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PubMed1996

In vitro hypoxia on rat pulmonary artery: effects on contractions to spasmogens and role of KATP channels.

The effect of in vitro hypoxia for 1 h on concentration-response curves to vasoconstrictor spasmogens was examined in rat isolated pulmonary arteries. Hypoxia, like levcromakalim (KATP channel opener), did not affect contractions to endothelin-1 but attenuated contractions to U46619 ((1,5,5,)-hydroxy-11 alpha, 9 alpha-epoxymethano) prosta 5Z, 13E-dienoic acid; thromboxane-mimetic), angiotensin II, noradrenaline and 5-hydroxytryptamine. The attenuation was prevented by glybenclamide. In pre-contracted arteries, subsequent exposure to hypoxia caused a response consisting of four phases (transient relaxation due to endothelium-derived nitric oxide; transient contraction; slow relaxation; sustained contraction). Glybenclamide, if added before hypoxia, did not eliminate either of the relaxant phases but, if added during the sustained contractile phase, caused further contraction. We conclude that exposure of pulmonary arteries to prolonged hypoxia causes KATP channels to open, as in systemic arteries; this diminishes contractions to some, but not all, vasoconstrictor spasmogens. The data suggest that endothelin-1, unlike other vasoconstrictors, would remain a highly effective pulmonary vasoconstrictor under severe hypoxic conditions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Fentanyl protects the heart against ischaemic injury via opioid receptors, adenosine A1 receptors and KATP channel linked mechanisms in rats.

We have investigated if fentanyl protects against myocardial ischaemic injury and if so, if the mechanism of this protection is mediated via opioid and adenosine A1 receptors, and KATP channels. Langendorff rat hearts were subjected to global ischaemia (30 min) and reperfusion (60 min). The drugs were administered before induction of ischaemia and maintained throughout the experiment. Treatment with fentanyl 740 nmol litre-1 improved post-ischaemic mechanical function, assessed as developed pressure, +dP/dtmax and -dP/dtmin, compared with controls after 60 min of reperfusion. These effects were abolished by naloxone 1 mumol litre-1, DPCPX 10 mumol litre-1, a selective adenosine A1 antagonist and sodium 5-hydroxydecanoate 100 mumol litre-1, a K+ATP channel blocker. We conclude that fentanyl protected the heart against post-ischaemic injury by a mechanism which was blocked by an opioid and an adenosine A1 receptor antagonist and also by a KATP channel antagonist.

Adenosine Triphosphate↗
PubMed2006

The cardioprotective peptide, urocortin, activates cardiac KATP channels in adult rat.

Urocortin (UCN), an endogenous cardioprotective peptide, has been reported to activate several ion channels but its effects on the cardiac KATP channels are unknown. In this paper, we showed that adult rat cardiac myocytes had small KATP currents that could be increased 20-fold by pinacidil. UCN also concentration-dependently activated the KATP current and this effect was influenced by ATP and PKA inhibitor peptide, Rp-cAMPS.

Adenosine Triphosphate↗
PubMed2003

The effects of KATP channel modulators on counterregulatory responses and cognitive function during acute controlled hypoglycaemia in healthy men: a pilot study.

AIMS: To examine the effects of agents that alter potassium adenosine triphosphate (KATP) channel activity in beta-cells on cognitive function and counterregulatory hormone responses during acute hypoglycaemia, given the physiological similarities between the pancreatic beta-cell and the hypothalamic glucose-sensitive neurones (GSN) and the widespread distribution of sulphonylurea receptors in neuronal cells throughout the brain. METHODS: Ten healthy males were studied on four occasions and in random order underwent three stepped hypoglycaemic (plasma glucose aims: 3.4, 2.8, 2.4 mmol/l) and one euglycaemic (plasma glucose aim: 5 mmol/l) insulin clamps. Prior to each hypoglycaemic study, volunteers received either 10 mg glibenclamide, or 5 mg/kg diazoxide or placebo orally. Cognitive function, symptom scores and counterregulatory hormone responses were measured at each glycaemic level. RESULTS: There was no statistically significant effect of either drug on the symptoms generated or the counterregulatory hormonal response during hypoglycaemia. However, cognitive function was better preserved during hypoglycaemia in the glibenclamide-treated arm, particularly four-choice reaction time which deteriorated at a plasma glucose 2.5 mmol/l compared with 3.0 mmol/l with diazoxide (P = 0.015) and 2.9 mmol/l with placebo (P = 0.114). CONCLUSIONS: Single doses of pharmacological agents which alter membrane KATP channel activity do not affect the counterregulatory response to hypoglycaemia but may modify cognitive function during cerebral glucopenia. The unexpected effects of glibenclamide on cortical function suggest a novel action of sulphonylureas that warrants further investigation.

Adenosine Triphosphate↗
PubMed2001

Reciprocal regulation of expression of pore-forming KATP channel genes by hypoxia.

The ATP-sensitive potassium (KATP) channel is thought to play an important role in the protection of heart and brain against tissue hypoxia. The genetic regulation of the components of the channel by hypoxia has not been previously described. Here, we investigated the regulation of the two pore-forming channel proteins, Kir6.1 and Kir6.2, in response to hypoxia in vivo and in vitro. We find that these two structurally-related inwardly-rectifying potassium channel proteins are reciprocally regulated by hypoxia in vivo, with upregulation of Kir6.1 and down-regulation of Kir6.2, thereby resulting in a significant change in the composition of the channel complex in response to hypoxia. In vitro we describe neuronal and cardiac cell lines in which Kir6.1 is up-regulated by hypoxia, demonstrating that Kir6.1 is a hypoxia-inducible gene. We conclude that the heart and brain display genetic plasticity in response to hypoxic stress through specific genetic reprograming of cytoprotective channel genes.

Adenosine Triphosphate↗
PubMed1995

Adenosine potentiates flow-induced dilation of coronary arterioles by activating KATP channels in endothelium.

Coronary microvascular diameter is significantly influenced by adenosine and flow. However, the interaction between these two regulatory mechanisms in the control of coronary microvascular tone remains unknown. Because adenosine can activate ATP-sensitive K+ (KATP) channels and these channels are located on the endothelium in addition to vascular smooth muscle, we hypothesized that adenosine can potentiate flow-induced vasodilation by activating endothelial KATP channels in the coronary microcirculation. To test this hypothesis, experiments were performed in porcine subepicardial coronary arterioles (50-150 microns) using isolated, cannulated vessel techniques to allow intraluminal pressure and flow to be independently controlled. All vessels developed active tone, approximately 67-73% of maximum diameter, at 60 cmH2O intraluminal pressure and showed graded dilation to stepwise increases in flow. The magnitude of flow-induced dilation was potentiated by a threshold dose of adenosine (10(-10) M) but not by nitroprusside (10(-10) M). Luminal application of a high K+ concentration ([K+]) (40 mM) completely blocked flow-induced arteriolar dilation. In addition, luminal glibenclamide (10(-6) M) abolished the adenosine-potentiated component of flow-induced response. Indomethacin (10(-5) M) did not alter the dose-dependent dilation to adenosine. However, endothelial denudation, NG-monomethyl-L-arginine (10(-5) M), and luminal administration of a high [K+] or glibenclamide each produced identical inhibition of adenosine-induced vasodilation by shifting the 50% effective dose to the right by an order of magnitude. In contrast, vasodilation in response to nitroprusside was not altered by these pharmacological interventions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1996

Infarct size-reducing effect of nicorandil is mediated by the KATP channel but not by its nitrate-like properties in dogs.

OBJECTIVES: We wished to determine whether the cardioprotective effect of nicorandil to reduce infarct size is blocked by glibenclamide, a selective KATP channel antagonist, or methylene blue, a nitric oxide (NO)/guanylate cyclase inhibitor, in dogs. The second aim was to determine if glyceryl trinitrate produces a cardioprotective effect in the same model and to test if this effect is blocked by methylene blue and not by glibenclamide. We also determined whether adenosine release from the ischemic-reperfused area is an accurate index of ischemic severity in the presence of these drugs. METHODS: Barbiturate-anesthetized dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. In the first three groups, either nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), glyceryl trinitrate (10 micrograms/kg bolus + 1 microgram/kg/min) or an equivalent volume of saline was given intravenously 15 min before LAD occlusion and continued to the time of reperfusion. In the next three groups, glibenclamide (0.3 mg/kg) was administered 15 min before drug infusion. In the final three groups, methylene blue (80 microM) was given intracoronarily 5 min before nicorandil or glyceryl trinitrate and continued until 15 min following reperfusion. Coronary venous blood samples were collected at various times during ischemia and following reperfusion and the concentration of adenosine measured. RESULTS: Nicorandil produced a marked reduction in infarct size expressed as a percent of the area at risk (NC group, 12.2 +/- 3.2% vs. Control group, 25.7 +/- 4.1%, P < 0.05) and this effect was completely abolished by pretreatment with glibenclamide. However, intracoronary administration of methylene blue did not block the cardioprotective effect of nicorandil. On the other hand, glyceryl trinitrate also produced a significant reduction in infarct size (GTN group, 13.0 +/- 3.1%) and this effect was reversed by methylene blue but not by glibenclamide. Adenosine concentrations in coronary venous blood were significantly reduced after reperfusion in the groups with small infarctions as compared with the Control group. CONCLUSIONS: These results suggest that at equieffective cardioprotective doses the infarct size-reducing effect of nicorandil in dogs is mediated via opening of myocardial KATP channels and that the cardioprotective effect of glyceryl trinitrate is most likely to be mediated via activation of guanylate cyclase at a site yet to be determined.

Adenosine↗
PubMed2001

Distinct myoprotective roles of cardiac sarcolemmal and mitochondrial KATP channels during metabolic inhibition and recovery.

The protective roles of sarcolemmal (sarc) and mitochondrial (mito) KATP channels are unclear despite their apparent importance to ischemic preconditioning. We examined these roles by monitoring intracellular calcium ([Ca]int), using fura-2 and fluo-3, in enzymatically isolated rat right ventricular myocytes. Myocyte mortality, estimated using a trypan blue assay, changed approximately in parallel with changes in [Ca]int. Chemically induced hypoxia (CIH), induced by application of cyanide and 2-deoxy-glucose, caused a steady rise in [Ca]int. Calcium increased more rapidly on 'reoxygenation' by return to control solutions. The protein kinase C (PKC) activator PMA abolished both phases of calcium increase. The mitoKATP channel-selective blocker 5-hydroxydecanoate partially prevented the PMA-induced protection during CIH, but not during reoxygenation. In contrast, HMR 1098, a sarcKATP channel-selective blocker, abolished protection only during the reoxygenation. Adenosine (A1) receptor activation prevented or reduced increases in [Ca]int and improved cell viability via a PKC and mito/sarcKATP channel-dependent mechanism. PKC-dependent protection against cytoplasmic calcium increases was also observed in a human cell line (tsA201) transiently expressing sarcKATP channels. Protection was abolished only during the reoxygenation phase by the amino acid substitution (T180A) in the pore-forming Kir6.2 subunit, a mutation previously shown to prevent PKC-dependent modulation. Our data suggest that sarc and mitoKATP channel populations play distinct protective roles, triggered by PKC and/or adenosine, during chemically induced hypoxia/reoxygenation.

ATP-Binding Cassette Transporters↗
PubMed2003

Epinephrine-induced hyperpolarization of islet cells without KATP channels.

This study examines the effect of epinephrine, a known physiological inhibitor of insulin secretion, on the membrane potential of pancreatic islet cells from sulfonylurea receptor-1 (ABCC8)-null mice (Sur1KO), which lack functional ATP-sensitive K+ (KATP) channels. These channels have been argued to be activated by catecholamines, but epinephrine effectively inhibits insulin secretion in both Sur1KO and wild-type islets and in mice. Isolated Sur1KO beta-cells are depolarized in both low (2.8 mmol/l) and high (16.7 mmol/l) glucose and exhibit Ca(2+)-dependent action potentials. Epinephrine hyperpolarizes Sur1KO beta-cells, inhibiting their spontaneous action potentials. This effect, observed in standard whole cell patches, is abolished by pertussis toxin and blocked by BaCl2. The epinephrine effect is mimicked by clonidine, a selective alpha2-adrenoceptor agonist and inhibited by alpha-yohimbine, an alpha2-antagonist. A selection of K+ channel inhibitors, tetraethylammonium, apamin, dendrotoxin, iberiotoxin, E-4130, chromanol 293B, and tertiapin did not block the epinephrine-induced hyperpolarization. Analysis of whole cell currents revealed an inward conductance of 0.11 +/- 0.04 nS/pF (n = 7) and a TEA-sensitive outward conductance of 0.55 +/- 0.08 nS/pF (n = 7) at -60 and 0 mV, respectively. Guanosine 5'-O-(3-thiotriphosphate) (100 microM) in the patch pipette did not significantly alter these currents or activate novel inward-rectifying K+ currents. We conclude that epinephrine can hyperpolarize beta-cells in the absence of KATP channels via activation of low-conductance BaCl2-sensitive K+ channels that are regulated by pertussis toxin-sensitive G proteins.

ATP-Binding Cassette Transporters↗
PubMed1999

Glucose-receptive neurones in the rat ventromedial hypothalamus express KATP channels composed of Kir6.1 and SUR1 subunits.

1. Patch-clamp recordings were made from rat ventromedial hypothalamic neurones in slices of brain tissue in vitro. In cell-attached recordings, removal of extracellular glucose or metabolic inhibition with sodium azide reduced the firing rate of a subpopulation of cells through the activation of a 65 pS channel that was blocked by the sulphonylureas tolbutamide and glibenclamide. 2. In whole-cell patch-clamp recordings, in the absence of ATP in the electrode solution, glucose-receptive neurones gradually hyperpolarized due to the induction of an outward current at -60 mV. This outward current and the resultant hyperpolarization were blocked by the sulphonylureas tolbutamide and glibenclamide. 3. In recordings where the electrode solution contained 4 mM ATP, this outward current was not observed. Under these conditions, 500 microM diazoxide was found to induce an outward current that was blocked by tolbutamide. 4. In cell-attached recordings diazoxide and the active fragment of leptin (leptin 22-56) reduced the firing rate of glucose-receptive neurones by the activation of a channel with similar properties to that induced by removal of extracellular glucose. 5. Reverse transcription followed by the polymerase chain reaction using cytoplasm from single glucose-receptive neurones demonstrated the expression of the ATP-sensitive potassium (KATP) channel subunits Kir6.1 and SUR1 but not Kir6.2 or SUR2. 6. It is concluded that glucose-receptive neurones within the rat ventromedial hypothalamus exhibit a KATP channel current with pharmacological and molecular properties similar to those reported in other tissues.

ATP-Binding Cassette Transporters↗
PubMed2006

Diazoxide provides maximal KATP channels independent protection if present throughout hypoxia.

BACKGROUND: It is not clear what the optimal timing of diazoxide administration for cardioprotection in human myocardium is. We aimed to establish it. We next checked whether protection depended on adenosine triphosphate (ATP)-inhibited potassium (KATP) channels. METHODS: Isolated human right atrial trabeculae were subjected to 90-minute hypoxia and 120-minute reoxygenation in vitro, followed by adding 10(-4) M norepinephrine. Diazoxide (100 microM) was added (1) as a 10-minute preconditioning signal with 10-minute washout before hypoxia or (2) 10-minute pretreatment without washout before hypoxia or (3) throughout hypoxia or (4) 10 minutes before and throughout hypoxia or (5) during the first 20 minutes of reoxygenation only. In the control, no diazoxide was added. In another set of experiments, diazoxide (100 microM) was present throughout hypoxia in control, while we tried to inhibit its protective effect with glibenclamide (1, 10, 100 microM) or 5-hydroxydecanoate (100 microM). RESULTS: The presence of diazoxide throughout hypoxia improved recovery of contractility during reoxygenation, allowed for significant response to norepinephrine at the end of reoxygenation, prevented "ischemic contracture" development, and reduced release of troponin I to tissue bath during hypoxia. Adding diazoxide 10 minutes before hypoxia conferred significantly weaker protective effects in all the above respects. We failed to show a protective effect of diazoxide used as a preconditioning signal or during reoxygenation. Neither 5-hydroxydecanoate nor glibenclamide significantly influenced protective effects of diazoxide added during hypoxia. CONCLUSIONS: Administration of diazoxide throughout hypoxia provided maximal protective effect, suggesting that diazoxide may be an important adjunct to cardioplegic solution. The protection offered by diazoxide used during hypoxia appears independent of its influence on KATP channels.

Cardiotonic Agents↗
PubMed1992

Anoxia induces time-independent K+ current through KATP channels in isolated heart cells of the guinea-pig.

1. Isolated ventricular heart cells of the guinea-pig were exposed to anoxia (PO2 < 0.1 Torr) which induced a time-independent K+ current. This current was studied with the patch clamp technique in the whole-cell and cell-attached configuration. 2. The latency until anoxia-induced changes of whole-cell current developed was distributed exponentially (mean 10.5 min; n = 41). The current was abolished within 2-4 s of reoxygenation. 3. The reversal potential of the anoxia-induced change of whole-cell current at 5.4 and 15 mM [K+]o was -82 and -61 mV, respectively. 4. Analysis of current noise in whole-cell current during the phase of the slow development of the anoxia-induced current yielded a slope conductance of unitary currents of 8.1 pS (5.4 mM [K+]o) which is far below the 30 pS of KATP channels in inside-out patches with no Na+ and Mg2+ in the bath. 5. Reduced unitary current induced by anoxia was recorded in single-channel measurements with 10.4 mM-K+ in the pipette. 6. Using 150 mM-K+ in the pipette, anoxia caused unitary inward currents with a slope conductance of 83 pS. The open probability of the channels (P(o)) reached maximum values between 0.6 and 0.95. The channels closed within 1-3 s of reoxygenation. 7. At voltages between -85 and -45 mV and maximum P(o), open time histograms were dominated by a fast exponential (tau 01 = 0.55 +/- 0.21 ms, mean +/- S.D.) and one or two slow exponentials. 8. Voltage ramp experiments showed that single-channel currents were slightly rectifying in the inward direction. 9. Glibenclamide (1 microM) reversibly blocked the anoxia-induced whole-cell and single-channel currents. 10. It is concluded that during anoxia it is only KATP channels which open by a sufficient decrease of submembrane ATP levels.

Action Potentials↗
PubMed1997

Effects of KRN4884, a novel pyridinecarboxamidine type KATP channel opener, on serum triglyceride levels in rats.

1. The effects of KRN4884, a novel pyridinecarboxamidine type KATP channel opener, on serum triglyceride levels were investigated in Sprague-Dawley rats. 2. Oral administration of KRN4884 (3 mg kg-1) for 10 days caused a significant reduction in serum triglyceride levels, which was comparable to that of clofibrate (160 mg kg-1). Reduction in serum triglyceride levels by KRN4884 and clofibrate were accompanied by a reduction in triglyceride levels both in chylomicron and in very low density lipoprotein. KRN4884 treatment did not affect serum concentrations of total cholesterol and phospholipid, but did increase free fatty acid levels. Clofibrate reduced total cholesterol, phospholipid and free fatty acid levels. 3. Administration of clofibrate significantly decreased triglyceride secretion rate as measured by the Triton WR-1339 injection procedure, while KRN4884 did not. 4. Rats receiving KRN4884 exhibited an increase in lipoprotein lipase (LPL) activity both in adipose tissue and in skeletal muscle. There was an inverse correlation between serum triglyceride levels and tissue LPL activities. KRN4884 did not change hepatic triglyceride lipase (HTGL) activity. Clofibrate affected neither LPL nor HTGL activities. 5. It is concluded that administration of KRN4884 results in reduced serum triglyceride levels which may be due to the enhancement of LPL activity in peripheral tissues.

ATP-Binding Cassette Transporters↗
PubMed1995

Regional short-term myocardial hibernation in swine does not involve endogenous adenosine or KATP channels.

Short-term hibernating myocardium is characterized by reduced contractile function during persistent ischemia, the recovery of metabolism over time, a recruitable inotropic reserve, and the lack of necrosis. The mechanisms underlying myocardial hibernation are unclear. The present study addressed the role of endogenous adenosine and that of activation of ATP-dependent potassium (KATP) channels. In 22 enflurane-anesthetized swine, coronary inflow was reduced to decrease regional myocardial work (W, measured by sonomicrometry) by 60-70% at 5 min of ischemia; this flow reduction has previously been shown to be compatible with the development of myocardial hibernation. Systemic hemodynamics, W, subendocardial blood flow (measured by microspheres), and the myocardial creatine phosphate content (measured by biopsies, mumol/g wet wt) were measured under control conditions and during 90 min of ischemia, with an intracoronary dobutamine infusion during the last 5 min of ischemia. The impact of endogenous adenosine was eliminated by infusion of intracoronary adenosine deaminase (ADA), and the impact of activation of KATP channels by glibenclamide. Creatine phosphate content recovered in the placebo-treated swine (n = 8, 3.8 +/- 1.9 to 5.8 +/- 2.0 mumol/g wet wt) as well as in swine receiving ADA (n = 7, 4.1 +/- 1.2 to 6.0 +/- 1.7 mumol/g wet wt) or glibenclamide (n = 7, 2.8 +/- 1.3 to 6.7 +/- 1.6 mumol/g wet wt) when ischemia was prolonged from 5 to 85 min. At the end of 90 min of ischemia, W increased during intracoronary dobutamine in all three groups to a comparable extent, and myocardial necrosis was absent in all three groups of swine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed2001

Treatment with sheng-mai-san reduces myocardial infarct size through activation of protein kinase C and opening of mitochondrial KATP channel.

Sheng-mei-san (SMS), a traditional Chinese formulation comprising Radix Ginseng, Radix Ophiopogonis and Fructus Schisandrae, has long been used for more than 700 years for patients with coronary heart disease. We attempted to clarify 1) whether SMS reduces myocardial infarct size, and 2) whether the infarct size-reducing effect of SMS is related to activation of protein kinase C and the opening of the mitochondrial KATP channels in Japanese white rabbits without collateral circulation. The results indicate that three days treatment but not acute treatment with SMS reduces myocardial infarct size through activation of protein kinase C and opening of the mitochondrial KATP channels.

Analysis of Variance↗
PubMed1992

Co-expression of sulfonylurea receptors and KATP channels in hamster insulinoma tumor (HIT) cells. Evidence for direct association of the receptor with the channel.

Cell membranes isolated from hamster insulinoma (HIT T15) cells at passages 65-74 contain high and low affinity receptors for a sulfonylurea derivative, 5-[125I]iodo,2-hydroxyglyburide (KD values of approximately 7 nM and 16 microM). Between passages 75 and 85, the estimated B(max) for the high affinity receptor decreases approximately 10-fold from approximately 1.6 to 0.16 pmol/mg membrane protein. By contrast, the density of low affinity binding sites, 800-1000 pmol/mg, is unaltered. The drop in high affinity receptors is paralleled by a decrease in the density of KATP channels assessed using patch-clamp and 86Rb(+)-efflux techniques. These results strongly support the idea that the high affinity sulfonylurea receptor is an integral part of the KATP channel.

ATP-Binding Cassette Transporters↗
PubMed2000

Regulation of glucagon release in mouse -cells by KATP channels and inactivation of TTX-sensitive Na+ channels.

The perforated patch whole-cell configuration of the patch-clamp technique was applied to superficial glucagon-secreting alpha-cells in intact mouse pancreatic islets. alpha-cells were distinguished from the beta- and delta-cells by the presence of a large TTX-blockable Na+ current, a TEA-resistant transient K+ current sensitive to 4-AP (A-current) and the presence of two kinetically separable Ca2+ current components corresponding to low- (T-type) and high-threshold (L-type) Ca2+ channels. The T-type Ca2+, Na+ and A-currents were subject to steady-state voltage-dependent inactivation, which was half-maximal at -45, -47 and -68 mV, respectively. Pancreatic alpha-cells were equipped with tolbutamide-sensitive, ATP-regulated K+ (KATP) channels. Addition of tolbutamide (0.1 mM) evoked a brief period of electrical activity followed by a depolarisation to a plateau of -30 mV with no regenerative electrical activity. Glucagon secretion in the absence of glucose was strongly inhibited by TTX, nifedipine and tolbutamide. When diazoxide was added in the presence of 10 mM glucose, concentrations up to 2 microM stimulated glucagon secretion to the same extent as removal of glucose. We conclude that electrical activity and secretion in the alpha-cells is dependent on the generation of Na+-dependent action potentials. Glucagon secretion depends on low activity of KATP channels to keep the membrane potential sufficiently negative to prevent voltage-dependent inactivation of voltage-gated membrane currents. Glucose may inhibit glucagon release by depolarising the alpha-cell with resultant inactivation of the ion channels participating in action potential generation.

Adenosine Triphosphate↗
PubMed1994

Evidence against KATP channel involvement in adenosine receptor-mediated dilation of epicardial vessels.

The purpose of this study was to determine whether ATP-glyburide-sensitive K+ (KATP-glyburide) channels are involved in the adenosine-induced vasorelaxation of porcine and canine epicardial vessels in vitro. Adenosine and its analogues, 2-chloroadenosine (CAD), 5'-N-ethylcarboxamidoadenosine (NECA), R-N6-(2-phenylisopropyl)adenosine (R-PIA), N6-cyclopentyladenosine (CPA), N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]adenosine (DPMA), 2-phenylaminoadenosine (CV-1808), 2-[m-(carboxyethyl)phenylamino]-5'-N-ethylcarboxamidoadenosine (CGS-22988), 2-[(2-cyclohexylethyl)amino]adenosine (CGS-22492), 2-[(p-amino)phenethylamino]adenosine (APE), and 2-(1-octynyl)adenosine (YT-146) (10 nM-100 microM), produced concentration-dependent relaxations in endothelium-intact and -denuded arterial ring segments contracted with 30 mM KCl, 10 nM endothelin-1, or 10 microM prostaglandin F2 alpha. Sodium nitroprusside (SNP; 1 nM-10 microM) and KATP-channel activator, pinacidil (10 nM-10 microM), also produced similar vasodilatory responses. Glyburide, a KATP-channel blocker, caused a rightward shift of the concentration-response curve to pinacidil but did not alter the responses elicited by SNP or adenosine and its analogues. The data suggest that KATP-glyburide channels are not involved in the mechanism whereby adenosine and its analogues elicit their vasorelaxant response in isolated porcine or canine epicardial vessels.

Adenosine Triphosphate↗