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PubMed2004

Fenofibrate, troglitazone, and 15-deoxy-Delta12,14-prostaglandin J2 close KATP channels and induce insulin secretion.

It is known that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands stimulate acute-phase insulin secretion with a rapid Ca2+ influx into pancreatic beta-cells, but the precise mechanisms are not clear. The effects of PPAR-alpha ligands on pancreatic beta-cells also remain unclear. We investigated the effects of PPAR-alpha ligands (fenofibrate and fenofibric acid), a PPAR-gamma ligand (troglitazone), and an endogenous ligand of PPAR-gamma [15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-Delta12,14-PGJ2)] on KATP channel activity in clonal hamster insulinoma cell line, HIT-T15 cells. As assessed by whole-cell patch clamp, fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14-PGJ2 reduced the KATP channel currents, and inhibition continued after washout of these agents. The concentration-response curves of fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14-PGJ2 showed half-maximal inhibition of KATP channel currents (IC50) at 3.26, 94, 2.1, and 7.3 micromol/l, respectively. Fenofibrate (> or = 10(-6) mol/l), 15-deoxy-Delta12,14-PGJ2 (> or = 5 x 10(-5) mol/l), and troglitazone (> or = 10(-6) mol/l) inhibited [3H]glibenclamide binding, but fenofibric acid did not. In addition, fenofibrate (> or = 10(-6) mol/l), fenofibric acid (10(-4) mol/l), troglitazone (10(-4) mol/l), and 15-deoxy-Delta12,14-PGJ2 (> or = 10(-5) mol/l) increased insulin secretion from HIT-T15 when applied for 10 min. Our data suggest that PPAR-alpha and -gamma ligands interact directly with the beta-cell membrane and stimulate insulin secretion.

Animals↗
PubMed1997

Hypoxic dilatation of porcine small coronary arteries: role of endothelium and KATP-channels.

1. The aim of the present study was to determine the cellular mechanims and potential mediators involved in hypoxic dilatation of porcine small coronary arteries. 2. Small coronary arteries were isolated from a branch of the left anterior descending artery of porcine hearts, cannulated with glass micropipettes and studied in a perfusion myograph system. At a transmural pressure of 40 mmHg, the arteries had an internal diameter of 167.8 +/- 6.6 microns (n = 37). 3. In arteries contracted with acetylcholine (ACh), hypoxia (0% O2, 30 min) caused dilatation (86.9 +/- 6.7% relaxation, n = 6) in vessels with endothelium but constriction in endothelium-denuded vessels. 4. Hypoxic vasodilatation occurring in arteries with endothelium was abolished by the KATP channel inhibitor, glibenclamide (0.44 microM), but was not affected by inhibition of nitric oxide synthase (L-NAME, 44 microM) or cyclo-oxygenase (indomethacin, 4.4 microM). 5. Bradykinin evoked endothelium-dependent relaxation that was inhibited by L-NAME (44 microM) but not glibenclamide 0.44 microM). Cromakalim (0.1-0.3 microM), a KATP channel opener, caused relaxation that was inhibited by glibenclamide, but was not affected by L-NAME (44 microM) and/or indomethacin (4.4 microM). 6. Endothelium-removal inhibited vasodilatation evoked by cromakalim, but increased vasodilator responses to the NO donor, SIN-1 (10(-8) to 10(-5) M). 7. These results indicate that hypoxia acted directly on vascular smooth muscle of small coronary arteries to cause contraction. However, this effect was overwhelmed by endothelium-dependent relaxation in response to hypoxia. This relaxation was most likely mediated by release of an endothelium-derived factor, distinct from nitric oxide or prostacyclin, that activated smooth muscle KATP-channels.

Animals↗
PubMed1995

KATP channel mediation of anoxia-induced outward current in rat dorsal vagal neurons in vitro.

1. Thin brainstem slices (150 microns thickness) were taken from mature rats, and membrane potentials (Em) and currents (Im) in the dorsal vagal neurons (DVN) were analysed with whole-cell patch clamp techniques during anoxia. 2. At a holding potential (Vh) of -50 mV, a sustained anoxia-induced outward current (AOC) of 92 +/- 44 pA (reversal potential (Erev), -78 +/- 12 mV) and a concomitant increase of membrane conductance (gm) from 2.2 +/- 0.45 to 5.9 +/- 2.4 nS were revealed in 40% of 142 DVN analysed. The AOC led to a hyperpolarization of the cells by 14.4 +/- 6.1 mV from a mean resting Em of -51 +/- 6 mV, and to blockade of spontaneous action potential discharges. In the remaining DVN, anoxia had almost no effect on Em, Im or gm and did not block spontaneous action potential discharges. 3. The AOC was not affected by 0.5 microM tetrodotoxin (TTX), 2 mM Mn2+, 50 microM cyanonitroquinoxaline dione (CNQX) or 100 microM bicuculline. 4. Elevation of the extracellular [K+] from 3 to 10 mM resulted in a positive shift of Erev of the AOC by 23 mV, whereas an increase in the [Cl-] of the patch pipette solution from 5 to 144 mM had no effect on Erev. 5. In DVN responding with an AOC, addition of 200 microM diazoxide, an activator of ATP-sensitive K+ (KATP) channels, to oxygenated solutions elicited a similar outward current (Erev = -79 +/- 5.5 mV, n = 12) and increase in gm. Diazoxide did not affect Em, Im or gm in cells which did not show an AOC. 6. In a subpopulation of DVN (n = 26), spontaneous activation of a KATP current with an Erev of -80 +/- 6 mV was observed. As analysed in four of these cells, an AOC was revealed during the initial phase of development of the spontaneous outward current but not under steady-state conditions. 7. The AOC, the diazoxide-induced current, and the spontaneous outward current were completely blocked upon bath application of the KATP channel blocker tolbutamide (100-200 microM). 8. The results indicate that the sustained anoxia-induced outward current of dorsal vagal neurons is due to activation of KATP channels. A possible physiological role of functional inactivation of these cells during metabolic disturbances is discussed.

Adenosine Triphosphate↗
PubMed1998

Shortening of action potential duration is not prerequisite for cardiac protection by ischemic preconditioning or a KATP channel opener.

Our purpose was to determine whether amelioration of myocardial contractile dysfunction by an ATP-sensitive potassium (KATP) channel opener or ischemic preconditioning is mediated by shortening of action potential duration during the early period of ischemia. Extracellular potassium concentration ([K+]e), monophasic action potential duration (MAPD) and thickening fraction were measured during ischemia and reperfusion of the left anterior descending coronary artery in anesthetized dogs. Control dogs were subjected to a 10-min occlusion (test occlusion) followed by a 120-min reperfusion. The five dogs which made up the pinacidil group, received 0.03 mg/kg as an i.v. bolus and then were infused at a rate of 0.04 mg/kg/h for 20 min prior to the test occlusion. In the preconditioning group, six dogs were subjected to a 5-min occlusion and a 10-min reperfusion prior to the test occlusion and reperfusion. Both pinacidil and preconditioning improved regional contraction during reperfusion after the test occlusion. In the control group, MAPD shortened and [K+]e increased during ischemia. Preconditioning abolished MAPD shortening and blunted the rise of [K+]e during ischemia. Pinacidil did not affect either the shortening of MAPD or [K+]e elevation during ischemia. These results suggest that the shortening of MAPD is not a prerequisite for amelioration of contractile dysfunction by a KATP channel opener or ischemic preconditioning.

Action Potentials↗
PubMed1997

Pharmacology of ATP-sensitive potassium channel (KATP) openers in models of myocardial ischemia and reperfusion.

Recently, much interest has been focused on the pharmacology of ATP-sensitive potassium channels (KATP) in myocardial ischemia. KATP are thought to be involved with the mechanism of myocardial preconditioning, therefore further increasing the level of interest in these channels. Pharmacologic KATP openers have been shown by numerous investigators to protect ischemic-reperfused myocardium. These agents reduce necrosis, improve postischemic functional recovery, and inhibit contracture formation. These protective effects are abolished by KATP blockers. The cardioprotective effects of KATP openers are independent of vasodilator and cardiodepressant effects, but seem to be mediated by energy conservation (reduced ATP hydrolysis). Action potential shortening is also not correlated with cardioprotection, suggesting a role for intracellular (mitochondrial) KATP. Agents have been developed that retain the glyburide-reversible cardioprotective effects of cromakalim but are devoid of vasodilator and action potential shortening activity. Currently, studies are underway to determine the mechanism of cardioprotection. The potential role of mitochondrial KATP in the pathogenesis of ischemia is discussed in this review article.

ATP-Binding Cassette Transporters↗
PubMed1995

Cross-talk and the role of KATP channels in the proximal tubule.

Over the last few years it has become evident that an assortment of functionally-related, but diverse, KATP channels provide an important and physiologically-regulated determinant of the K conductive pathways in many, if not all, epithelial cells expressed along the nephron. As such, KATP plays central roles in regulating and maintaining a number of transport processes in concert with physiological demands of the kidney. In the renal proximal tubule, KATP channels and changes in the hydrolytic activity of the Na,K-ATPase permit ATP to act as a coupling modulator of parallel Na,K-ATPase-K recycling. The response insures that cell membrane potential, intracellular K activity and cell volume are protected in the face of physiological variations in transcellular ion transport. In addition to demonstrating the physiological relevance of KATP in renal epithelial, these studies have provided a long awaited answer to the underlying mechanism of pump-leak coupling, a universal and essential homeostatic mechanism observed in nearly all salt translocating epithelia.

Adenosine Triphosphate↗
PubMed1999

Involvement of the N-terminus of Kir6.2 in the inhibition of the KATP channel by ATP.

1. ATP-sensitive potassium (KATP) channels are composed of pore-forming Kir6.2 and regulatory SUR subunits. A truncated isoform of Kir6.2, Kir6.2DeltaC26, expresses ATP-sensitive channels in the absence of SUR1, suggesting the ATP-inhibitory site lies on the Kir6. 2 subunit. 2. We examined the effect on the channel ATP sensitivity of mutating the arginine residue at position 50 (R50) in the N-terminus of Kir6.2, by recording macroscopic currents in membrane patches excised from Xenopus oocytes expressing wild-type or mutant Kir6.2DeltaC26. 3. Substitution of R50 by serine, alanine or glycine reduced the Ki for ATP inhibition from 117 microM to 800 microM, 1.1 mM and 3.8 mM, respectively. The single-channel conductance and kinetics were unaffected by any of these mutations. Mutation to glutamate, lysine, asparagine, glutamine or leucine had a smaller effect (Ki, approximately 300-400 microM). The results indicate that the side chain of the arginine residue at position 50 is unlikely to contribute directly to the binding site for ATP, and suggest it may affect ATP inhibition by allosteric interactions. 4. Mutation of the isoleucine residue at position 49 to glycine (I49G) reduced the channel ATP sensitivity, while the mutation of the glutamate residue at position 51 to glycine (E51G) did not. 5. When a mutation in the N-terminus of Kir6.2DeltaC26 that alters ATP sensitivity (R50S; Ki, 800 microM) was combined with one in the C-terminus (E179Q; Ki, 300 microM), the Ki for the apparent ATP sensitivity was increased to 2.8 mM. The Hill coefficient was also increased. This suggests that the N- and C-termini of Kir6.2 may co-operate to influence channel closure by ATP.

Adenosine Triphosphate↗
PubMed1998

State-dependent inhibition of the mitochondrial KATP channel by glyburide and 5-hydroxydecanoate.

The mitochondrial KATP channel (mitoKATP) is hypothesized to be the receptor for the cardioprotective effects of K+ channel openers (KCO) and for the blocking of cardioprotection by glyburide and 5-hydroxydecanoate (5-HD). Studies on glyburide have indicated that this drug is inactive in isolated mitochondria. No studies of the effects of 5-HD on isolated mitochondria have been reported. This paper examines the effects of glyburide and 5-HD on K+ flux in isolated, respiring mitochondria. We show that mitoKATP is completely insensitive to glyburide and 5-HD under the experimental conditions in which the open state of the channel is induced by the absence of ATP and Mg2+. On the other hand, mitoKATP became highly sensitive to glyburide and 5-HD when the open state was induced by Mg2+, ATP, and a physiological opener, such as GTP, or a pharmacological opener, such as diazoxide. In these open states, glyburide (K1/2 values 1-6 microM) and 5-HD (K1/2 values 45-75 microM) inhibited specific, mitoKATP-mediated K+ flux in both heart and liver mitochondria from rat. These results are consistent with a role for mitoKATP in cardioprotection and show that different open states of mitoKATP, although catalyzing identical K+ fluxes, exhibit very different susceptibilities to channel inhibitors.

Animals↗
PubMed1992

Nucleotide-dependent activation of KATP channels by diazoxide in CRI-G1 insulin-secreting cells.

1. Patch-clamp recording techniques were used, to examine the effects of diazoxide on KATP currents in CRI-G1 insulin-secreting cells in the presence of non-hydrolysable nucleotides. 2. In the presence of non- or slowly-hydrolyzed ATP analogues, bathing the intracellular aspect of cell-free membrane patches diazoxide inhibited KATP channel activity. 3. Under whole-cell recording conditions, with various non-hydrolysable nucleotides present intracellularly (after dialysis), diazoxide induced KATP current activation. The largest activation occurred with Mg-adenylyl-(beta, gamma-methylene) diphosphate (Mg-AMP-PCP) present in the dialysing solution. This activation was diazoxide- and nucleotide-concentration-dependent. 4. In the absence of Mg2+, or in the presence of manganese (Mn2+) ions intracellularly, diazoxide did not induce KATP current activation, regardless of the species of nucleotide present in the pipette. 5. Intracellularly applied trypsin prevented the activation of KATP currents by diazoxide in the presence of Mg-AMP-PCP, an effect reversed by co-application of intracellular polymethylsulphonyl fluoride with the trypsin. 6. The application, by dialysis, of a CRI-G1 cell lysate, with negligible Mg-ATP, resulted in a substantial activation of the KATP current by diazoxide. 7. It is concluded that diazoxide can activate KATP channel currents by two separate pathways, one requiring a phosphorylation process, the other the presence of an intracellular protein coupled with a Mg-purine nucleotide.

Adenine Nucleotides↗
PubMed1996

Glyburide, a KATP channel antagonist, attenuates the cardioprotective effects of isoflurane in stunned myocardium.

This investigation examined the role of myocardial adenosine triphosphate-regulated potassium (KATP) channels in isoflurane-induced enhancement of myocardial function after reversible tissue injury produced by a 15-min left anterior descending coronary artery occlusion (LAD) and reperfusion. Dogs (n = 14) were chronically instrumented for measurement of left ventricular (LV) and aortic blood pressure, cardiac output, coronary blood flow velocity, and subendocardial segment length. Regional myocardial contractility was evaluated with preload recruitable work area (PRWA). Isovolumic relaxation was assessed with a time constant (tau). Hemodynamic variables and LV function were measured in the conscious state, during 2% isoflurane anesthesia for 45 min before and during a 15-min LAD occlusion, and at several intervals after reperfusion in dogs pretreated with glyburide (0.3 mg/kg, intravenously) or drug vehicle. LAD occlusion caused regional dyskinesia and increases in tau. Vehicle-pretreated dogs demonstrated full recovery of segment shortening by 5 h postreperfusion and recovery of PRWA and tau by 30 min postreperfusion. In contrast, dogs pretreated with glyburide demonstrated sustained systolic and diastolic dysfunction. Segment shortening recovered to only 70% +/- 5%, PRWA remained depressed at 48% +/- 10% and tau was prolonged to 116% +/- 5% of control values at 5 h postreperfusion. The results indicate that isoflurane enhances recovery of myocardial contractile function by 5 h postreperfusion, in comparison to previous findings in conscious dogs. These effects are partially blocked by glyburide pretreatment, indicating that KATP channel activation by isoflurance may mediate these cardioprotective effects.

Anesthetics, Inhalation↗
PubMed2001

Effects of the cardioselective KATP channel blocker HMR 1098 on cardiac function in isolated perfused working rat hearts and in anesthetized rats during ischemia and reperfusion.

It has been argued that activation of KATP channels in the sarcolemmal membrane of heart muscle cells during ischemia provides an endogenous cardioprotective mechanism. In order to test whether the novel cardioselective KATP channel blocker HMR 1098 affects cardiac function during ischemia, experiments were performed in rat hearts during ischemia and reperfusion. Isolated perfused working rat hearts were subjected to 30 min of low-flow ischemia in which the coronary flow was reduced to 10% of its control value, followed by 30-min reperfusion. In the first set of experiments the hearts were electrically paced at 5 Hz throughout the entire protocol. At the end of the 30-min ischemic period the aortic flow had fallen to 44 +/- 2% (n=8) of its nonischemic value in vehicle-treated hearts, whereas in the presence of 0.3 micromol/l and 3 micromol/l HMR 1098 it had fallen to 29 +/- 7% (n=5, not significant) and 8 +/- 2% (n=12, P<0.05), respectively. Glibenclamide (3 micromol/l) reduced the aortic flow to 9.5 +/- 7% (n=4, P<0.05). In control hearts the QT interval in the electrocardiogram shortened from 63 +/- 6 ms to 36 +/- 4 ms (n=10, P<0.05) within 4-6 min of low-flow ischemia. This shortening was completely prevented by 3 micromol/l HMR 1098 (60 +/- 5 ms before ischemia, 67 +/- 6 ms during ischemia, n=9, not significant). When rat hearts were not paced, the heart rate fell spontaneously during ischemia, and HMR 1,098 (3 micromol/l) caused only a slight, statistically non-significant reduction in aortic flow during the ischemic period. In order to investigate whether HMR 1098 shows cardiodepressant effects in a more pathophysiological model, the left descending coronary artery was occluded for 30 min followed by reperfusion for 60 min in anesthetized rats. Treatment with HMR 1098 (10 mg/kg i.v.) had no statistically significant effects on mean arterial blood pressure and heart rate during the control, ischemia and reperfusion periods. At the end of the reperfusion period, aortic blood flow was slightly reduced by HMR 1098, without reaching statistical significance (two-way analysis of ANOVA, P=0.15). Myocardial infarct size as a percentage of area at risk was not affected by HMR 1098 (vehicle: 75 +/- 3%, HMR 1098: 72 +/- 2%, n=7 in each group). In conclusion, cardiodepressant effects of HMR 1098 were observed only in isolated perfused working rat hearts which were continuously paced during global low-flow ischemia. In the model of anesthetized rats subjected to regional ischemia, HMR 1098 had no significant effect on cardiac function or infarct size.

Anesthesia↗
PubMed1998

Cerebral arteriolar dilations by KATP channel activators need L-lysine or L-arginine.

We investigated the effects of various amino acids on responses to ATP-sensitive potassium (KATP) channel openers in anesthetized cats equipped with cranial windows. The application of pinacidil by superfusion caused transient vasodilation, whereas there was sustained vasodilation from the application of stationary solution of pinacidil. In the presence of L-arginine or L-lysine, pinacidil by superfusion led to sustained vasodilation, suggesting that the rapid flow of fluid displaced these amino acids from binding on the channel and that such binding was essential for opening the channel. NG-nitro-L-arginine blocked responses to pinacidil, and this blockade was reversed by L-lysine or L-arginine but not by D-arginine, D-lysine, methyl-L-arginine, glycine, L-histidine, dimethylarginine, dimethyl-L-arginine, or hydroxylysine. The blockade of responses to pinacidil induced by glyburide was also reversed completely by L-arginine or L-lysine but not by D-arginine, suggesting that these amino acids act on the sulfonylurea receptor. Hydroxylysine but not methyl-L-lysine, dimethylarginine, or dimethyl-L-arginine blocked responses to pinacidil. The findings show that KATP channels in cerebral arterioles need L-lysine or L-arginine to open in response to agonists.

Adenosine Triphosphate↗
PubMed1997

Adrenomedullin mediates coronary vasodilation through adenosine receptors and KATP channels.

The following experiments were conducted to determine whether, and the mechanisms through which, endogenous peptides alter coronary artery blood flow. Ultrasonic transit time probes were placed around the ascending aorta and left anterior descending coronary artery in groups of anesthetized, open-chest dogs. A Millar pressure catheter monitored left ventricular developed pressure. Intracoronary artery bolus injections of adenosine (a purinergic receptor activator), pinacidil (a KATP channel activator), calcitonin gene-related peptide (CGRP; which causes vascular smooth muscle relaxation by intracellular increases in cyclic-AMP), and adrenomedullin (mechanism unknown) each significantly (P < 0.05, Student's t test) increased coronary blood flow in a dose-dependent fashion, without altering systemic hemodynamic measurements. Intracoronary artery injection of U37883A (a KATP channel antagonist) significantly (P < 0.05) blocked the coronary vasodilator responses to adenosine, adrenomedullin, and pinacidil. Intracoronary xanthine amine congener (an adenosine receptor antagonist) blocked only the responses to adenosine and adrenomedullin, not pinacidil. Intracoronary CGRP8-37 (CGRP receptor antagonist) blocked only the vasodilator response to CGRP. These data suggest that the coronary vasodilator effect of adrenomedullin is initiated first by activation of adenosine receptors, and subsequently through KATP channels-not by activation of CGRP receptors. That there were no changes in left ventricular developed pressure or in systemic hemodynamics after intracoronary artery infusions of adrenomedullin indicates that this endogenous peptide may have clinical utility in facilitating myocardial protection or preconditioning.

Adamantane↗
PubMed1999

Ischemic preconditioning mediated by activation of KATP channels in rat small intestine.

AIM: To study whether the protective effects of ischemic preconditioning against rat small intestine ischemia/reperfusion injury could be mediated by KATP channel opener. METHODS: Preconditioning (Pc) was induced by 3 cycles of 8-min superior mesenteric artery (SMA) occlusion and 10-min reperfusion before prolonged ischemia. Cromakalim (Cro 75 micrograms.kg-1) and glibenclamide (Gli 8 mg.kg-1) were injected i.v. 10 min before prolonged ischemia and Pc, respectively. RESULTS: Compared with ischemic reperfusion (IR) group, Pc before prolonged ischemia (Pc + IR) decreased LDH release [(380 +/- 55) vs (559 +/- 49) U.L-1, P < 0.05], attenuated intestinal edema [wet weight/dry weight (WW/DW), 5.6 +/- 0.6 vs 6.34 +/- 0.29, P < 0.05], ameliorated intestinal histological damage (grading scale, 3.4 vs 5.7, P < 0.01), and improved reperfusion-induced hypotension. These effects of Pc were mimicked by Cro [LDH, (298 +/- 40) vs (559 +/- 49) U.L-1, P < 0.05; WW/DW, 5.6 +/- 0.4 vs 6.34 +/- 0.29, P < 0.05; grading scale, 3.6 vs 5.7, P < 0.01] and abolished in the presence of Gli [LDH, (624 +/- 44) vs (559 +/- 49) U.L-1; WW/DW, 6.6 +/- 0.6 vs 6.34 +/- 0.29; grading scale, 5.7 vs 5.7; P > 0.05] compared with IR group, respectively. CONCLUSION: Ischemic preconditioning on the rat small intestine is mediated by activation of KATP channels.

Adenosine Triphosphate↗
PubMed1999

Anoxia generates rapid and massive opening of KATP channels in ventricular cardiac myocytes.

OBJECTIVE: The aim was to improve the measurement of both the time course and amplitude of anoxia-induced KATP-channel current (IKATP) in isolated heart cells to specify the role of these channels in the time course of K+ accumulation in the ischemic myocardium. METHODS: Ionic currents in isolated ventricular heart cells of the mouse were measured with a patch clamp technique under normoxic conditions (atmospheric pO2), during wash-out of oxygen, and under anoxic conditions (pO2 < 0.2 mmHg). During the measurement, the actual pO2 in the close proximity of the cell was determined with an optical technique by exciting Pd-meso-tetra(4-carboxyphenyl)porphin with light flashes of 508-570 nm and evaluating the quenching kinetics of the emitted phosphorescence signal at 630-700 nm. These quenching kinetics steeply depend on pO2 and can be evaluated best at pO2 values near 0 mmHg. RESULTS: Out of 28 cells, 23 cells started to develop IKATP at pO2 values between 0 and 0.4 mmHg, i.e. in the range of the level of half maximum activity of the cytochrome oxidase. The remaining five cells developed IKATP between 0.4 and 1.8 mmHg. With respect to the time course, 18 out of 27 cells started to develop IKATP within the first minute after pO2 had decreased to values below 0.2 mmHg. The amplitude of IKATP induced by anoxia and various metabolic inhibitors was large, 29 +/- 12 and 48 +/- 21 nA (+40 mV), respectively. The anoxia-induced IKATP was significantly smaller than IKATP induced by metabolic inhibitors. During the pulses of 50 ms duration to +40 mV, the amplitude of IKATP decayed and, after clamping back to -80 mV, IKATP generated large tail currents. This suggests a notable change in the concentration gradient of K+ ions in the time range of tens of milliseconds. CONCLUSIONS: The results in isolated myocytes indicate that KATP channels open sufficiently rapidly after starting anoxia and generate sufficiently large conductance at maintained anoxia to explain both the time course and magnitude of the ischemic K+ accumulation if an appropriate counter-ion flux is available.

Animals↗
PubMed1998

KATP channel formation by the sulphonylurea receptors SUR1 with Kir6.2 subunits in rat dorsal vagal neurons in situ.

1. Functional and molecular properties of ATP-sensitive K+ (KATP) channels were studied in dorsal vagal neurons (DVNs) of rat brainstem slices using patch-clamp and single-cell antisense RNA amplification-polymerase chain reaction (PCR) techniques. 2. In the cell-attached configuration, 1 mM cyanide resulted in block of spontaneous firing and concomitant opening of single channels with a mean single open time of 2-3 ms and a burst duration of up to several hundred milliseconds. Inhibition of such single-channel activity with 200 microM tolbutamide led to the reappearance of spontaneous discharge. 3. Whole-cell recordings during anoxia revealed a hyperpolarization of the DVNs. Harvesting of cytoplasm, antisense RNA amplification and subsequent PCR showed coexpression for single DVNs of mRNA for the sulphonylurea receptor SUR1 isoform and for the inwardly rectifying K+ channel subunit Kir6.2, but not for the SUR2 or Kir6.1 isoforms of these channel/receptor subclasses. 4. Upon anoxia, a stable depolarization by less than 10 mV was observed in non-excitable cells in the dorsal vagal nucleus. These cells, which expressed glial fibrillary acidic protein (GFAP), showed a high level of mRNA for Kir6.2, a weak signal for SUR1, whereas SUR2 or Kir6.1 were not detected. 5. The results suggest that functional KATP channels in DVNs are constituted by the formation of Kir6.2 subunits with SUR1 receptors.

ATP-Binding Cassette Transporters↗
PubMed2006

Elimination of allosteric modulation of myocardial KATP channels by ATP and protons in two Kir6.2 polymorphisms found in sudden cardiac death.

The major cause of sudden cardiac death (SCD) is ventricular arrhythmias due to unstable myocardial electrical activity in which the ATP-sensitive K+ (KATP) channels play a role. Genetic disruption of these channels predisposes the myocardium to arrhythmias. Two point mutations in the Kir6.2 subunit are found in SCD with acute myocardial infarction. Here we show evidence for the functional consequences of the P266T and R371H variants. Baseline single-channel properties, expression density, and channel modulations were studied in patch clamp. We focused on channel modulations by intracellular ATP and protons, as the concentration of these two important KATP channel regulators changes widely with hypoxic ischemia. We found that both variants expressed functional currents even though they occur at two highly conserved regions. The open state probability of P266T was twice as high as the wild-type (WT) channel, whereas its channel density was only approximately 20% of the WT channel. Although the outward current was not affected by these two mutations at neutral pH, it was approximately 20% lower at acidic pH in the P266T than in the WT channel. Both P266T and R371H mutations significantly reduced ATP sensitivity and increased pH sensitivity. More dramatically, allosteric regulation by intracellular ATP and protons was almost completely eliminated in the polymorphic P266T and R371H channels. Such an abnormality was seen in both inward and outward currents. Given the importance and beneficial effects of allosteric regulation in cellular responses to metabolic stress, the loss of such a regulatory mechanism in the P266T and R371H variants appears consistent with the adverse consequences occurring during acute myocardial infarction in patients.

ATP-Binding Cassette Transporters↗
PubMed2003

KATP channels and myocardial preconditioning: an update.

Ischemic or myocardial preconditioning (IPC) is a phenomenon whereby brief periods of ischemia have been shown to protect the myocardium against a more sustained ischemic insult. The result of IPC may be manifest as a marked reduction in infarct size, myocardial stunning, or incidence of cardiac arrhythmias. Whereas many endogenous neurotransmitters, peptides, and hormones have been proposed to play a role in the signal transduction pathways mediating the cardioprotective effect of IPC, nearly universal evidence indicates the involvement of the ATP-sensitive potassium (KATP) channel. Initial evidence suggested that the surface or sarcolemmal KATP (sarcKATP) channel triggered or mediated the cardioprotective effects of IPC; however, more recent findings have suggested a major role for a mitochondrial site or possibly a mitochondrial KATP channel (mitoKATP). This review presents evidence that supports a role for these two channels as a trigger and/or downstream mediator in the phenomenon of IPC or pharmacologically induced PC as well as recent evidence that suggests the involvement of a mitochondrial calcium-activated potassium (mitoKca) channel or the electron transport chain in mediating the beneficial effects of IPC or pharmacologically induced PC.

Adenosine Triphosphate↗