Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effective refractory period was measured in paced (4 Hz) perfused guinea-pig hearts in vitro. The effective refractory period was linearly correlated with temperature of the perfusing solution: as temperature was reduced the effective refractory period was increased. Reduction of the coronary flow rate to 10% of control resulted in a marked reduction in the effective refractory period. UK-66,914, dofetilide, ibutilide and phentolamine caused a prolongation in the effective refractory period, but during ischaemia the effective refractory period was reduced by the same degree as in vehicle-treated hearts. Glibenclamide had no effect on the effective refractory period prior to ischemia but it abolished the ischaemia-induced shortening. These results suggest that the opening of KATP channels may be responsible for the ischaemia-induced shortening of the effective refractory period in perfused guinea-pig hearts and that the class III effects of UK-66,914, dofetilide and ibutilide are attenuated during ischaemia.
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PMID:Glibenclamide, but not class III drugs, prevents ischaemic shortening of the refractory period in guinea-pig hearts. 824 42

The Role of ATP-sensitive K+ channels (KATP) in action potential shortening and protection of myocardium in ischemia were explored using isolated ventricular myocytes and arterially perfused right ventricular walls of guinea pigs. Conditions "simulating" some aspects of ischemia--(10.8 mM K+o, 6.9 pHo, 20 mM lactate, no glucose; 10 mM 2-deoxy-D-glucose; and either 1 mM cyanide or no O2 (bubbled with 95/5% N2/CO2)--caused a decline in action potential duration (APD) and the elaboration of time- and voltage-independent, steady-state outward conductance due to KATP, which could be inhibited with glibenclamide (50 microM) in myocytes studied via the perforated patch (nystatin) whole-cell technique. Right ventricular walls subjected to no-flow ischemia +/- glibenclamide (10 microM) to block, or +/- pinacidil (1 and 10 microM) to activate, KATP, respectively, exhibited varied ischemic injury. Glibenclamide caused a greater fall in resting membrane potential, inhibited the decline in APD, caused an early rise in resting tension, and inhibited recovery of contractile function upon reflow. Pinacidil caused a greater decline in APD, inhibited changes in resting tension, and improved recovery during reperfusion. These results indicate that KATP contributes to action potential shortening in isolated myocytes in simulated ischemia and intact myocardium in no-flow ischemia. Activation of this membrane current may be an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.
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PMID:ATP-sensitive K+ channels in cardiac ischemia: an endogenous mechanism for protection of the heart. 825 23

Vasodilatation following tissue ischemia is assumed to partially result from activation of ATP-dependent K+ channels (KATP). To assess the effect of cytosolic adenosine nucleotides, the balance of which depends on tissue pO2, on KATP, we have measured steady state outward currents (SSC) by the whole-cell clamp technique in smooth muscle cells of the guinea pig portal vein at different concentrations of ATP and ADP in the pipette solution. Glibenclamide, a selective inhibitor of KATP, was used as a pharmacological tool. With no nucleotides in the pipette solution (Ca(2+)-free), the SSC determined at +20 mV was unaffected by glibenclamide, while with 0.1 mM ATP or with 0.1 mM ADP, the SSC exhibited a glibenclamide-sensitive component indicating activation of KATP. At 5 mM ATP and no ADP, hardly any effect of glibenclamide on the SSC was detected, suggesting inhibition of KATP by this high concentration of ATP. With 0.1 mM ADP at 5 mM ATP however, activation of KATP was achieved. At 10(-7) M Ca2+ in the pipette solution, an increased SSC was measured, but the responses to the nucleotides and/or glibenclamide were not modified. These findings suggest that in vivo, ADP may be involved in the regulation of vascular KATP, linking tissue pO2 with vascular tone and tissue perfusion.
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PMID:Intracellular ADP activates ATP-sensitive K+ channels in vascular smooth muscle cells of the guinea pig portal vein. 848 87

Previous studies have indicated that the ATP-sensitive potassium channels blocker glibenclamide (glyburide) can abolish preconditioning in canine models of myocardial ischemia. Recently, an isolated rat heart model of preconditioning has been developed that may be ideal for studying the mechanisms of preconditioning. In the present study, we determined the effect of glyburide on preconditioning in isolated rat hearts. Rat hearts were isolated and retrogradely perfused with oxygenated Krebs'-Henseleit solution. They were then subjected to four periods of total global ischemia of 5-min duration, separated by 5-min reperfusion. The hearts were then subjected to 30-min global ischemia followed by 30-min reperfusion and contractile function and lactate dehydrogenase release determined. Non-preconditioned hearts sustained severe damage. Glyburide (1-100 microM) pretreatment had no effect on the severity of 30-min global ischemia and 30-min reperfusion. Preconditioning caused significant improvements in reperfusion contractile function (25-fold increase in left ventricular developed pressure) and reductions in reperfusion lactate dehydrogenase release and reperfusion end diastolic pressure (contracture). Glyburide had modest preischemic cardiodepressant and vasoconstrictor effects at 1-30 microM, whereas 100 microM caused a 50% reduction in preischemic coronary flow. Despite these effects, none of these concentrations of glyburide affected the efficacy of preconditioning. These studies indicate that preconditioning in isolated rat hearts does not occur via a glyburide- (and thus presumably ATP-sensitive potassium channel) sensitive mechanism.
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PMID:The ATP-sensitive potassium channel blocker glibenclamide (glyburide) does not abolish preconditioning in isolated ischemic rat hearts. 849 6

Glibenclamide, a K+ ATP channel antagonist, blocks the anti-infarct effect of ischemic preconditioning in rabbits, but only when the latter are anesthetized with ketamine-xylazine. Furthermore, the protection triggered by pinacidil, a K+ ATP channel opener, can be aborted by treatment with the adenosine antagonist 8-(P-sulfophenyl)theophylline. This study tests whether either the anesthetic regimen or glibenclamide affects infarct size by modulating interstitial adenosine levels. Interstitial adenosine and total purine concentrations were assessed in open-chest rabbits by the microdialysis technique. Dialysis fibers were inserted into myocardium served by a coronary artery branch surrounded by a snare. All animals sustained a 30-min coronary occlusion and then 120-min reperfusion. Rabbits were anesthetized with either sodium pentobarbital or a ketamine-xylazine mixture. Half of the latter animals also received glibenclamide. The control levels of adenosine in the dialysate were comparable in the three groups, as were those of total purines, and the infusion of glibenclamide caused no change. Ischemia led to 10- to 20-fold increases in interstitial adenosine and 10- to 40-fold rises in total purine concentrations. These increases were equivalent in all groups. Further-more, infarct size as a percentage of the myocardium at risk was also comparable in the three groups. Neither the anesthetic agent nor glibenclamide appears to modulate interstitial adenosine release from ischemic tissue.
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PMID:Effects of anesthesia and K+ ATP channel blockade on interstitial adenosine accumulation in ischemic rabbit myocardium. 858 63

Although a decrease in extravascular pH has been suggested to be involved in coronary flow regulations during hypoxia, ischemia, and increased metabolic demand of the heart, its vasomotor control mechanism has not been elucidated. To examine the effect of acidosis of vasomotor tone, porcine coronary arterioles (40 to 110 microns) were isolated, cannulated, and pressurized to 60 cm H2O intraluminal pressure without flow for in vitro study. Acidosis (pH 7.4 to 7.0) was produced by adding HCl to the extravascular solution. The involvement of potassium channels in the vasomotor response to acidosis was evaluated by using BaCl2 (100 mumol/L, nonspecific potassium channel inhibitor), glibenclamide (5 mumol/L, ATP-sensitive potassium channel inhibitor), and iberiotoxin (100 nmol/L, calcium-activated potassium channel inhibitor). To determine whether endothelial hyperpolarization contributes to the acidosis-induced dilation, the pH-diameter relation of the vessel was examined under a high intraluminal concentration of KCl (40 mmol/L). The involvement of nitric oxide and prostaglandins was assessed by using NG-monomethyl-L-arginine (L-NMMA, 10 mumol/L) and indomethacin (10 mumol/L), respectively. To evaluate the role of endothelium in the acidosis-induced dilation, the pH-diameter relation was studied after endothelial removal. All vessels developed a similar level of spontaneous tone (internal diameter, 75 +/- 4 microns [approximately 69 +/- 1% of maximum diameter) and dilated to HCl in dose-dependent manner. Glibenclamide completely abolished vasodilation to a mild level of acidosis (pH 7.2 to 7.3) and attenuated the vasodilation by 70% at pH 7.0. Acidosis-induced dilation was also inhibited by BaCl2 but not by iberiotoxin. L-NMMA, indomethacin, and intraluminal KCl did not alter the pH-diameter relation. Vasodilation to acidosis of the endothelium-denuded vessels was identical to that of the endothelium-intact vessels. In addition, glibenclamide attenuated the acidosis-induced arteriolar dilation of endothelium-denuded vessels. These results suggest that the opening of ATP-sensitive potassium channels in vascular smooth muscle mediates the coronary arteriolar dilation during acidosis.
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PMID:Acidosis-induced coronary arteriolar dilation is mediated by ATP-sensitive potassium channels in vascular smooth muscle. 860 5

Glibenclamide, an ATP-sensitive K (K ATP) channel blocker, worsens the ischemia-induced metabolic derangement in the heart through inhibition of K ATP channels. We examined whether the hypoglycemic effect of glibenclamide was involved in the worsening of myocardial energy metabolism during ischemia. Pentobarbital-anesthetized dogs were subjected to 15-min ligation of the left anterior descending coronary artery. Either vehicle (dimethyl sulfoxide, DMSO) or glibenclamide (1 mg/kg) was injected i.v. 10 min before the ligation. In half of the animals given glibenclamide, glucose was continuously infused at 3 mg/kg per min immediately after glibenclamide injection. Glibenclamide increased the serum insulin level and decreased the blood glucose level. Glucose infusion completely abolished the hypoglycemia due to glibenclamide. Glibenclamide enhanced the decrease in ATP and total adenine nucleotides and increase in tissue lactate caused by ischemia. Glucose infusion did not cancel the augmentation of ischemia-induced alterations of myocardial energy metabolism caused by glibenclamide. These results suggest that K ATP channels directly play an important role in endogenous mechanisms of myocardial protection against ischemic damage.
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PMID:Effect of glibenclamide on ischemic canine myocardium with glucose infusion. 874 25

The objective of this study was to examine if the opening of ATP-sensitive K+ (KATP) channels play an important role in ischemic preconditioning (PC) in the rat heart. A second goal was to test the role of acetylcholine (ACh) in mimicking PC and test if it could be blocked by KATP antagonist. Glibenclamide, a specific antagonist of the KATP channel, was given as two doses of 0.3 mg/kg each at 60 and 30 min before PC. Six groups of rats were subjected to ischemia and reperfusion (I/R) using these protocols: 1) control (I/R), 30-min ischemia followed by 90-min reperfusion (n = 6 rats); 2) preconditioned hearts given 5-min ischemia 10 min before I/R (n = 9 rats); 3) glibenclamide (0.3 mg/kg) treatment 60 and 30 min before PC (n = 13 rats); 4) glibenclamide treatment before I/R (n = 15 rats); 5) ACh infusion for 5 min (18 micrograms/ml) at a rate of 0.15 ml/min followed by equilibration for 10 min before I/R, n = 13 rats; and 6) glibenclamide treatment before ACh infusion followed by I/R (n = 11 rats). Preconditioning reduced the infarcted area (expressed as percent area at risk) from 42.0 +/- 4.4% in control to 8.7 +/- 6% (mean +/- SE, P < 0.05). Glibenclamide blocked the protection conferred by PC (39.1 +/- 4.5%, P < 0.05) without having a significant effect on control nonpreconditioned hearts. ACh infusion in lieu of PC also reduced infarct size to 25.0 +/- 5.63% (P < 0.05 compared with control), which was again blocked by glibenclamide (44.2 +/- 5.0%, P < 0.05). The data suggest that opening of KATP channels for ischemic and ACh-mediated preconditioning is also important in the rat heart.
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PMID:KATP channels in rat heart: blockade of ischemic and acetylcholine-mediated preconditioning by glibenclamide. 876 Jan 53

PD 81,723 (PD) acts allosterically to increase agonist binding to A1 adenosine receptors and to enhance functional A1 receptor-mediated responses in the heart and other tissues. To determine if PD lowers the threshold for ischemic preconditioning (PC), pentobarbital-anesthetized dogs were subjected to 60 minutes of left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. Ischemic PC was produced by either 2.5 or 5 minutes of LAD occlusion 10 minutes before the 60-minute occlusion. PD (100 micrograms/kg total dose, 5 to 50 mumol/L in coronary arterial blood) or vehicle was infused intracoronarily for 17.5 minutes before the 60-minute occlusion period in non-PC dogs or in dogs preconditioned with 2.5 minutes of ischemia. Myocardial infarct size was determined by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Compared with the control group (26.3 +/- 3.6%, mean +/- SEM), infarct size was not significantly affected by 2.5 minutes of PC alone (23.4 +/- 4.2%) or by PD alone (26.5 +/- 1.7%) but was decreased by PD + PC (14.6 +/- 1.7%, P < .05) or by a longer period (5 minutes) of PC alone (12.5 +/- 3.3%). The intravenous administration of the selective antagonist of A1 adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (1 mg/kg), or the ATP-sensitive K+ channel blocker, glibenclamide (0.3 mg/kg), for 15 minutes before PD + PC blocked the protection (23.6 +/- 2.3% or 25.9 +/- 3.3%, respectively). None of the compounds studied affected systemic hemodynamics, collateral blood flow, or AAR. To determine which subtypes of canine adenosine receptors were affected by 10 mumol/L PD, radioligand binding studies were conducted using membranes derived from COS-7 cells expressing recombinant canine receptors and agonist radioligands. PD enhanced the binding of [125I]N6-4-amino-3-iodobenzyladenosine (125I-ABA) to A1 receptors by increasing the t1/2 for dissociation by 2.18-fold, but PD had no effect on the dissociation kinetics of 125I-ABA from A3 receptors or [125I]-[2-(4-amino-3-iodo-phenyl)ethylamino] adenosine from A2A receptors. Glibenclamide at concentrations up to 10 mumol/L had no effect on the binding of radioligands to recombinant canine A1, A2A, or A3 receptors. These data suggest that PD reduces the amount of time required for ischemia to produce preconditioning by enhancing adenosine binding to its A1 receptor. Glibenclamide prevents the protection afforded by A1 receptor activation by a mechanism not involving adenosine receptor blockade.
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PMID:PD 81,723, an allosteric enhancer of the A1 adenosine receptor, lowers the threshold for ischemic preconditioning in dogs. 878 75

Tissues maintain O2 consumption (VO2) when blood flow and O2 delivery (DO2) are decreased by better matching of blood flow to meet local cellular O2 demand, a process that increases extraction of available O2. This study tested the hypothesis that ATP-sensitive K+ channels play a significant role in the response of pig hindlimb to ischemia. We pump perfused the vascularly isolated but innervated right hindlimb of 14 anesthetized pigs with normoxic blood while measuring hindlimb DO2, VO2, perfusion pressure, and cytochrome aa3 redox state. In one-half of the pigs, the pump-perfused hindlimb was also infused with 10 micrograms.min-1.kg-1 of glibenclamide, a potent blocker of ATP-sensitive K+ channels. Control animals were infused with 5% glucose solution alone. Blood flow was then progressively reduced in both groups in 10 steps at 10-min intervals. Glibenclamide had no effect on any preischemic hindlimb or systemic measurements. Hindlimb VO2 and cytochrome aa3 redox state began to decrease at a significantly higher DO2 in glibenclamide-treated compared with control pigs. At this critical DO2, the O2 extraction ratio (VO2/DO2) was 53 +/- 4% in the glibenclamide group and 73 +/- 5% in the control group (P < 0.05). Hindlimb vascular resistance increased significantly with ischemia in the glibenclamide group but did not change in the control group. We conclude that ATP-sensitive K+ channels may be importantly involved in the vascular recruitment response that tried to meet tissue O2 needs as blood flow was progressively reduced in the pig hindlimb.
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PMID:ATP-sensitive K+ channel blockade impairs O2 extraction during progressive ischemia in pig hindlimb. 884 71


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