (10 microM; 15 min), prior to the insult, induced resistance, which could be abolished by the specific channel blocker glibenclamide (2 microM). Glibenclamide also abolished the protection acquired by preconditioning of the neurons with iodoacetate (IA; 100 microM), the adenosine A1 agonist N6-(R)-phenylisopropyladenosine (R-PIA; 100 microM), or with the protein kinase C (PKC) activator 1,2 dioctanoyl-rac-glycerol (DOG; 1 microM). The results indicate that in the neurons, opening of the K(ATP) channels confers protection against an ATP-depleting crisis, and suggest that the protective effects induced by adenosine and by activation of PKC, are mediated by the opening of these channels.
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PMID:Opening of ATP-sensitive potassium channels by cromakalim confers tolerance against chemical ischemia in rat neuronal cultures. 969 31

The activation of the ATP-sensitive potassium channel (KATP) during myocardial ischemia leads to potassium efflux, reductions in action potential duration and the formation of ventricular fibrillation (VF). Drugs that inactivate KATP should prevent these changes and thereby prevent VF. However, most KATP antagonists also alter pancreatic channels, which promote insulin release and hypoglycemia. Recently, a cardioselective KATP antagonist, HMR 1883, has been developed that may offer cardioprotection without the untoward side effects of existing compounds. Therefore, VF was induced in 13 mongrel dogs with healed myocardial infarctions by a 2-min coronary artery occlusion during the last minute of a submaximal exercise test. On subsequent days, the exercise-plus-ischemia test was repeated after pretreatment with HMR 1883 (3.0 mg/kg i.v., n = 13) or glibenclamide (1.0 mg/kg i.v., n = 7). HMR 1883 (P < .001) and glibenclamide (P < .01) prevented VF in 11 of 13 and 6 of 7 animals, respectively. Glibenclamide, but not HMR 1883, elicited increases in plasma insulin and reductions in blood glucose. Glibenclamide also reduced (P < .01) both mean coronary blood flow and left ventricular dP/dt maximum as well as the reactive hyperemia induced by 15-sec coronary occlusions (-30.3 +/- 11%), whereas HMR 1883 did not alter this increase in coronary flow (-3.0 +/- 4.7%). Finally, myocardial ischemia (n = 10) significantly (P < .01) reduced refractory period (control, 121 +/- 2 msec; occlusion, 115 +/- 2 msec), which was prevented by either glibenclamide or HMR 1883. Thus, the cardioselective KATP antagonist HMR 1883 can prevent ischemically induced reductions in refractory period and VF without major hemodynamic effects or alterations in blood glucose levels. These data further suggest that the activation of KATPs may play a particularly important role in both the reductions in refractory period and lethal arrhythmia formation associated with myocardial ischemia.
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PMID:HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part II: effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs. 973 12

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