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)

We have shown previously that acute ischemia leads to depolarization of pulmonary microvascular endothelial cells that is prevented with cromakalim, suggesting the presence of ATP-sensitive K+ (KATP) channels in these cells. Thus KATP channel expression and activity were evaluated in rat pulmonary microvascular endothelial cells (RPMVEC) by whole cell current measurements, dot blot (mRNA), and immunoblot (protein) for the inwardly rectifying K+ channel (KIR) 6.2 subunit and fluorescent ligand binding for the sulfonylurea receptor (SUR). Low-level expression of a KATP channel was detected in endothelial cells in routine (static) culture and led us to examine whether its expression is inducible when endothelial cells are adapted to flow. Channel expression (mRNA and both KIR6.2 and SUR proteins) and inwardly rectified membrane current by patch clamp increased significantly when RPMVEC were adapted to flow at 10 dyn/cm2 for 24 h in either a parallel plate flow chamber or an artificial capillary system. Induction of the KATP channel with flow adaptation was also observed in bovine pulmonary artery endothelial cells. Flow-adapted but not static RPMVEC showed cellular plasma membrane depolarization upon stop of flow that was inhibited by a KATP channel opener and prevented by addition of cycloheximide to the medium during the flow adaptation period. These studies indicate the induction of KATP channels by flow adaptation in pulmonary endothelium and that the expression and activity of this channel are essential for the endothelial cell membrane depolarization response with acute decrease in shear stress.
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PMID:Shear stress increases expression of a KATP channel in rat and bovine pulmonary vascular endothelial cells. 1282 4

Sulfonylureas, which have evolved through two generations since their introduction nearly 50 years ago, remain the most frequently prescribed oral agents for treatment of patients with type 2 diabetes mellitus. Glyburide, glipizide, and glimepiride, the newest sulfonylureas, are as effective at lowering plasma glucose concentrations as first-generation agents but are more potent, better tolerated, and associated with a lower risk of adverse effects. Differences in their binding affinity to the beta-cell sulfonylurea receptor have been described, with preservation of cardioprotective responses to ischemia with glimepiride. Clinical studies have shown glimepiride to be safe and effective in reducing fasting and postprandial glucose levels, as well as glycosylated hemoglobin concentrations, with dosages of 1-8 mg/day. In comparative trials, glimepiride was as effective in lowering glucose levels as glyburide and glipizide, but glimepiride was associated with a reduced likelihood of hypoglycemia and a smaller increase in fasting insulin and C-peptide levels than glyburide, and a more rapid lowering of fasting plasma glucose levels than glipizide. Glimepiride also improves first-phase insulin secretion, which plays an important role in reducing postprandial hyperglycemia. Insulin secretagogues, specifically glimepiride, merit consideration as first-line therapy for patients with type 2 diabetes.
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PMID:Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepiride. 1516 95

ATP-sensitive K+ channels (KATP channels) are present in various tissues, including pancreatic beta-cells, heart, skeletal muscles, vascular smooth muscles, and brain. KATP channels are hetero-octameric proteins composed of inwardly rectifying K+ channel (Kir6.x) and sulfonylurea receptor (SUR) subunits. Different combinations of Kir6.x and SUR subunits comprise KATP channels with distinct electrophysiological and pharmacological properties. Recent studies of genetically engineered mice have provided insight into the physiological and pathophysiological roles of Kir6.x-containing KATP channels. Analysis of Kir6.2 null mice has shown that Kir6.2/SUR1 channels in pancreatic beta-cells and the hypothalamus are essential in glucose-induced insulin secretion and hypoglycemia-induced glucagon secretion, respectively, and that Kir6.2/SUR2 channels are involved in glucose uptake in skeletal muscles. Kir6.2-containing KATP channels in brain also are involved in protection from hypoxia-induced generalized seizure. In cardiovascular tissues, Kir6.1-containing KATP channels are involved in regulation of vascular tonus. In addition, the Kir6.1 null mouse is a model of Prinzmetal angina in humans. Our studies of Kir6.2 null and Kir6.1 null mice reveal that KATP channels are critical metabolic sensors in acute metabolic changes, including hyperglycemia, hypoglycemia, ischemia, and hypoxia.
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PMID:Roles of ATP-sensitive K+ channels as metabolic sensors: studies of Kir6.x null mice. 1556 8

ATP-sensitive K+ (K(ATP)) channels play many important roles in cellular functions, including control of membrane excitability of skeletal muscle and neurons, K+ recycling in renal epithelia, cytoprotection in cardiac ischemia, and insulin secretion from pancreatic beta-cells. K(ATP) channels are composed of pore-forming inwardly rectifying potassium channel (Kir6.2 or Kir6.1) subunits and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits. Kir6.2 or Kir6.1 subunits conjoined with a SUR subunit constitute the various tissue-specific K(ATP) channels with distinct pharmacological properties. Both sulfonylureas and non-sulfonylurea hypoglycemic agents are used in treatment of type 2 diabetes mellitus. While the sulfonylurea receptor (SUR) is the target molecule of all of these hypoglycemic agents, the binding sites differ according to the moiety containing in the agent, and alter the pharmachological properties. In addition, chronic exposure of pancreatic beta-cells to the various agents affects the agent-specific sensitivities differently. Here we distinguish differences in pharmacological profile among the various hypoglycemic agents that reflect their chemical composition. We also suggest possible risk in the use of certain hypoglycemic agents in patients with ischemic heart disease.
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PMID:Sulfonylurea and non-sulfonylurea hypoglycemic agents: pharmachological properties and tissue selectivity. 1556 85

Activation of ATP-sensitive potassium (KATP) channels is known to have cardioprotective effects during periods of ischemia and reperfusion, making these channels important targets for clinical drug discovery. Using electrophysiological techniques we identify KATP channels in a mouse atrial cell line (HL-1). HL-1 KATP channels exhibited a concentration-dependent inhibition by ATP (IC50 = 23.3 +/- 3.2 microM), a unitary single-channel conductance of 55 pS, and sensitivity to the isoform-specific KATP channel opener P1075 and inhibitor HMR1098. Adenoviral infection of a dominant-negative Kir6.2 subunit significantly reduced the P1075-sensitive sarcKATP current. Taken together, the data indicate that HL-1 KATP channels are composed of sulfonylurea receptor isoform SUR2A coupled to the pore-forming Kir6.2 subunit--the molecular makeup of sarcKATP channels found in native cardiac myocytes. Pharmacological activation of HL-1 cell KATP channels also resulted in action potential shortening. Using the membrane potential-sensitive dye DiBac4(3), we demonstrated that the sarcKATP channel opener P1075 (20 microM) produced a concentration-dependent hyperpolarization of a monolayer of HL-1 cells that could be reversed by channel inhibition with HMR1098 (20 microM). We conclude that the HL-1 cells are an excellent cell line for studying cardiac sarcKATP channels, and these cells may also provide an important tool for the testing of novel pharmacological modulators of KATP channels in fluorescence-based assays.
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PMID:Identification and pharmacological characterization of sarcolemmal ATP-sensitive potassium channels in the murine atrial HL-1 cell line. 1561 76

K-ATP channels consist of two structurally different subunits: a pore-forming subunit of the Kir6.0-family (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2, SUR2A, SUR2B) with regulatory activity. The functional diversity of K-ATP channels in brain is broad and of fundamental importance for neuronal activity. Here, using immunocytochemistry with monospecific antibodies against the Kir6.1 and Kir6.2 subunits, we analyze the regional and cellular distribution of both proteins in the adult rat brain. We find Kir6.2 to be widely expressed in all brain regions, suggesting that the Kir6.2 subunit forms the pore of the K-ATP channels in most neurons, presumably protecting the cells during cellular stress conditions such as hypoglycemia or ischemia. Especially in hypothalamic nuclei, in particular the ventromedial and arcuate nucleus, neurons display Kir6.2 immunoreactivity only, suggesting that Kir6.2 is the pore-forming subunit of the K-ATP channels in the glucose-responsive neurons of the hypothalamus. In contrast, Kir6.1-like immunolabeling is restricted to astrocytes (Thomzig et al. [2001] Mol Cell Neurosci 18:671-690) in most areas of the rat brain and very weak or absent in neurons. Only in distinct nuclei or neuronal subpopulations is a moderate or even strong Kir6.1 staining detected. The biological functions of these K-ATP channels still need to be elucidated.
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PMID:Pore-forming subunits of K-ATP channels, Kir6.1 and Kir6.2, display prominent differences in regional and cellular distribution in the rat brain. 1573 38

Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, incorporating Kir6.x and sulfonylurea receptor subunits, are weak inward rectifiers that are thought to play a role in neuronal protection from ischemic insults. However, the involvement of Kir6.2-containing KATP channel in hippocampus and neocortex has not been tested directly. To delineate the physiological roles of Kir6.2 channels in the CNS, we used knockout (KO) mice that do not express Kir6.2. Immunocytochemical staining demonstrated that Kir6.2 protein was expressed robustly in hippocampal neurons of the wild-type (WT) mice and absent in the KO. To examine neuronal sensitivity to metabolic stress in vitro, and to ischemia in vivo, we 1) exposed hippocampal slices to transient oxygen and glucose deprivation (OGD) and 2) produced focal cerebral ischemia by middle cerebral artery occlusion (MCAO). Both slice and whole animal studies showed that neurons from the KO mice were severely damaged after anoxia or ischemia, whereas few injured neurons were observed in the WT, suggesting that Kir6.2 channels are necessary to protect neurons from ischemic insults. Membrane potential recordings from the WT CA1 pyramidal neurons showed a biphasic response to OGD; a brief hyperpolarization was followed by a small depolarization during OGD, with complete recovery within 30 min after returning to normoxic conditions. By contrast, CA1 pyramidal neurons from the KO mice were irreversibly depolarized by OGD exposure, without any preceding hyperpolarization. These data suggest that expression of Kir6.2 channels prevents prolonged depolarization of neurons resulting from acute hypoxic or ischemic insults, and thus protects these central neurons from the injury.
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PMID:Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels. 1635 31

ATP-sensitive potassium channels (K(ATP)) couple cell metabolism to electrical activity by regulating potassium movement across the membrane. These channels are octameric complex with two kind of subunits: four regulatory sulfonylurea receptor (SUR) embracing four poreforming inwardly rectifying potassium channel (Kir). Several isoforms exist for each type of subunits: SUR1 is found in the pancreatic beta-cell and neurons, whereas SUR2A is in heart cells and SUR2B in smooth muscle; Kir6.2 is in the majority of tissues as pancreatic beta-cells, brain, heart and skeletal muscle, and Kir6.1 can be found in smooth vascular muscle and astrocytes. The K(ATP) channels play multiple physiological roles in the glucose metabolism regulation, especially in beta-cells where it regulates insulin secretion, in response to an increase in ATP concentration. They also seem to be critical metabolic sensors in protection against metabolic stress as hypo or hyperglycemia, hypoxia, ischemia. Persistent hyperinsulinemic hypoglycaemia (HI) of infancy is a heterogeneous disorder which may be divided into two histopathological forms (diffuse and focal lesions). Different inactivating mutations have been implicated in both forms: the permanent inactivation of the K(ATP) channels provokes inappropriate insulin secretion, despite low ATP. Diazoxide, used efficiently in certain cases of HI, opens the K(ATP) channels and therefore overpass the mutation effect on the insulin secretion. Conversely, several studies reported sequencing of KCNJ11, coding for Kir6.2, in patients with permanent neonatal diabetes mellitus and found different mutations in 30 to 50% of the cases. More than 28 heterozygous activating mutations have now been identified, the most frequent mutation being in the aminoacid R201. These mutations result in reduced ATP-sensitivity of the K(ATP) channels compared with the wild-types and the level of channel block is responsible for different clinical features: the "mild" form confers isolated permanent neonatal diabetes whereas the severe form combines diabetes and neurological symptoms such as epilepsy, deve-lopmental delay, muscle weakness and mild dimorphic features. Sulfonylureas close K(ATP) channels by binding with high affinity to SUR suggesting they could replace insulin in these patients. Subsequently, more than 50 patients have been reported as successfully and safely switched from subcutaneous insulin injections to oral sulfonylurea therapy, with an improvement in their glycated hemoglobin. We therefore designed a protocol to transfer and evaluate children who have insulin treated neonatal diabetes due to KCNJ11 mutation, from insulin to sulfonylurea. The transfer from insulin injections to oral glibenclamide therapy seems highly effective for most patients and safe. This shows how the molecular understan-ding of some monogenic form of diabetes may lead to an unexpected change of the treatment in children. This is a spectacular example by which a pharmacogenomic approach improves the quality of life of our young diabetic patients in a tremendous way.
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PMID:Diabetes and hypoglycaemia in young children and mutations in the Kir6.2 subunit of the potassium channel: therapeutic consequences. 1729 10

Pharmacological mitochondrial ATP-sensitive K(+) channel (mitoK(ATP)) opening protects against ischemic damage and mimics ischemic preconditioning. However, physiological and pathological signaling events that open this channel are still not fully understood. We found that catalase, which removes H(2)O(2), is capable of reversing the beneficial effects of ischemic preconditioning but not of mitoK(ATP) agonist diazoxide. On the other hand, 2-mercaptopropionylglycine prevented cardioprotection in both cases, suggesting that this compound may present effects other than scavenging of reactive oxygen species. Indeed, 2-mercaptopropionylglycine and a second thiol-reducing agent, dithiothreitol, impair diazoxide-mediated activation of mitoK(ATP) in isolated heart mitochondria. This demonstrates that mitoK(ATP) activity is regulated by thiol redox status. Furthermore, stimulating the generation of endogenous mitochondrial reactive oxygen species or treating samples with H(2)O(2) strongly enhances mitoK(ATP) activity, in a manner probably dependent on redox sensors located in the channel's sulfonylurea receptor. We also demonstrate that mitoK(ATP) channel activity effectively prevents mitochondrial reactive oxygen release. Collectively, our results suggest that mitoK(ATP) acts as a reactive oxygen sensor that decreases mitochondrial free radical generation in response to enhanced local levels of oxidants. As a result, these channels regulate mitochondrial redox state under physiological conditions and prevent oxidative stress under pathological conditions such as ischemia/reperfusion.
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PMID:Mitochondrial ATP-sensitive K+ channels are redox-sensitive pathways that control reactive oxygen species production. 1734 31

Sulfonylurea receptor 1 (SUR1) is a molecule with more diverse and critically important functions than previously recognized. Long viewed simply as a subunit involved in formation of a subset of K(ATP) channels, accumulating evidence indicates that SUR1 is newly upregulated in CNS ischemia and injury and is surprisingly promiscuous in its association with different pore-forming subunits, which endow it with new roles not previously envisioned. In this review, we focus on the SUR1-regulated NC(Ca-ATP) channel, its emerging role in CNS ischemia and trauma, and the growing evidence from preclinical and clinical studies demonstrating the potential importance of block of SUR1 by sulfonylureas such as glibenclamide (glyburide) in conditions as seemingly diverse as stroke and spinal cord injury.
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PMID:Drugs acting on SUR1 to treat CNS ischemia and trauma. 1803 10


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