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PubMed2000

KATP channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines. Implications for liver growth control and potential therapeutic targeting.

To determine whether K(ATP) channels control liver growth, we used primary rat hepatocytes and several human cancer cell lines for assays. K(ATP) channel openers (minoxidil, cromakalim, and pinacidil) increased cellular DNA synthesis, whereas K(ATP) channel blockers (quinidine and glibenclamide) attenuated DNA synthesis. The channel inhibitor glibenclamide decreased the clonogenicity of HepG2 cells without inducing cytotoxicity or apoptosis. To demonstrate the specificity of drugs for K(+) channels, whole-cell patch-clamp recordings were made. Hepatocytes revealed K(+) currents with K(ATP) channel properties. These K(+) currents were augmented by minoxidil and pinacidil and attenuated by glibenclamide as well as tetraethylammonium, in agreement with established responses of K(ATP) channels. Reverse transcription of total cellular RNA followed by polymerase chain reaction showed expression of K(ATP) channel-specific subunits in rat hepatocytes and human liver cell lines. Calcium fluxes were unperturbed in glibenclamide-treated HepG2 cells and primary rat hepatocytes following induction with ATP and hepatocyte growth factor, respectively, suggesting that the effect of K(ATP) channel activity upon hepatocyte proliferation was not simply due to indirect modulation of intracellular calcium. The regulation of mitogen-related hepatocyte proliferation by K(ATP) channels advances our insights into liver growth control. The findings have implications in mechanisms concerning liver development, regeneration, and oncogenesis.

ATP-Binding Cassette Transporters↗
PubMed2003

[Molecular and electrophysiological investigation of ATP-sensitive K+ channels in lower urinary tract function: the aims for clinical treatment of unstable detrusor].

It is a common sequelae of bladder outlet obstruction caused by benign prostatic hyperplasia in adult males and gives rise to significant bladder dysfunction such as frequency and urgency of micturition. The unstable detrusor contractions may lead to urge incontinence. Since it has been reported that experimentally-induced bladder instability can be abolished by ATP-sensitive K+ channel (KATP channel) openers, various types of detrusor-selective KATP channels have been newly synthesized, targeting KATP channels in urinary bladder. Thus, the significant differences in molecular and pharmacological properties of KATP channels between urinary bladder and urethra hold out some hope for the development of tissue-selective KATP channel openers for urge urinary incontinence, and detrusor-selective KATP channel openers should be screened against urethral as well as vascular smooth muscle. In functional expression experiments, pharmacological and electrophysiological studies have reported that SUR1/Kir6.2 represents the pancreatic beta-cell KATP channel and that SUR2A/Kir6.2 is thought to represent the cardiac KATP channel, whereas SUR2B/Kir6.1 represents the smooth muscle-type KATP channel. In general, the smooth muscle type-KATP channel is (i) of a relatively small conductance (about 20 pS under quasi-physiological conditions, approximately 40 pS in symmetrical 140 mM K+ conditions), (ii) intracellular Ca(2+)-insensitive, (iii) inhibited by intracellular ATP, (iv) abolished by glibenclamide at a submicromolar concentration, and (v) reactivated by intracellular nucleoside diphosphates (NDPs). There has been no report concerning the properties of KATP channels in human detrusor by use of single-channel recordings. We would like to introduce our recent evidence of novel synthesized detrusor-selective KATP channel openers and properties of KATP channels in the lower urinary tract.

Adenosine Triphosphate↗
PubMed2003

Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia.

Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O(2)) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-1alpha and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 +/- 6% and 67 +/- 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 +/- 2% of baseline in Hypo vs. 67 +/- 3% in Norm (P < 0.05). Improved postischemic right ventricular function in Hypo (93 +/- 2% and 96 +/- 2% of baseline) was observed with 95% O(2) or 21% O(2) in the perfusate, and it was not attenuated by glibenclamide (5 and 10 micromol/l) (86 +/- 4% and 106 +/- 6% recovery). HIF-1alpha mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K(+) channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts.

ATP-Binding Cassette Transporters↗
PubMed2006

Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits.

Cardiac ATP-sensitive K+ (K(ATP)) channels are formed by Kir6.2 and SUR2A subunits. We produced transgenic mice that express dominant negative Kir6.x pore-forming subunits (Kir6.1-AAA or Kir6.2-AAA) in cardiac myocytes by driving their expression with the alpha-myosin heavy chain promoter. Weight gain and development after birth of these mice were similar to nontransgenic mice, but an increased mortality was noted after the age of 4-5 mo. Transgenic mice lacked cardiac K(ATP) channel activity as assessed with patch clamp techniques. Consistent with a decreased current density observed at positive voltages, the action potential duration was increased in these mice. Some myocytes developed EADs after isoproterenol treatment. Hemodynamic measurements revealed no significant effects on ventricular function (apart from a slightly elevated heart rate), whereas in vivo electrophysiological recordings revealed a prolonged ventricular effective refractory period in transgenic mice. The transgenic mice tolerated stress less well as evident from treadmill stress tests. The proarrhythmogenic features and lack of adaptation to a stress response in transgenic mice suggest that these features are intrinsic to the myocardium and that K(ATP) channels in the myocardium have an important role in protecting the heart from lethal arrhythmias and adaptation to stress situations.

ATP-Binding Cassette Transporters↗
PubMed2000

Ischemic preconditioning: from adenosine receptor to KATP channel.

Ischemic preconditioning is a phenomenon whereby exposure of the myocardium to a brief episode of ischemia and reperfusion markedly reduces tissue necrosis induced by a subsequent prolonged ischemia. It is hoped that elucidation of the mechanism for preconditioning will yield therapeutic strategies capable of reducing myocardial infarction. In the rabbit, the brief period of preconditioning ischemia and reperfusion releases adenosine, bradykinin, opioids, and oxygen radicals. The combined effect of the release of these substances on G proteins and the cell's phospholipases induces the translocation and activation of the epsilon isozyme of protein kinase C. Protein kinase C appears to be the first element of a complex kinase cascade that is activated during the prolonged ischemia in preconditioned hearts. Current evidence indicates that this cascade contains at least one tyrosine kinase and ultimately leads to the activation of p38 mitogen-activated protein kinase. p38 Mitogen-activated protein kinase phosphorylates mitogen-activated protein kinase-activated protein kinase 2. Mitogen-activated protein kinase-activated protein kinase 2 phosphorylates HSP27, a 27-kDa heat shock protein that controls actin filament polymerization, and, therefore, affects the integrity of the cytoskeleton. Finally, mitochondrial adenosine 5'-triphosphate-sensitive K+ channels open, and the latter may be the final mediator of protection for ischemic preconditioning. The protective pathway has many built-in redundancies, perhaps creating a safety factor. These redundancies may also explain some of the species-related differences seen in ischemic preconditioning in which one redundant pathway may predominate over another.

ATP-Binding Cassette Transporters↗
PubMed2005

Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels.

Hydrogen sulfide (H(2)S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) mediate enzymatic generation of H(2)S in mammalian cells. Here we have investigated the role of H(2)S in modulating nociception to colorectal distension, a model that mimics some features of the irritable bowel syndrome. Four graded (0.4-1.6 ml of water) colorectal distensions (CRDs) were produced in conscious rats (healthy and postcolitic), and rectal nociception was assessed by measuring the behavioral response during CRD. Healthy rats were administered with sodium hydrogen sulfide (NaHS) (as a source of H(2)S), L-cysteine, or vehicle. In a second model, we investigated nociception to CRD in rats recovering from a chemically induced acute colitis. We found that CBS and CSE are expressed in the colon and spinal cord. Treating rats with NaHS resulted in a dose-dependent attenuation of CRD-induced nociception with the maximal effect at 60 micromol/kg (p < 0.05). Administration of L-cysteine, a CSE/CBS substrate, reduced rectal sensitivity to CRD (p < 0.05). NaHS-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor, and N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric-oxide (NO) synthase inhibitor. The antinociceptive effect of NaHS was maintained during the resolution of colon inflammation induced by intrarectal administration of a chemical irritant. In summary, these data show that H(2)S inhibits nociception induced by CRD in both healthy and postcolitic rats. This effect is mediated by K(ATP) channels and NO. H(2)S-releasing drugs might be beneficial in treating painful intestinal disorders.

ATP-Binding Cassette Transporters↗
PubMed2005

Lack of manifestations of diazoxide/5-hydroxydecanoate-sensitive KATP channel in rat brain nonsynaptosomal mitochondria.

Pharmacological modulation of the mitochondrial ATP-sensitive K+ channel (mitoKATP) sensitive to diazoxide and 5-hydroxydecanoate (5-HD) represents an attractive strategy to protect cells against ischaemia/reperfusion- and stroke-related injury. To re-evaluate a functional role for the mitoKATP in brain, we used Percoll-gradient-purified brain nonsynaptosomal mitochondria in a light absorbance assay, in radioisotope measurements of matrix volume, and in measurements of respiration, membrane potential (DeltaPsi) and depolarization-induced K+ efflux. The changes in mitochondrial morphology were evaluated by transmission electron microscopy (TEM). Polyclonal antibodies raised against certain fragments of known sulphonylurea receptor subunits, SUR1 and SUR2, and against different epitopes of K+ inward rectifier subunits Kir 6.1 and Kir 6.2 of the ATP-sensitive K+ channel of the plasma membrane (cellKATP), were employed to detect similar subunits in brain mitochondria. A variety of plausible blockers (ATP, 5-hydroxydecanoate, glibenclamide, tetraphenylphosphonium cation) and openers (diazoxide, pinacidil, chromakalim, minoxidil, testosterone) of the putative mitoKATP were applied to show the role of the channel in regulating matrix volume, respiration, and DeltaPsi and K+ fluxes across the inner mitochondrial membrane. None of the pharmacological agents applied to brain mitochondria in the various assays pinpointed processes that could be unequivocally associated with mitoKATP activity. In addition, immunoblotting analysis did not provide explicit evidence for the presence of the mitoKATP, similar to the cellKATP, in brain mitochondria. On the other hand, the depolarization-evoked release of K+ suppressed by ATP could be re-activated by carboxyatractyloside, an inhibitor of the adenine nucleotide translocase (ANT). Moreover, bongkrekic acid, another inhibitor of the ANT, inhibited K+ efflux similarly to ATP. These observations implicate the ANT in ATP-sensitive K+ transport in brain mitochondria.

ATP-Binding Cassette Transporters↗
PubMed1999

ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies.

ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. By cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the receptors for sulfonylureas (SUR1 and SUR2), researchers have clarified the molecular structure of KATP channels. KATP channels comprise two subunits: a Kir6.0 subfamily subunit, which is a member of the inwardly rectifying K+ channel family; and a SUR subunit, which is a member of the ATP-binding cassette (ABC) protein superfamily. KATP channels are the first example of a heteromultimeric complex assembled with a K+ channel and a receptor that are structurally unrelated to each other. Since 1995, molecular biological and molecular genetic studies of KATP channels have provided insights into the structure-function relationships, molecular regulation, and pathophysiological roles of KATP channels.

ATP-Binding Cassette Transporters↗
PubMed2000

Familial hyperinsulinism and pancreatic beta-cell ATP-sensitive potassium channels.

Familial hyperinsulinism, also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a genetic disease characterized by mild to severe hypoglycemia in the presence of inappropriately high levels of insulin. The recessive form is caused by mutations in the adenosine 5'-triphosphate (ATP)-sensitive K+ channel (KATP channel) present in the plasma membrane of pancreatic beta-cells. This channel is formed by two subunits, the high-affinity sulfonylurea receptor, SUR1, and KIR6.2, a member of the inwardly rectifying family of K+ channels. KATP channels regulate insulin secretion by linking membrane excitability with glucose metabolism. Approximately 50 mutations, in both channel subunits, that abolish or alter the regulation of beta-cell KATP channels have been identified in patients with the recessive form of PHHI.

Adenosine Triphosphate↗
PubMed1991

Essential role of nucleotide diphosphates in nicorandil-mediated activation of cardiac ATP-sensitive K+ channel. A comparison with pinacidil and lemakalim.

Vasorelaxant agents such as pinacidil, lemakalim, and nicorandil, known as K+ channel openers, can activate the ATP-sensitive K+ channel (KATP channel) in cardiac myocytes. The aim of this study was to elucidate the molecular mechanisms underlying the K+ channel opener-mediated cardiac KATP channel activation by using the inside-out patch-clamp technique in guinea pig ventricular myocytes. Effects of pinacidil, lemakalim, and nicorandil on the KATP channel were examined both before and after channel "run-down". Since nucleotide diphosphates (NDPs) could activate the channel after complete run-down, effects of the drugs on the NDP-induced channel openings were also examined. We made the following observations: 1) Pinacidil (10-100 microM) and lemakalim (300 microM) activated the KATP channel before run-down and after run-down when NDPs were present. 2) Nicorandil (30 microM-1 mM) activated the KATP channel only in the presence of NDPs regardless of the condition of the channel with respect to run-down. 3) None of these K+ channel openers activated the channel after run-down in the absence of NDPs. These observations suggest that NDP binding is essential for nicorandil-mediated activation of the KATP channel and indicate that the molecular mechanisms underlying nicorandil activation are distinct from those of pinacidil and lemakalim activation of the KATP channel. We discuss the possible interactions between the drugs and the KATP channel based on a functional channel model.

Adenosine Diphosphate↗
PubMed1995

Hypoxia-induced activation of KATP channels limits energy depletion in the guinea pig heart.

The functional role of ATP-dependent potassium (KATP) in hypoxic cardiac failure was investigated in isolated guinea pig hearts with glibenclamide and rimalkalim as inhibitor and activator, respectively. Monophasic action potential duration at 90% of repolarization (MAP50), left ventricular function, and cardiac energy status (31P nuclear magnetic resonance spectroscopy) were measured during normotoxic (95% O2) and hypoxic (20% O2) perfusion. In normoxic hearts, 1 microM glibenclamide did not affect MAP50, left ventricular function, and coronary flow (n = 4). In contrast, rimalkalim rapidly shortened MAP50 and left ventricular pressure (LVP) in a dose-dependent fashion (e.g., by 60.2 +/- 3.5 and 80.8 +/- 8.2%, respectively, with 0.6 microM rimalkalim). This latter effect was reversed by 1 microM (glibenclamide (n = 4). With hypoxic perfusion, a reduction in LVP was observed, along with a shortening of the action potential (MAP90; 202 +/- 13 vs. 164 +/- 9 ms) and an increase in coronary flow. Glibenclamide (1 microM) reversed the MAP90 shortening and the increase in coronary flow. In addition, glibenclamide increased LVP transiently (n = 4). When coronary flow of hypoxic hearts was kept constant, however, glibenclamide elicited a sustained positive inotropic effect (n = 7). After glibenclamide, an increase in LVP from 54 +/- 4 to 64 +/- 3 mmHg was observed, along with a reduction in the free energy change of ATP hydrolysis from -54.5 +/- 1.9 to -52.9 +/- 0.2 nJ/mol and a further increase in the coronary venous adenosine from 269 +/- 48 to 1,680 +/- 670 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1994

Nitric oxide opens ATP-sensitive K+ channels through suppression of phosphofructokinase activity and inhibits glucose-induced insulin release in pancreatic beta cells.

Nitric oxide (NO) is known to be a potent messenger in the intracellular signal transduction system in many tissues. In pancreatic beta cells, NO has been reported to be formed from L-arginine through NO synthase. To elucidate the effect of NO on insulin secretion and to investigate the intracellular mechanism of its effect, we have used sodium nitroprusside (SNP) as a NO donor. SNP inhibited glucose-induced insulin secretion in a dose-dependent manner, and its effect was reversed by hemoglobin, a known NO scavenger. However, glyceraldehyde-induced insulin secretion was not affected by SNP. Since the closure of ATP-sensitive K+ channels (KATP channel) has been established as a key step in glucose-induced insulin secretion, we have directly assessed the effect of SNP on KATP channel activity using the patch clamp technique. The KATP channel activity reduced by glucose was found to be reversibly activated by the addition of SNP, and this activation was able to be similarly reproduced by applying S-Nitroso-N-acetyl-DL-penicillamine (SNAP), another NO generator. Furthermore, these activating effects were completely eliminated by hemoglobin, in accordance with the reversibility in inhibition of glucose-induced insulin release. However, SNP could not affect the KATP channel suppression by ATP applied to the inside of the plasma membrane. The activation of the KATP channel by NO, therefore, seems to be due to the decreased ATP production attributable to impairment of glucose metabolism in beta cells. Since SNP exhibited no effect on glyceraldehyde-induced KATP channel inhibition, NO may disturb a glycolytic step before glyceraldehyde-3-phosphate. The KATP channel activation by 2-deoxyglucose through presumable ATP consumption due to its phosphorylation by glucokinase was, however, not affected even in the presence of SNP. But in the permeabilized beta cells made by exposure to a low concentration (0.02 U/ml) of streptolysin O (open cell-attached configuration), SNP reopens KATP channels which have been eliminated by fructose-6-phosphate, while this effect was not observed in the KATP channels inhibited by fructose-1,6-bisphosphate. On the other hand, in rat ventricular myocyte KATP channels were not activated by SNP even under a low concentration of glucose. From these observations, the inhibition of phosphofructokinase activity is probably the site responsible for the impairment of glucose metabolism induced by NO in pancreatic beta cells. NO, therefore, seems to be a factor in the deterioration of glucose-induced insulin secretion from pancreatic beta cells through a unique intracellular mechanism.

Adenosine Triphosphate↗
PubMed1995

Modulation of adenosine triphosphate-sensitive potassium channel and voltage-dependent calcium channel by activin A in HIT-T15 cells.

The ATP-sensitive potassium channel (KATP channel) determines the membrane potential of pancreatic beta-cells and plays a critical role in the regulation of insulin secretion. The present study was conducted to investigate the effect of activin A, a member of the transforming growth factor-beta supergene family, on the KATP channel in HIT-T15 clonal hamster insulinoma cells. In an excised inside-out patch, ATP-sensitive currents with a single channel conductance of approximately 20 picosiemens were observed. In an outside-out patch, currents with identical unitary conductance were also observed. In either case, the currents were augmented by diazoxide and blocked by glibenclamide, verifying that they were KATP channel currents. When KATP channel currents were monitored in an outside-out patch, activin A added to the bath solution inhibited KATP channel currents. Upon removal of activin A, the KATP channel currents were restored, suggesting that the inhibition was not due simply to spontaneous disappearance of channel activity (run-down). The KATP channel activity was markedly reduced after the addition of activin A and was reversed by diazoxide. Besides the inhibition of KATP channel, activin A increased, in a perforated patch, the amplitude of the inward Ba2+ current in response to a depolarizing pulse from -40 to +10 mV. Under the current clamp condition, activin A induced gradual depolarization, followed by a burst of action potentials. Activin-mediated action potentials were accompanied by an elevation of the cytoplasmic free calcium concentration. These results indicate that activin A causes depolarization of the plasma membrane by inhibiting the activity of the KATP channel. In addition, activin A directly modulates the voltage-dependent calcium channel and augments calcium entry.

Action Potentials↗
PubMed1994

Blockade of adenosine triphosphate-sensitive potassium channels eliminates isoflurane-induced coronary artery vasodilation.

BACKGROUND: The mechanisms by which volatile anesthetics induce vasodilation are unknown. Recent studies of adenosine triphosphate-sensitive potassium channels (KATP channels) in the vascular smooth muscle of the coronary circulation suggest that these channels play a role in the coronary artery dilation produced by hypoxemia, the coronary blood flow (CBF) reactive hyperemic response, and in CBF auto regulation. We therefore conducted this study to determine the role of KATP channels in isoflurane-induced coronary vasodilation. METHODS: Studies were conducted in six open-chest, anesthetized swine. The left anterior descending coronary artery was cannulated and perfused by blood passed through a membrane oxygenator. This preparation allowed us to administer drugs and volatile anesthetics regionally to the perfused myocardium, minimizing systemic effects. Regional CBF response to 1.5% and 3.0% isoflurane administered via the membrane oxygenator was measured before and after blockade of KATP channels, and was compared to the vasodilation produced by regional administration of several doses of sodium nitroprusside and adenosine. Blockade of KATP channels was achieved by regional intracoronary administration of glibenclamide (1-22 micrograms.kg-1.min-1), a specific blocker of these channels. RESULTS: Administration of 1.5 and 3.0 percent isoflurane increased regional CBF by 29 +/- 29% and by 62 +/- 28%, respectively. Under control conditions, blockade of KATP channels decreased mean CBF by 18%, but did not cause ischemia. KATP channel blockade totally eliminated the vasodilator response to both doses of isoflurane. During KATP channel blockade the response to 3% isoflurane was converted to net vasoconstriction: mean delta CBF = -5% +/- 6%, P = < 0.05 versus control. Negative inotropic effects of isoflurane were not eliminated by glibenclamide. Because KATP channel blockade was so effective in eliminating isoflurane-induced coronary vasodilation, the dose of glibenclamide was decreased in sequential experiments, but total blockade of isoflurane vasodilation was achieved even at the smallest dose of glibenclamide studied (1 microgram.kg-1.min-1). The vasodilator response to nitroprusside was not affected, and the vasodilator response to adenosine was partially inhibited (consistent with their known mechanisms of action). CONCLUSIONS: Blockade of KATP channels by glibenclamide completely inhibits isoflurane-induced coronary vasodilation in the regionally perfused swine myocardium. The response to sodium nitroprusside, a drug that induces vasodilation via a different mechanism, was unaffected. The response to adenosine, a drug whose vasodilation is partially mediated via KATP channels, was partially inhibited. These results suggest that in vivo isoflurane-induced coronary artery vasodilation is predominantly mediated by KATP channels.

Adenosine↗
PubMed2004

The impact of ATP-sensitive K+ channel subtype selectivity of insulin secretagogues for the coronary vasculature and the myocardium.

Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K+ channel (KATP channel) in the pancreatic beta-cell membrane. KATP channels subserve important functions also in the heart. First, KATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, KATP channels in the sarcolemma of cardiomyocytes (sarcKATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcKATP channels and of KATP channels in the inner membrane of mitochondria (mitoKATP channels) plays a central role in ischemic preconditioning. Opening of sarcKATP channels also underlies the ST-segment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular KATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular KATP channels, being either highly selective (approximately 1,000x; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10-20x; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2x; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested.

Adenosine Triphosphate↗
PubMed2003

Cardioselective anti-ischemic ATP-sensitive potassium channel (KATP) openers: benzopyranyl indoline and indole analogues.

This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (K(ATP)) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation potencies were very low (concentration for 50% inhibition of vasorelaxation >30 microM). The cardioprotective effect of 14 was completely reversed by 5-hydroxydecanoate, a selective mitochondrial K(ATP) blocker, indicating its provable protective mechanism through the mitochondrial K(ATP) opening. In addition, we performed conformational analyses using 2D-NMR, X-ray crystallography and molecular modeling to study the structure-activity relationships in this series of compounds.

Adenosine Triphosphate↗
PubMed2003

Activation of ATP-sensitive K+ (K(ATP)) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release.

In many cells, ATP-sensitive K+ channels (KATP channels) couple metabolic state to excitability. In pancreatic beta cells, for example, this coupling regulates insulin release. Although KATP channels are abundantly expressed in the brain, their physiological role and the factors that regulate them are poorly understood. One potential regulator is H2O2. We reported previously that dopamine (DA) release in the striatum is modulated by endogenous H2O2, generated downstream from glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor activation. Here we investigated whether H2O2-sensitive KATP channels contribute to DA-release modulation by glutamate and gamma-aminobutyric acid (GABA). This question is important because DA-glutamate interactions underlie brain functions, including motor control and cognition. Synaptic DA release was evoked by using local electrical stimulation in slices of guinea pig striatum and monitored in real time with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. The KATP-channel antagonist glibenclamide abolished the H2O2-dependent increase in DA release usually seen with AMPA-receptor blockade by GYKI-52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] and the decrease in DA release seen with GABA-type-A-receptor blockade by picrotoxin. In contrast, 5-hydroxydecanoate, a mitochondrial KATP-channel blocker, was ineffective, as were sulpiride, a D2-receptor antagonist, and tertiapin, a G protein-coupled K+-channel inhibitor. Diazoxide, a sulfonylurea receptor 1 (SUR1)selective KATP-channel opener, prevented DA modulation by H2O2, glutamate, and GABA, whereas cromakalim, a SUR2-selective opener, did not. Thus, endogenous H2O2 activates SUR1-containing KATP channels in the plasma membrane to inhibit DA release. These data not only demonstrate that KATP channels can modulate CNS transmitter release in response to fast-synaptic transmission but also introduce H2O2 as a KATP-channel regulator.

Adenosine Triphosphate↗
PubMedDate not supplied

ATP-sensitive K+ channels in the kidney.

ATP-sensitive K+ channels (KATP channels) form a link between the metabolic state of the cell and the permeability of the cell membrane for K+ which, in turn, is a major determinant of cell membrane potential. KATP channels are found in many different cell types. Their regulation by ATP and other nucleotides and their modulation by other cellular factors such as pH and kinase activity varies widely and is fine-tuned for the function that these channels have to fulfill. In most excitable tissues they are closed and open when cell metabolism is impaired; thereby the cell is clamped in the resting state which saves ATP and helps to preserve the structural integrity of the cell. There are, however, notable exceptions from this rule; in pancreatic beta-cells, certain neurons and some vascular beds, these channels are open during the normal functioning of the cell. In the renal tubular system, KATP channels are found in the proximal tubule, the thick ascending limb of Henle's loop and the cortical collecting duct. Under physiological conditions, these channels have a high open probability and play an important role in the reabsorption of electrolytes and solutes as well as in K+ homeostasis. The physiological role of their nucleotide sensitivity is not entirely clear; one consequence is the coupling of channel activity to the activity of the Na-K-ATPase (pump-leak coupling), resulting in coordinated vectorial transport. In ischemia, however, the reduced ATP/ADP ratio would increase the open probability of the KATP channels independently from pump activity; this is particularly dangerous in the proximal tubule, where 60 to 70% of the glomerular ultrafiltrate is reabsorbed. The pharmacology of KATP channels is well developed including the sulphonylureas as standard blockers and the structurally heterogeneous family of channel openers. Blockers and openers, exemplified by glibenclamide and levcromakalim, show a wide spectrum of affinities towards the different types of KATP channels. Recent cloning efforts have solved the mystery about the structure of the channel: the KATP channels in the pancreatic beta-cell and in the principal cell of the renal cortical collecting duct are heteromultimers, composed of an inwardly rectifying K+ channel and sulphonylurea binding subunit(s) with unknown stoichiometry. The proteins making up the KATP channel in these two cell types are different (though homologous), explaining the physiological and pharmacological differences between these channel subtypes.

Adenosine Triphosphate↗