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At least 19 recordsLinked to original sources
PubMed1999

The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP channels.

KATP channels are heteromultimers of a sulfonylurea receptor SUR and KIR6.2 with the inward rectifier forming the pore which is regulated by SUR. We have examined the contributions of the cytoplasmic domains of KIR6.2 to control of spontaneous bursting and ATP-inhibition in human SUR1/KIR6.2 KATP channels. Truncations of the N-terminus of KIR6.2 nearly eliminate transitions to interburst closed states without affecting the open or intraburst closed states, thus producing SUR1/DeltaNKIR6.2 channels with an extremely high open probability in the absence of nucleotides. These channels have a decrease apparent ATP-sensitivity which is consistent with the involvement of the N-terminus in a transition to an interburst closed state that preferentially binds inhibitory ATP. Mutations in both the N- and proximal C-termini of KIR6.2 can synergistically attenuate the ATP-inhibition. The results identify the N-terminus of KIR6.2 as a determinant of the interburst kinetics of KATP channels and suggest that the two cytoplasmic domains of KIR6.2 participate in ATP-inhibitory gating through distinct mechanisms.

ATP-Binding Cassette Transporters↗
PubMed1999

Sulfonylurea receptors set the maximal open probability, ATP sensitivity and plasma membrane density of KATP channels.

KATP channels are heteromultimers of SUR and KIR6.2. C-terminal truncation of KIR6.2 allows surface expression of the pore. KIR6.2deltaC35 channels display approximately 7-fold lower maximal open probability, approximately 35-fold reduced ATP sensitivity, reduced mean open time, a markedly increased transition rate from a burst into a long-lived closed state, and have no counterpart in vivo. SUR1 and SUR2A restore wild-type bursting, ATP sensitivity and increase channel density in the plasma membrane. The high IC50(ATP) of approximately 4 mM for KIR6.2deltaCK185Q channels results from the additive effects of SUR removal and KIR6.2 modification. The results demonstrate allosteric interaction(s) are essential for normal intrinsic activity, ATP inhibition, and trafficking of KATP channels.

ATP-Binding Cassette Transporters↗
PubMed1997

Different sulfonylurea and ATP sensitivity characterizes the juvenile and the adult form of KATP channel complex of rat skeletal muscle.

We have described here the changes of the biophysical and pharmacological properties of the sarcolemmal ATP-sensitive K+ channels (KATP) of rat skeletal muscle fibres, occurring from an early postnatal period (5 days) to adulthood (210 days). The age-dependent changes of the mean current of the KATP channel (channel activity) and the effects of the blockers, ATP and glybenclamide, were examined by using the patch-clamp technique. Measurements of the single channel conductance, open probability and channel density were also performed. Excision of cell-attached patches into an ATP-free solution dramatically increased the KATP channel activity; however, the intensity of this activity was age dependent. The relative activity was low at 5-6 days of postnatal life, increased to a plateau at 12-13 days, then declined toward adult values after 37 days. Two distinct types of the KATP channel complex could be distinguished. The early developmental period (5-6 days) was dominated by a KATP channel having a conductance of 66 pS, a high open probability of 0.602, and an IC50 for ATP and glybenclamide of 123.1 microM and 3.97 microM, respectively. This type of channel disappeared with maturation of the muscle to be replaced by the adult form of the KATP channel. The later developmental period (from 56 days) was dominated by a KATP channel having a 71 pS conductance, but a low open probability of 0.222. This adult channel was also 3.2 and 73.5 times more sensitive to ATP and glybenclamide, respectively. We have also observed that the sensitivity of the KATP channel to ATP and glybenclamide develops differently. Indeed, the greater increase in the sensitivity of the channel to ATP was observed between 5 and 12 days of age. Conversely, the greater enhancement of the sensitivity of the channel to glybenclamide occurred between 12 and 37 days. A further increase of this parameter was also observed between 37 and 56 days of age. The differential age-dependent acquisition of the sensitivity of KATP channels to ATP and glybenclamide poses the hypothesis that in rat skeletal muscle the ATP regulatory site and sulfonylurea site are located on different subunits of the KATP channel complex. The intense KATP channel activity recorded between 12 and 37 days of postnatal life sustains the high resting macroscopic K+ conductance characteristic of the early postnatal development.

Adenosine Triphosphate↗
PubMed1993

Stimulation of the KATP channel by ADP and diazoxide requires nucleotide hydrolysis in mouse pancreatic beta-cells.

1. The mechanisms by which ADP and the hyperglycaemic compound diazoxide stimulate the activity of the ATP-regulated K+ channel (KATP channel) were studied using inside-out patches isolated from mouse pancreatic beta-cells maintained in tissue culture. 2. The ability of diazoxide and ADP to increase KATP channel activity declined with time following patch excision and no stimulation was observed after 15-40 min. 3. Activation of KATP channels by ADP required the presence of intracellular Mg2+. The stimulatory effect of ADP was mimicked by AMP but only in the presence of ATP. Replacement of ATP with the non-hydrolysable analogue beta, gamma-methylene ATP did not interfere with the ability of ADP to stimulate KATP channel activity. By contrast, enhancement of KATP channel activity was critically dependent on hydrolysable ADP and no stimulation was observed after substitution of alpha,beta-methylene ADP for standard ADP. 4. The ability of diazoxide to enhance KATP channel activity was dependent on the presence of both internal Mg2+ and ATP. Diazoxide stimulation of KATP channel activity was not observed after substitution of beta,gamma-methylene ATP for ATP. However, in the presence of ADP, at a concentration which in itself had no stimulatory action (10 microM), diazoxide was stimulatory also in the presence of the stable ATP analogue. 5. The stimulatory action of diazoxide on KATP channel activity in the presence of ATP was markedly enhanced by intracellular ADP. This potentiating effect of ADP was not reproduced by the stable analogue alpha,beta-methylene ADP and was conditional on the presence of intracellular Mg2+. A similar enhancement of channel activity was also observed with AMP (0.1 mM). In the absence of ATP, diazoxide was still capable of stimulating channel activity provided ADP was present. This effect was not reproduced by AMP. 6. In both nucleotide-free solution and in the presence of 0.1 mM ATP, the distribution of the KATP channel open times were described by a single exponential with a time constant of approximately 20 ms. Addition of ADP or diazoxide resulted in the appearance of a second component with a time constant of > 100 ms which comprised 40-70% of the total number of events. Under the latter experimental conditions, the open probability of the channel increased more than fivefold relative to that observed in the presence of ATP alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Diphosphate↗
PubMed1996

Rapid activation of KATP channels by aldosterone in principal cells of frog skin.

1. In epithelial cells of frog skin, potassium ions are recycled across the basolateral membrane via an inward-rectifier, ATP-sensitive K+ channel (KATP channel). In this study, we show that aldosterone has a stimulatory effect on KATP channel activity and we have investigated the involvement of Na+-H+ exchange and intracellular pH (pHi) in this phenomenon. 2. Aldosterone (10 nM) produced an increase in the open probability of the KATP channel within 15 min from 0.21 +/- 0.05 to 0.93 +/- 0.10 (n = 8), measured in cell-attached patches. Aldosterone also increased the tolbutamide-sensitive K+ current across the basolateral membrane within 30 min from 17.2 +/- 1.9 to 30.3 +/- 1.6 microA cm-2 (n = 8) in nystatin-permeabilized whole skins. 3. The KATP channel is very sensitive to variations in cytosolic pH within the physiological range 7.0-7.4. 4. The intracellular pH of principal cells is regulated by Na+-H+ exchange, and the stimulatory effect of aldosterone on KATP channel activity was abolished by amiloride (100 microM) added on the basolateral side of the epithelium either before or after aldosterone treatment. 5. We propose that aldosterone activates the KATP channels via stimulation of Na+-H+ exchange. The rapidity of aldosterone activation of KATP channels is presented as evidence for a novel non-genomic steroid hormone effect on epithelial ion transport.

Adenosine Triphosphate↗
PubMed1998

Effects of hydroxyl radicals on KATP channels in guinea-pig ventricular myocytes.

We studied the effects of oxygen free radicals on the ATP-sensitive potassium channel (KATP channel) of guinea-pig ventricular myocytes. Single KATP channel currents were recorded from inside-out patches in the presence of symmetrical K+ concentrations (140 mM in both bath and pipette solutions). Reaction of xanthine oxidase (0.1 U/ml) on hypoxanthine (0.5 mM) produced superoxide anions (.O2-) and hydrogen peroxide (H2O2). Exposure of the patch membrane to.O2- and H2O2 increased the opening of KATP channels, but this activation was prevented by adding 1 microM glibenclamide to the bath solution. In the presence of ferric iron (Fe3+: 0.1 mM), the same procedure produced hydroxyl radicals (.OH) via the iron-catalysed Haber-Weiss reaction.OH also activated KATP channels; however, this activation could not be prevented by, even very high concentrations of glibenclamide (10 microM). These different effects of glibenclamide suggest that the mode of action of these oxygen free radicals on KATP channels is different and that.OH is more potent than.O2-/H2O2 in activating KATP channels in the heart.

Adenosine Triphosphate↗
PubMed1994

Diverse effects of pinacidil on KATP channels in mouse skeletal muscle in the presence of different nucleotides.

OBJECTIVE: The potassium channel opener pinacidil relaxes smooth muscle and exerts cardioprotective effects. The aim of the study was to investigate the actions of pinacidil on ATP sensitive potassium channels (KATP channels) in mammalian skeletal muscle and to explore the interrelations of this drug with various nucleotides. METHODS: Single skeletal muscle fibres were prepared enzymatically from flexor digitorum brevis muscles of adult mice. Membrane patches of the inside-out configuration were excised in a Ca(2+)-free solution, and currents through single KATP channels were recorded at -40 mV. The cytoplasmic face of the patch was exposed to a K(+)-rich solution with MgCl2 (1 mM), and pinacidil (0.1 or 0.4 mM) and the nucleotides (0.1 mM) were added to this internal solution. RESULTS: KATP channels were not activated by pinacidil in the presence of the nonhydrolysable ATP analogue AMP-PNP, in contrast to the reported channel activation by pinacidil and ATP. KATP channels had a high activity in the control and were blocked by ADP; the subsequent addition of pinacidil did not enhance the open probability of KATP channels. Pinacidil in the presence of a mixture of AMP-PNP and ADP activated KATP channels. CONCLUSIONS: The diverse effects of pinacidil are interpreted with a model of the KATP channel containing a binding site for pinacidil and two sites for nucleotides, one activatory (A) site and one inhibitory (I) site. Occupation of the A site by ATP or ADP activates the channel, while occupation of the I site by ATP, AMP-PNP, ADP closes the channel. Pinacidil activates the channel and displaces blockers from the I site only if the A site is occupied.

Action Potentials↗
PubMed2000

Cardioprotective effects of nicorandil in rabbits anaesthetized with halothane: potentiation of ischaemic preconditioning via KATP channels.

1. The roles of ATP-sensitive K+ channels (KATP channels) in ischaemic or pharmacological preconditioning in the rabbit heart remain unclear. Infarct limitation by ischaemic preconditioning was abolished by the KATP channel blocker glibenclamide under ketamine/xylazine anaesthesia, but not under anaesthesia induced by pentobarbital. Infarct limitation by the KATP channel opener pinacidil was detected under ketamine/xylazine anaesthesia, but not under pentobarbital anaesthesia. Thus, these effects appear to be anaesthetic dependent. 2. In the present study, we examined whether nicorandil (a KATP channel opener nitrate) exhibits cardioprotective actions under halothane anaesthesia, another commonly used volatile anaesthetic. Control animals were subjected to 40 min coronary occlusion and 120 min reperfusion. Before 40 min ischaemia, the nicorandil group received nicorandil (100 microg/kg per min, i.v., for 10 min), the 5' preconditioning (PC) group received 5 min ischaemia/20 min reperfusion, the 2.5'PC group received 2.5 min preconditioning ischaemia/20 min reperfusion, the nicorandil +2.5'PC group received both nicorandil and 2.5 min ischaemia/20 min reperfusion, the nicorandil +2.5'PC + 5-hydroxydecanoate (5HD) group received both nicorandil and 2.5 min ischaemia/20 min reperfusion in the presence of 5-hydroxydecanoate (5HD; a KATP blocker) and the 5HD group received 5 mg/kg, i.v., 5HD alone. Myocardial infarct size in control (n = 7), nicorandil (n = 5), 5'PC (n = 8), 2.5'PC (n = 5), nicorandil + 2.5'PC (n = 5), nicorandil + 2.5'PC + 5HD (n = 5) and 5HD (n = 4) groups averaged 44.4 +/- 3.6, 41.7 +/- 5.7, 17.8 +/- 3.2,* 34.1 +/- 4.8, 21.3 +/- 4.2,* 39.1 +/- 5.6 and 38.9 +/- 5.0% of the area at risk, respectively (*P <0.05 vs control). 3. Thus, nicorandil alone did not have an infarct size-limiting effect in halothane-anaesthetized rabbits. However, the results suggest that even when nicorandil alone does not demonstrate a direct cardioprotective effect, it may enhance ischaemic preconditioning via KATP channels. Key words: ATP-sensitive K+ (KATP) channel, ischaemic preconditioning, myocardial infarction, nicorandil, rabbit.

ATP-Binding Cassette Transporters↗
PubMed1998

Novel subunit composition of a renal epithelial KATP channel.

Unique ATP-inhibitable K+ channels (KATP) in the kidney determine the rate of urinary K+ excretion and play an essential role in extracellular K+ balance. Here, we demonstrate that functionally similar low sulfonylurea affinity KATP channels are formed by two heterologous molecules, products of Kir1.1a and cystic fibrosis transmembrane conductance regulator (CFTR) genes. Co-injection of CFTR and Kir1.1a cRNA into Xenopus oocytes lead to the expression of K+ selective channels that retained the high open probability behavior of Kir1.1a but acquired sulfonylurea sensitivity and ATP-dependent gating properties. Similar to the KATP channels in the kidney but different from KATP channels in excitable tissues, the Kir1.1a/CFTR channel was inhibited by glibenclamide with micromolar affinity. Since the expression of Kir1.1a and CFTR overlap at sites in the kidney where the low sulfonylurea affinity KATP are expressed, our study offers evidence that these native KATP channels are comprised of Kir1.1a and CFTR. The implication that Kir subunits can interact with ABC proteins beyond the subfamily of sulfonylurea receptors provides an intriguing explanation for functional diversity in KATP channels.

Adenosine Diphosphate↗
PubMed1997

Phentolamine block of KATP channels is mediated by Kir6.2.

The ATP-sensitive K+-channel (KATP channel) plays a key role in insulin secretion from pancreatic beta cells. It is closed both by glucose metabolism and the sulfonylurea drugs that are used in the treatment of noninsulin-dependent diabetes mellitus, thereby initiating a membrane depolarization that activates voltage-dependent Ca2+ entry and insulin release. The beta cell KATP channel is a complex of two proteins: Kir6.2 and SUR1. The former is an ATP-sensitive K+-selective pore, whereas SUR1 is a channel regulator that endows Kir6.2 with sensitivity to sulfonylureas. A number of drugs containing an imidazoline moiety, such as phentolamine, also act as potent stimulators of insulin secretion, but their mechanism of action is unknown. We have used a truncated form of Kir6.2, which expresses independently of SUR1, to show that phentolamine does not inhibit KATP channels by interacting with SUR1. Instead, our results argue that phentolamine may interact directly with Kir6.2 to produce a voltage-independent reduction in channel activity. The single-channel conductance is unaffected. Although the ATP molecule also contains an imidazoline group, the site at which phentolamine blocks is not identical to the ATP-inhibitory site, because phentolamine block of an ATP-insensitive mutant (K185Q) is normal. KATP channels also are found in the heart where they are involved in the response to cardiac ischemia: they also are blocked by phentolamine. Our results suggest that this may be because Kir6.2, which is expressed in the heart, forms the pore of the cardiac KATP channel.

ATP-Binding Cassette Transporters↗
PubMed1997

Binding and effects of KATP channel openers in the vascular smooth muscle cell line, A10.

1. The ATP-sensitive K+ channel (KATP channel) in A10 cells, a cell line derived from rat thoracic aorta, was characterized by binding studies with the tritiated KATP channel opener, [3H]-P1075, and by electrophysiological techniques. 2. Saturation binding experiments gave a KD value of 9.2 +/- 5.2 nM and a binding capacity (BMax) of 140 +/- 40 fmol mg-1 protein for [3H]-P1075 binding to A10 cells; from the BMax value a density of binding sites of 5-10 per microns2 plasmalemma was estimated. 3. KATP channel modulators such as the openers P1075, pinacidil, levcromakalim and minoxidil sulphate and the blocker glibenclamide inhibited [3H]-P1075 binding. The extent of inhibition at saturation depended on the compound, levcromakalim inhibiting specific [3H]-P1075 binding by 85%, minoxidil sulphate and glibenclamide by 70%. The inhibition constants were similar to those determined in strips of rat aorta. 4. Resting membrane potential, recorded with microelectrodes, was -51 +/- 1 mV. P1075 and levcromakalim produced a concentration-dependent hyperpolarization by up to -25 mV with EC50 values of 170 +/- 40 nM and 870 +/- 190 nM, respectively. The hyperpolarization induced by levcromakalim (3 microM) was completely reversed by glibenclamide with an IC50 value of 86 +/- 17 nM. 5. Voltage clamp experiments were performed in the whole cell configuration under a physiological K+ gradient. Levcromakalim (10 microM) induced a current which reversed around -80 mV; the current-voltage relationship showed considerable outward rectification. Glibenclamide (3 microM) abolished the effect of levcromakalim. 6. Analysis of the noise of the levcromakalim (10 microM)-induced current at -40 and -20 mV yielded estimates of the channel density, the single channel conductance and the probability of the channel to be open of 0.14 micron-2, 8.8 pS and 0.39, respectively. 7. The experiments showed that A10 cells are endowed with functional KATP channels which resemble those in vascular tissue; hence, these cells provide an easily accessible source of channels for biochemical and pharmacological studies. The density of binding sites for [3H]-P1075 was estimated to be one order of magnitude higher than the density of functional KATP channels; assuming a plasmalemmal localization of the binding sites this suggests a large receptor reserve for the openers in A10 cells.

Animals↗
PubMed1994

KATP channels of mouse skeletal muscle: mechanism of channel blockage by AMP-PNP.

Single ATP-sensitive potassium channels (KATP channels) were studied in inside-out membrane patches excised from mouse skeletal muscle. Channel blockage by the non-hydrolysable ATP analogue AMP-PNP was investigated in the absence or presence of 1 mM MgCl2 with K(+)-rich solutions bathing the internal membrane surface. Currents through single. KATP channels were recorded at -40 and +40 mV. AMP-PNP (5 to 500 microM; Li salt) reduced the open-probability po of KATP channels and decreased the single-channel currents at high nucleotide concentrations by approximately 10%. Half maximal reduction of po at -40 mV was observed at nucleotide concentrations of 29 microM in the absence and of 39 microM in the presence of Mg2+. The steepness of the AMP-PNP concentration-response curves was strongly affected by Mg2+, the Hill coefficients of the curves were 0.6 in the absence and 1.6 in the presence of 1 mM MgCl2. The efficacies of channel blockage by AMP-PNP at -40 and +40 mV were not significantly different. The results indicate that a KATP channel can bind more divalent Mg(2+)-complexes of AMP-PNP than trivalent protonated forms of the nucleotide and that channel blockage is hardly affected by the membrane electric field. To estimate the contribution of lithium ions to the observed results, we studied the effects of LiCl (0.8 to 10 mM) in the Mg(2+)-free solution on the single channel current i. At a Li+ concentration of 10 mM, i was hardly affected at -40 mV but reduced by a factor of 0.75 at +40 mV. The results are interpreted by a fast, voltage-dependent blockage of KATP channels by internal Li+ ions.

Adenosine Triphosphate↗
PubMedDate not supplied

KATP channel openers reverse immune complex-induced airways hyperreactivity independently of smooth muscle relaxation.

Many openers of ATP-dependent potassium channels (KATP channel openers) cause bronchorelaxation, whereas only a few of them have been claimed to reverse airways hyperreactivity. We investigated whether the antihyperreactive effect is a general feature of KATP channel openers and whether this property is linked to their ability to relax airways smooth muscle. For this purpose, the potency of the four KATP channel openers, bimakalim, rilmakalim, levcromakalim and SDZ PCO 400 ((-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent -1 -enyloxy)-2H-1-benzopyran-6-carbonitrile), to inhibit bombesin- or histamine-induced bronchoconstriction and to reverse immune complex-induced airways hyperreactivity to histamine in guinea pigs, was compared to salbutamol, following intratracheal administration to minimize pharmacokinetic differences. Total lung resistance (RL) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as increase in RL, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8-10 micrograms/kg). Airways hyper-reactivity was induced by acute i.v. administration of preformed immune complexes. I.v. bolus injections of histamine were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Levcromakalim (ED50 = 150 micrograms/kg), bimakalim (ED50 = 4 micrograms/kg), rilmakalim (ED50 = 40 micrograms/kg) and SDZ PCO 400 (ED50 = 280 micrograms/kg) reverse bombesin-induced bronchoconstriction with lower potency than salbutamol (ED50 = 1 microgram/kg). The four KATP channel openers and salbutamol also reversed immune complex-induced airways hyperreactivity to histamine with ED50 values which were markedly lower than those for reversal of bombesin-induced bronchoconstriction; the rank order of potency was rilmakalim (ED50 = 0.2 microgram/kg) > bimakalim (ED50 = 0.5 microgram/kg) > SDZ PCO 400 (ED50 = 3.2 micrograms/kg) > levcromakalim (ED50 = 22 micrograms/kg). Salbutamol (ED50 = 0.008 microgram/kg) was the most potent compound in this test. Bimakalim, levcromakalim and SDZ PCO 400 did not inhibit histamine-induced bronchoconstriction in normoreactive guinea pigs at doses which completely reversed immune complex-induced airways hyperreactivity to histamine. For rilmakalim and salbutamol, 60-130 times higher doses were needed for protection against histamine-induced bronchoconstriction in normoreactive guinea pigs than for reversal of airways hyperreactivity. There was a poor correlation between the ED50 values for inhibition of histamine- or bombesin-induced bronchoconstriction in normoreactive guinea pigs and the reversal of immune complex-induced airways hyperreactivity. It is thus concluded that the ability of KATP channel openers to reverse immune complex-induced airways hyperreactivity is independent of their ability to reverse or prevent bronchoconstriction and thus from their ability relax airway smooth muscle.

Albuterol↗
PubMed1994

Characterization of the G protein coupling of a glucagon receptor to the KATP channel in insulin-secreting cells.

The G-protein-mediated coupling of a glucagon receptor to ATP-dependent K channels--KATP--has been studied in insulin-secreting cells using the patch clamp technique. In excised outside-out patches, KATP channel activity was inhibited by low concentrations of glucagon (IC50 = 2.4 nM); the inhibitory effect vanished at concentrations greater than 50 nM. In cell-attached patches, inhibition by bath-applied glucagon was seen most often, although stimulation was observed in a few cases. A dual action of the hormone is proposed to resolve these apparently divergent results. In excised inside-out patches, KATP channel activity was inhibited by addition of beta gamma subunits purified from either erythrocyte or retina (IC50 = 50 pM and 1 nM, respectively). Subsequent exposure of the patch to alpha i or alpha o reversed this effect. In excised inside-out patches, increasing Mg2+ in the bath stimulated the channel activity between 0 and 0.5 nM, but blocked it at higher concentrations (IC50 = 2.55 mM). In most cases (70%), GTP had a stimulatory effect at concentrations up to 100 microns. However, in three cases, similar GTP levels had clear inhibitory effects. In excised inside-out patches, cholera toxin (CTX) caused channel inhibition. Although the effect could not be reversed by removal of the toxin, the activity was restored by subsequent addition of purified alpha i or alpha o. These results are compatible with a model whereby channel inhibition by activated Gs-coupled receptors occurs, at least in part, via association of the beta gamma subunits of Gs with alpha i/alpha o subunits and deactivation of the alpha i/alpha o-dependent stimulatory pathway. On the basis of this hypothesis, a model is developed to describe the effects of G proteins on the KATP channel, as well as to account for the concentration-dependent stimulation and inhibition of KATP channel by Mg2+. An interpretation of the ability of glucagon to potentiate, but not initiate, insulin release is also given in terms of this model and the effects of ATP on KATP channels.

Adenosine Triphosphate↗
PubMed2001

Synthesis and characterization of a novel tritiated KATP channel opener with a benzopyran structure.

The synthesis of a tritiated benzopyran-type opener of the ATP-dependent K+ channel (KATP channel), [3H]-PKF217 - 744 (3S,4R)-N-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(2-methyl-4-pyridinyl)-2H-1-benzopyran-4-yl]-3-[2,6-3H]pyridinecarboxamide with a specific activity of 50 Ci mmol(-1) is described. Binding of the ligand was studied in membranes from human embryonic kidney cells transfected with the sulphonylurea receptor isoforms, SUR2B and SUR2A, respectively. PKF217 - 744 was confirmed as being a KATP channel opener by its ability to open the Kir6.1/SUR2B channel, the recombinant form of the vascular KATP channel, and to inhibit binding of the pinacidil analogue, [3H]-P1075, to SUR2B (Ki=26 nM). The kinetics of [3H]-PKF217 - 744 binding to SUR2B was described by rate constants of association and dissociation of 6.9x10(6) M(-1) min(-1) and 0.09 min(-1), respectively. Binding of [3H]-PKF217 - 744 to SUR2B/2A was activated by MgATP (EC50 approximately 3 microM) and inhibited (SUR2B) or enhanced (SUR2A) by MGADP: Binding of [3H]-PKF217 - 744 to SUR2B was inhibited by representatives of the different structural classes of openers and sulphonylureas. Ki values were identical with those obtained using the opener [3H]-P1075 as the radioligand. Glibenclamide accelerated dissociation of the SUR2B-[3H]-PKF217 - 744 complex. The data show that the affinity of [3H]-PKF217 - 744 binding to SUR2B is approximately 6 times lower than that of [3H]-P1075. This is due to a surprisingly slow association rate of the benzopyran-type ligand, suggesting a complex mechanism of opener binding to SUR. The other pharmacological properties of the two opener radioligands are identical.

ATP-Binding Cassette Transporters↗
PubMed1994

KATP channels in vascular smooth muscle.

ATP sensitive potassium channels (KATP channels) appear widely distributed in the vascular system. At the single channel level, channels with both small and large conductance have been described, though the former appear to be activated by potassium channel openers or ATP depletion in whole cell studies. KATP channels are inhibited by cytoplasmic ATP, and may be activated by intracellular nucleotide diphosphates. Regulation by intracellular metabolites confers a degree of sensitivity of the channel to the metabolic status of the cell, and there is evidence that KATP currents are activated during metabolic inhibition. In general, activation of KATP channels will lead to membrane hyperpolarisation and so to vasorelaxation. The functional role of the channel is being intensively studied at present. The channel may form a target for a number of endogenous vasodilators, and may be inhibited by some vasoconstrictors. It may be involved in the vasodilator response to hypoxia, and may contribute to the resting membrane potential of smooth muscle in some blood vessels.

Adenosine Triphosphate↗
PubMed1999

Role of KATP channel in heat shock and pharmacological preconditioning.

Heat shock (HS) and 4-monophosphoryl lipid A (MLA, a non-toxic analogue of endotoxin) protects the myocardium against ischemia-reperfusion injury. We studied the involvement of ATP-sensitive potassium channel (KATP channel) in ischemic protection induced by these stimuli. Anesthetized rabbits were preconditioned with either HS (by raising temperature to 42 degrees C for 15 min) or intravenous pretreatment with MLA (35 micrograms/kg). After 24 h, animals were re-anesthetized and subjected to 30-min regional ischemia followed by 180-min reperfusion (I/R). KATP channel blockers glibenclamide and/or 5-hydroxydecanoate (5-HD) were used to inhibit channel function. The 72 kD heat shock protein (HSP-72) was measured by Western blots. HS produced a marked reduction in infarct size (39.4 +/- 8.1% to 14.3 +/- 2.5%, p < 0.05) that was abolished by glibenclamide (42.3 +/- 3.2%) and 5-HD (33.7 +/- 4.8%) when given before I/R. These drugs failed to block HS protection when given before HS. Expression of HSP-72 was increased in all HS groups as compared to non-HS groups in both glibenclamide and 5-HD-treated rabbits. Similarly, pretreatment with MLA reduced infarct size from 40 +/- 8.6% to 15.1 +/- 1.5% (p < 0.05). The infarct size increased to 51.9 +/- 5.8 with 5-HD in MLA-treated rabbits. 5-HD did not alter infarct size significantly when given in vehicle-treated control rabbits. These data suggest that HS and MLA exert their anti-ischemic effect through activation of KATP channel.

ATP-Binding Cassette Transporters↗
PubMed2003

Roles of KATP channels in delayed cardioprotection and intracellular Ca(2+) in the rat heart as revealed by kappa-opioid receptor stimulation with U50488H.

The effect of preconditioning with U50488 H (UP), a selective kappa-opioid receptor (kappa-OR) agonist, on infarct size and intracellular Ca2+ ([Ca2+]i) in the heart subjected to ischaemic insults were studied and evaluated. U50488 H administered intravenously reduced the infarct size 18-48 h after administration in isolated hearts subjected to regional ischaemia/reperfusion (I/R). The effect was dose dependent. A peak effect was reached at 10 mg x kg-1 U50488 H and at 24 h after administration. The effect of 10 mg x kg-1 U50488 H at 24 h after administration was abolished by nor-binaltorphimine (nor-BNI), a selective kappa-OR antagonist, indicating the effect was kappa-OR mediated. The infarct reducing effect of U50488 H was attenuated when a selective blocker of mitochondrial (5-hydroxydecanoic acid, 5-HD) or sarcolemmal (HRM-1098) ATP-sensitive potassium channel (KATP) was coadministered with U50488 H 24 h before ischaemia or when 5-HD was administered just before ischaemia. U50488 H also attenuated the elevation in [Ca2+]i and reduction in electrically induced [Ca2+]i transient in cardiomyocytes subjected to ischaemic insults. The effects were reversed by blockade of KATP channel, which abolished the protective effect of preconditioning with U50488 H. The results indicated that mitochondrial KATP channel serves as both a trigger and a mediator, while sarcolemmal KATP channel as a trigger only, of delayed cardioprotection of kappa-OR stimulation. The effects of these channels may result from prevention/attenuation of [Ca2+]i overload induced by ischaemic insults.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗