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PubMed1998

KATP channels are common mediators of ischemic and calcium preconditioning in rabbits.

Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 +/- 3% (mean +/- SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 +/- 2, 17 +/- 2, and 12 +/- 3%, respectively (P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 +/- 4 and 41 +/- 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.

Adenosine Triphosphate↗

PubMed1997

Protein kinase C-mediated preconditioning of cardiac myocytes: role of adenosine receptor and KATP channel.

Activation of the adenosine receptor, protein kinase C (PKC), and the ATP-sensitive potassium (KATP) channel is known to induce preconditioning. The objective here was to determine the signaling role of the adenosine receptor, PKC, and the KATP channel and the temporal sequence of activation of these three mediators in preconditioning of cardiac myocytes. Chick embryo ventricular myocytes were used as a myocyte model of preconditioning. Brief hypoxic or adenosine exposure preconditioned the myocytes, and the PKC inhibitors chelerythrine or calphostin C blocked this preconditioning effect, suggesting that PKC is an effector distal to the adenosine receptor in initiating the hypoxia- or adenosine-induced preconditioning. The PKC activator phorbol 12-myristate 13-acetate (PMA), but not the inactive phorbol 4 alpha-phorbol [2,13-didecanoate or 4 alpha-phorbol 12-myristate 13-acetate, could precondition the myocyte; the PMA-induced preconditioning effect was blocked by chelerythrine or calphostin C. Glibenclamide or 5-hydroxydecanoate, when present during a 5-min exposure to PMA or a 90-min hypoxic period, blocked the PMA-induced preconditioning. However, the presence of 8-sulfophenyltheophylline during exposure to PMA failed to block the PMA-induced preconditioning, whereas 8-sulfophenyltheophylline was able to abolish this preconditioning effect when added during the 90-min hypoxic period. The data provide direct evidence that the KATP channel, not the adenosine receptor, is the effector down-stream from PKC in initiating PKC-mediated preconditioning. Both the adenosine receptor and KATP channel are required to exert the actual protective effect during the sustained hypoxia.

Adenosine Triphosphate↗

PubMed1996

Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels.

ATP-sensitive inwardly rectifying potassium channels are expressed in a variety of tissues, including heart, skeletal, and smooth muscle, and pancreatic beta-cells. Physiological and pharmacological studies suggest the presence of distinct KATP channels in these tissues. Recently, the KATP channel of beta-cells has been reconstituted in functional form by coexpression of SUR, the sulfonylurea-binding protein, and the inwardly rectifying K+ channel subunit, KIR6.2. In this article, we describe the isolation of cDNAs encoding SUR-like proteins from mouse, SUR2A and SUR2B. Northern blotting showed that the highest expression of the SUR2 isoforms is in the heart and skeletal muscle, with lower levels in all other tissues. By reverse transcription-polymerase chain reaction, SUR2B is ubiquitously expressed, while the apparently alternatively spliced variant, SUR2A, is expressed exclusively in heart. In situ hybridization shows that the SUR2 isoforms are expressed in the parenchyma of the heart and skeletal muscle and in the vascular structures of other tissues. Human SUR2 was localized to chromosome 12, p12.1 by fluorescent in situ hybridization. The structure of the predicted protein and expression pattern of SUR2 suggests that it is the drug-binding channel-modulating subunit of the extrapancreatic KATP channel. Differences in sequence between SUR and between SUR2 isoforms may underlie the tissue-specific pharmacology of the KATP channel.

Amino Acid Sequence↗

PubMed1999

Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels.

Previous studies demonstrated that opioid receptor activation mimics the cardioprotective effect of ischemic preconditioning via KATP channels in the intact heart. However, it is unknown whether this beneficial effect is exerted at the level of the cardiac myocyte or coronary vasculature or is mediated via the sarcolemmal or the mitochondrial KATP channel. Thus, the purpose of the present study was to investigate whether opioid receptor stimulation could mimic the cardioprotective effect of preconditioning in a cardiac myocyte model of simulated ischemia. Cardiac ventricular myocytes cultured from chick embryos 14 days in ovo were used as an in vitro model for ischemic preconditioning. A 5-minute exposure of the myocytes to the opioid receptor agonist morphine protected the myocytes during a subsequent 90-minute period of simulated ischemia, which was manifested as a pronounced reduction in the percentage of cardiac cells killed and the amount of creatine kinase released during ischemia. The preconditioning-like effect of morphine was concentration-dependent, reached a maximal effect at 1 micromol/L, and was reversed by naloxone (0.1 to 10 micromol/L). When KATP channel antagonists, such as glibenclamide, or the mitochondrial selective inhibitor 5-hydroxydecanoic acid were present during preexposure to morphine, they abolished the protective effect of morphine. Thus, cardiac myocytes express functional opioid receptors, and their activation mimics the cardioprotective effect of ischemic preconditioning. These results provide direct evidence that the preconditioning-like effect of morphine in the intact heart can be exerted at the level of cardiac myocytes and is most likely the result of mitochondrial KATP channel activation.

Adenosine Triphosphate↗

PubMed1999

Molecular biology of adenosine triphosphate-sensitive potassium channels.

KATP channels are a newly defined class of potassium channels based on the physical association of an ABC protein, the sulfonylurea receptor, and a K+ inward rectifier subunit. The beta-cell KATP channel is composed of SUR1, the high-affinity sulfonylurea receptor with multiple TMDs and two NBFs, and KIR6.2, a weak inward rectifier, in a 1:1 stoichiometry. The pore of the channel is formed by KIR6.2 in a tetrameric arrangement; the overall stoichiometry of active channels is (SUR1/KIR6.2)4. The two subunits form a tightly integrated whole. KIR6.2 can be expressed in the plasma membrane either by deletion of an ER retention signal at its C-terminal end or by high-level expression to overwhelm the retention mechanism. The single-channel conductance of the homomeric KIR6.2 channels is equivalent to SUR/KIR6.2 channels, but they differ in all other respects, including bursting behavior, pharmacological properties, sensitivity to ATP and ADP, and trafficking to the plasma membrane. Coexpression with SUR restores the normal channel properties. The key role KATP channel play in the regulation of insulin secretion in response to changes in glucose metabolism is underscored by the finding that a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in KATP channel subunits that result in the loss of channel activity. KATP channels set the resting membrane potential of beta-cells, and their loss results in a constitutive depolarization that allows voltage-gated Ca2+ channels to open spontaneously, increasing the cytosolic Ca2+ levels enough to trigger continuous release of insulin. The loss of KATP channels, in effect, uncouples the electrical activity of beta-cells from their metabolic activity. PHHI mutations have been informative on the function of SUR1 and regulation of KATP channels by adenine nucleotides. The results indicate that SUR1 is important in sensing nucleotide changes, as implied by its sequence similarity to other ABC proteins, in addition to being the drug sensor. An unexpected finding is that the inhibitory action of ATP appears to be through a site located on KIR6.2, whose affinity for ATP is modified by SUR1. A PHHI mutation, G1479R, in the second NBF of SUR1 forms active KATP channels that respond normally to ATP, but fail to activate with MgADP. The result implies that ATP tonically inhibits KATP channels, but that the ADP level in a fasting beta-cell antagonizes this inhibition. Decreases in the ADP level as glucose is metabolized result in KATP channel closure. Although KATP channels are the target for sulfonylureas used in the treatment of NIDDM, the available data suggest that the identified KATP channel mutations do not play a major role in diabetes. Understanding how KATP channels fit into the overall scheme of glucose homeostasis, on the other hand, promises insight into diabetes and other disorders of glucose metabolism, while understanding the structure and regulation of these channels offers potential for development of novel compounds to regulate cellular electrical activity.

Adenosine Triphosphate↗

PubMed1996

The high-affinity sulphonylurea receptor regulates KATP channels in nerve terminals of the rat motor cortex.

The coexpression of sulphonylurea binding sites and ATP-sensitive K+(KATP) channels was examined in the rat motor cortex, an area of the CNS exhibiting a high density of sulphonylurea binding. These channels were not detected on neuronal cell bodies, but sulphonylurea-sensitive KATP channels and charybdotoxin-sensitive, large-conductance calcium-activated K+ BKCa channels were detected by patch clamping of fused nerve terminals from the motor cortex. Subcellular fractionation revealed that high-affinity sulphonylurea binding sites were enriched in the nerve terminal fraction, whereas glibenclamide increased calcium-independent glutamate efflux from isolated nerve terminals. It is concluded that neuronal sulphonylurea receptors and KATP channels are functionally linked in the motor cortex and that they are both selectively expressed in nerve terminals, where the KATP channel may serve to limit glutamate release under conditions of metabolic stress.

ATP-Binding Cassette Transporters↗

PubMed1996

KATP channel opening does not contribute significantly to the vasodilatory effect of SH-group-containing ACE inhibitors.

Angiotensin-converting enzyme (ACE) inhibitors are widely used in the management of hypertension, heart failure, and nephropathy. It has been suggested that ACE inhibitors containing the sulfhydryl group (SH) have an additional effect on KATP channels. To prove this hypothesis, we studied the effects of the SH-containing ACE inhibitors, captopril and zofenopril, on KATP channel opening of bovine coronary arteries and guinea pig thoracic aortas. Bovine coronary arteries were precontracted with the thromboxane A2 analogue, U46619, and guinea pig thoracic aortas were precontracted with phenylephrine and then relaxed with either captopril or zofenopril (n = 8). Inhibition of KATP channel opening with glibenclamide moderately attenuated the zofenopril-induced relaxation of guinea pig thoracic aorta. However, in the bovine coronary arteries, the relaxing effect of both captopril and zofenopril remained uneffected by glibenclamide. In experiments with enalapril (a non SH-containing ACE inhibitor; n = 6) on guinea pig thoracic aortas, no effect on KATP channels could be seen. From our experiments, we conclude that the postulated opening of KATP channels by SH-group-containing ACE inhibitors contributes little to the vasodilation of guinea pig thoracic aortas caused by ACE inhibitors, and that SH groups have no influence upon KATP channels of bovine coronary arteries.

Adenosine Triphosphate↗

PubMed2000

Interaction of isoflurane and cromakalim, a KATP channel opener, on coronary and systemic haemodynamics in chronically instrumented dogs.

BACKGROUND: Although isoflurane has been shown to cause coronary and systemic vasodilation through KATP channel activation, the interaction of KATP channel openers and isoflurane has not been fully investigated. The present study was carried out to determine the haemodynamic actions of cromakalim, a KATP channel opener, under the conscious state and during isoflurane anaesthesia in chronically instrumented dogs. METHODS: Fourteen dogs were chronically instrumented to measure systemic and coronary haemodynamics. Each dog was randomly assigned to receive doses of either cromakalim, 4 and 10 microg x kg(-1) i.v., or isoflurane, 2.1% end-tidal (1.5 MAC), plus cromakalim, 4 and 10 microg x kg(-1) i.v. RESULTS: Cromakalim dose-relatedly decreased mean arterial pressure and systemic vascular resistance and increased coronary blood flow in both conscious and anaesthetized states. With isoflurane, the duration of effects of cromakalim were prolonged. Isoflurane exerted an additive effect on the increase in coronary blood flow induced by a low-dose cromakalim, whereas it did not influence the effect of a high-dose cromakalim. The maximum rate of increase in left ventricular pressure and segment shortening were increased by cromakalim in the conscious state but unchanged during isoflurane anaesthesia. CONCLUSION: The results suggest that the coronary vasodilating effects of isoflurane and cromakalim are basically additive until cromakalim exerts the maximal effect, and that the action of cromakalim on the coronary vasculature is prolonged by isoflurane.

ATP-Binding Cassette Transporters↗

PubMed1998

Myocardial preconditioning produced by ischemia, hypoxia, and a KATP channel opener: effects on interstitial adenosine in dogs.

Previous research has demonstrated that a transient increase in interstitial adenosine and subsequent activation of ATP-sensitive K+ (KATP) channels are involved in triggering ischemic preconditioning (PC), however, the role of adenosine in mediating the cardioprotection of hypoxic PC and that produced by KATP channel openers is less clear. Thus, the aim of the present study was to determine the role of adenosine in mediating the cardioprotective effects of PC produced by 5 min of ischemia, hypoxia, or by a 5-min intracoronary (i.c.) infusion of the KATP channel opener bimakalim (1 microgram/min). A single microdialysis probe was implanted into the midwall of the ischemic area for sampling of interstitial fluid adenosine and its breakdown products during the PC stimulus, prolonged occlusion (60 min) and during the first 30 min of the reperfusion (3 h) period. Ischemic, hypoxic and bimakalim pretreatment significantly reduced infarct size, 5.3 +/- 1.5; 8.9 +/- 2.5; 11.4 +/- 3.2, respectively, as compared to control: 27.3 +/- 6.5. Both ischemic and hypoxic PC produced similar and significant increases (0.56 +/- 0.13 mumol/l to 1.12 +/- 0.12 mumol/l and 1.32 mumol, control, ischemic and hypoxic PC, respectively) in dialysate adenosine concentration which persisted during the brief 10-min reperfusion period following PC. However, i.c. bimakalim resulted in a significant decrease in dialysate adenosine (0.56 +/- 0.13 mumol/l to 0.22 +/- 0.04 mumol/l) which persisted during the 10-min drug-free period. All three PC protocols resulted in similar decreases in dialysate adenosine, inosine and uric acid concentrations throughout the prolonged ischemic period as compared to control animals. In conclusion (1): PC produced by ischemia or hypoxia results in an increase in interstitial adenosine prior to a prolonged occlusion period; (2) the KATP channel agonist, bimakalim, significantly decreased interstitial adenosine prior to a prolonged occlusion period; (3) ischemic PC, hypoxic PC, and bimakalim pretreatment produced a similar reduction in interstitial adenosine and its breakdown products during the prolonged ischemic period. These results suggest that an increase in interstitial adenosine may be necessary for the initiation of the protective effect of ischemic and hypoxic PC but an increase in adenosine is not necessary for the cardioprotective effect of a direct opener of the KATP channel.

Adenine Nucleotides↗

PubMed1997

Acceleration of stiffness in underperfused diabetic rat hearts by glyburide, a KATP channel blocker, and its prevention by levcromakalim and insulin.

OBJECT: To clarify the role of the KATP channels in myocardial dysfunction during underperfusion with norepinephrine (NE) in the diabetic heart, particularly the heart treated with sulphonylurea derivatives. METHODS: Isolated 6-week streptozotocin-diabetic rat hearts with a balloon in the left ventricle (LV) were paced and perfused with normoxic Krebs-Henseleit solution. Agents were infused for 15-25 min before as well as during 60-min underperfusion (2 ml/min/g heart weight) with 10(-6) M NE. Regional myocardial flow distribution was measured using dye microspheres. The effects of ex vivo glyburide (10(-6) M, a sulphonylurea anti-diabetic drug and a specific KATP channel inhibitor) on contractile dysfunction and abnormal regional myocardial energy metabolism were examined during underperfusion with NE in the absence of presence of levcromakalim (10(-4) M, a selective K+ channel opener) and insulin (2 mU/min/g heart weight). RESULTS: The flow rate was greater in the LV subendocardium than the subepicardium during normal perfusion, and smaller at 60-min underperfusion with NE. The LV diastolic tension and pressure during underperfusion with NE increased more rapidly in the presence of glyburide. At 60-min underperfusion with NE, the diastolic pressure elevation was still higher in the glyburide-treated heart, and decreases in tissue ATP, creatine phosphate (CP), energy charge, phosphorylation potential and CP/inorganic phosphate (P(i)) ratio, and increases in AMP, P(i) and lactate were more marked in the glyburide-treated heart, particularly in the LV subendocardium. Thus, ex vivo glyburide enhanced the increase in LV stiffness and abnormal myocardial energy metabolism during underperfusion with NE in diabetic hearts. These changes were reduced by levcromakalim to the level during underperfusion with NE without glyburide. Insulin did not prevent the glyburide-induced earlier exacerbation of the increase in LV stiffness during underperfusion with NE, but reduced the detrimental effects 20 min after the onset of underperfusion. CONCLUSIONS: KATP channels in the diabetic myocardium probably open during underperfusion with NE, and it helps delay the initiation of the increase in cardiac stiffness. Glyburide may have harmful effects in the ischemic diabetic heart; the myocardial KATP channel blockade during underperfusion with NE enhanced the increase in LV stiffness and abnormal myocardial energy metabolism. The glyburide-induced detrimental effects in the ischemic diabetic heart are prevented by levcromakalim and partly by insulin.

Animals↗

PubMed1999

Sevoflurane selectively increases coronary collateral blood flow independent of KATP channels in vivo.

BACKGROUND: Volatile anesthetic agents produce coronary vasodilation via activation of adenosine triphosphate-sensitive potassium (KATP) channels. The authors tested the hypothesis that sevoflurane selectively increases coronary collateral blood flow and assessed the role of KATP channel activation in this process. METHODS: Experiments were conducted in dogs 8 weeks after long-term implantation of a left anterior descending coronary artery (LAD) ameroid constrictor to stimulate coronary collateral growth. Dogs were instrumented for measurement of retrograde LAD blood flow (an index of large coronary collateral blood flow) and LAD tissue flow (via radioactive microspheres; an index of small collateral blood flow). Coronary collateral perfusion and normal (left circumflex coronary artery [LCCA]) zone tissue blood flow were determined in four groups of dogs pretreated with intracoronary glyburide (50 microg/kg) or vehicle in the presence or absence of sevoflurane (1 minimum alveolar concentration). Dose-response relationships to the KATP channel agonist nicorandil were established in each dog using doses (25, 50, and 100 microg/min) previously shown to increase coronary collateral blood flow. RESULTS: Sevoflurane increased blood flow through large and small collaterals and increased collateral vascular conductance in the presence of glyburide but did not affect LCCA blood flow or conductance. In contrast, nicorandil increased blood flow through small but not large collaterals. Nicorandil also increased LCCA blood flow and conductance, actions that were attenuated by glyburide. CONCLUSIONS: The results demonstrate that sevoflurane selectively increases large and small coronary collateral blood flow via mechanism(s) independent of KATP channel activation.

Adenosine Triphosphate↗

PubMed1997

Beta 2-adrenergic dilation of resistance coronary vessels involves KATP channels and nitric oxide in conscious dogs.

BACKGROUND: We considered that beta 2-adrenergic stimulation may dilate resistance coronary vessels by opening ATP-sensitive potassium (KATP) channels, thereby triggering NO formation. METHODS AND RESULTS: In conscious instrumented dogs after beta 1-adrenergic blockade, intracoronary (IC) injections of acetylcholine (ACh), nitroglycerin (NTG), and pirbuterol (PIR), a selective beta 2-adrenergic agonist, were performed before and after blockade of NO formation with IC N omega-nitro-L-arginine methyl ester (L-NAME, 50 micrograms.kg-1.min-1 x 12 minutes) or blockade of KATP channels with IC glibenclamide (25 micrograms.kg-1.min-1 x 12 minutes followed by 2 micrograms.kg-1.min-1). PIR (50.0 ng/kg) increased coronary blood flow (CBF) by 32 +/- 6 from 43 +/- 7 mL/min and by only 11 +/- 2 (P < .01) from 40 +/- 7 mL/min after L-NAME. Increases in CBF to ACh were also reduced by L-NAME, but NTG responses were not. Before glibenclamide, PIR increased CBF by 33 +/- 5 from 45 +/- 7 mL/min and by only 14 +/- 3 (P < .01) from 36 +/- 5 mL/min thereafter. CBF responses to ACh and NTG were maintained after glibenclamide. Lemakalim, a selective opener of KATP channels, caused dose-dependent increases in CBF that were partially inhibited by L-NAME. In experiments in which CBF was controlled, the fall in distal coronary pressure caused by PIR was less after L-NAME or glibenclamide than before. CONCLUSIONS: beta 2-Adrenergic dilation of resistance coronary vessels involves both the opening of KATP channels and NO formation. L-NAME antagonized lemakalim responses consistent with a link between the opening of KATP channels and NO formation in canine resistance coronary vessels.

Acetylcholine↗

PubMed1998

The antiarrhythmic agent cibenzoline inhibits KATP channels by binding to Kir6.2.

We reported previously that cibenzoline, an antiarrhythmic agent, inhibits the ATP-sensitive K+ (KATP) channels of pancreatic beta-cells through a binding site distinct from that for glibenclamide. In the present study, we have determined the locus of the action of cibenzoline on KATP channels reconstituted with mutant Kir6.2 and SUR1. We expressed a C-terminal truncated Kir6.2 (Kir6. 2DeltaC26) with and without SUR1 in COS7 cells. Both Kir6.2DeltaC26 and Kir6.2DeltaC26 + SUR1 formed functional KATP channels. Glibenclamide inhibited Kir6.2DeltaC26 + SUR1 channels but failed to inhibit Kir6.2DeltaC26. In contrast, cibenzoline inhibited equally Kir6.2DeltaC26 and Kir6.2DeltaC26 + SUR1 channels, in a dose-dependent manner, the half-maximal concentrations of channel inhibition being 22.2 +/- 6.1 and 30.9 +/- 9.4 microM, respectively. Furthermore, we determined also that [3H]cibenzoline bound to Kir6. 2DeltaC26. These findings confirm that cibenzoline inhibits KATP channels by a novel inhibitory mechanism in which cibenzoline directly affects the pore-forming Kir6.2 subunit rather than the SUR1 subunit.

ATP-Binding Cassette Transporters↗

PubMed1995

Time-dependent fading of the activation of KATP channels, induced by aprikalim and nucleotides, in excised membrane patches from cardiac myocytes.

1. The effects of the potassium channel opener (KCO) aprikalim (RP 52891) on the nucleotide-induced modulation of ATP-sensitive K+ (KATP) channels in freshly dissociated ventricular myocytes of guinea-pig heart, were studied by use of the inside-out patch-clamp technique. The internal surface of the excised membrane patch was initially bathed with a standard solution (Mg(2+)-free with EDTA), then sequentially superfused with solutions containing nucleoside diphosphates (NDPs: 200 microM ADP and 50 microM GDP) and NDPs plus 1 mM MgCl2 (with EGTA; referred to as Mg-NDP solution). 2. The normalized concentration-response (channel closing) relationship to ATP was shifted to the right when the standard solution was replaced by the Mg-NDP solution. Hence, the internal concentration of ATP ([ATP]i) inhibiting the channel activity by half (Ki) increased from 56 microM to 180 microM, with an apparently constant slope factor (s = 2.37). NDPs in the absence of Mg2+ did not decrease the sensitivity of the channels to ATP. 3. In standard solution, aprikalim (100 microM) activated KATP channels in the presence of a maximally inhibitory [ATP]i (500 microM). This effect was strongly enhanced when aprikalim was applied to patches exposed to Mg-NDP solution, as demonstrated by the 9 fold increase in Ki for [ATP]i (from 180 microM to 1.5 mM and s = 2.37). 4. The ability of aprikalim to overcome the channel closing effects of ATP in Mg-NDP solution waned rapidly. Similarly, the NDP-induced activation of ATP-blocked channels was also time-dependent. Both activation processes disappeared before the channel run-down phenomenon appeared in ATP-free conditions. 5. In conclusion, aprikalim is much more potent in opening KATP channels in membrane patches bathed in Mg-NDP solution than in standard solution. However, under the former experimental conditions, the effect of aprikalim waned rapidly. It is proposed that the waning phenomenon results from changes in the intrinsic enzymatic activity of the KATP channel protein (possibly linked to the experimental conditions) which lead to the channel closure.

Adenosine Triphosphate↗

PubMed1998

Intracellular Ca2+ during metabolic activation of KATP channels in spontaneously active dorsal vagal neurons in medullary slices.

Intracellular Ca2+ ([Ca2+]i) and membrane properties were measured in fura-2 dialysed dorsal vagal neurons (DVN) spontaneously active at a frequency of 0.5-5 Hz. [Ca2+]i increased by about 30 nm upon rising spike frequency by more than 200% due to 20-50 pA current pulses or 10 micrometer serotonin. It fell by 30 nm upon block of spiking by current-injection, tetrodotoxin or Ni2+ and also during hyperpolarization due to gamma-aminobutyric acid or opening of adenosine triphosphate (ATP) -sensitive K+ (KATP) channels with diazoxide. KATP channel-mediated hyperpolarizations during anoxia or cyanide produced an initial [Ca2+]i decrease which reversed into a secondary Ca2+ rise by less than 100 nm. Similar moderate rises of [Ca2+]i were observed during block of aerobic metabolism under voltage-clamp as well as in intact cells, loaded with fura-2 AM. The magnitude of the metabolism-related [Ca2+]i transients did not correlate with the amplitude of the KATP channel-mediated outward current. [Ca2+]i did not change during diazoxide-induced or spontaneous activation of KATP outward current observed in 10% of cells after establishing whole-cell recording. Increasing [Ca2+]i with cyclopiazonic acid did not activate KATP channels. [Ca2+]i was not affected upon block of outward current with sulphonylureas, but these KATP channel blockers were effective to reverse inhibition of spike discharge and, thus, the initial [Ca2+]i fall upon spontaneous or diazoxide-, anoxia- and cyanide-induced KATP channel activation. A sulphonylurea-sensitive hyperpolarization and [Ca2+]i fall was also revealed in the early phase of iodoacetate-induced metabolic arrest, whereas after about 20 min, occurrence of a progressive depolarization led to an irreversible rise of [Ca2+]i to more than 1 micrometer. The results indicate that KATP channel activity in DVN is not affected by physiological changes of intracellular Ca2+ and the lack of a major perturbance of Ca2+ homeostasis contributes to their high tolerance to anoxia.

Action Potentials↗

PubMed1996

KATP channels mediate adenosine-induced hyperemia in retina.

PURPOSE: The authors and others have shown previously that the purine nucleoside adenosine is a potent vasodilator in the retinal microcirculation, mediating increases in retinal blood flow (RBF) in response to several autoregulatory stimuli. The current experiments were undertaken to elucidate the involvement of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels and the adenylate cyclase--cyclic adenosine monophosphate (cAMP) second-messenger system in the transduction of adenosine's hyperemic response. METHODS: Retinal fluorescein angiograms were videorecorded in isoflurane-anesthetized newborn pigs, and changes in arteriovenous transit times and retinal arteriolar and venular diameters were used to estimate stimulus-induced changes in RBF. RESULTS: Intravitreal perivascular microsuffusion of 5 nmol and 50 nmol adenosine caused dose-dependent increases in RBF of 79% +/- 4% (P < 0.05; n = 5) and 323% +/- 61% (P < 0.05; n = 5), respectively. The KATP channel antagonist glibenclamide (0.5 nmol and 5 nmol) caused a significant, dose-dependent attenuation of the hyperemic response to 5 nmol adenosine. The specificity of glibenclamide for blocking KATP channels was demonstrated by its ability to block by 94% +/- 6% (P < 0.05; n = 5) the increase in RBF (94% +/- 7%; P < 0.05) elicited by the intravitreal microsuffusion of the KATP channel agonist cromakalim (5 nmol), whereas it had no effect on the 103% +/- 12% increase in RBF (P < 0.05; n = 5) induced by the nitric oxide donor sodium nitroprusside (15 nmol). Adenosine-induced hyperemia was not potentiated by forskolin (1.7 nmol; n = 4), an adenylate cyclase activator, and was not attenuated by dideoxyadenosine (5 nmol; n = 4), an adenylate cyclase inhibitor. In addition, no significant increases in RBF could be elicited by 2.5 to 25 nmol 8-bromo-cAMP (n = 4), a membrane-permeable cAMP analog. CONCLUSIONS: These results in the piglet indicate that adenosine increases blood flow in the retina by activating KATP channels, not by increasing in cyclic AMP secondary to adenylate cyclase activation. They also underscore the potential importance of KATP channels in the transduction of retinal vasodilatative responses to other agonists.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1995

Femoral vasodilation to cromakalim is blocked by U37883A, a non-sulphonylurea that selectively inhibits KATP channels.

The purpose of the present study was to determine the effects of U37883A, a non-sulphonylurea inhibitor of KATP channels, in the femoral vascular bed of the anaesthetized dog. Administration of U37883A, 4-morpholinecarboxamidine-N-1-adamentyl-N"-cyclohexyl hydrochloride (2.5 mg kg-1, i.v.), significantly inhibited the femoral vasodilator response to intra-femoral arterial injection of cromakalim, an activator of KATP channels. In contrast, U37883A had no effect on the femoral vasodilator responses to nitroglycerin, isoprenaline, 5-HT, or 5-carboxamidotryptamine, suggesting this agent is a novel and selective inhibitor of hindlimb vasodilation induced by KATP-channel activation. Since U37883A did not significantly alter baseline femoral blood flow and femoral vascular resistance, the present data suggest that KATP channels do not contribute, in large measure, to regulating the canine femoral vascular bed under resting conditions in-vivo.

Adamantane↗

PubMed1994

Ketamine-xylazine anaesthesia permits a KATP channel antagonist to attenuate preconditioning in rabbit myocardium.

OBJECTIVE: ATP sensitive potassium (KATP) channels have been implicated in the mechanism of ischaemic preconditioning, though apparently not in the pentobarbitone anaesthetised rabbit model. The aim of this study was to test whether potassium channel activation and blockade would alter protection in ketamine-xylazine anaesthetised rabbits. METHODS: In situ rabbit hearts (n = 50) received 30 min regional ischaemia and 3 h reperfusion. Some hearts were preconditioned by 5 min regional ischaemia and 10 min reperfusion prior to the long ischaemia. Infarct size was determined by tetrazolium staining. RESULTS: In rabbits anaesthetised with ketamine-xylazine, brief preconditioning ischaemia continued to produce much smaller infarcts than in non-preconditioned animals [19(SEM 2)% v 47(3)%, p < or = 0.05]. blocking KATP channels by pretreating with glibenclamide resulted in 35(3)% infarction in non-preconditioned hearts and aborted protection in preconditioned hearts [35(4)% infarction]. Substituting the potassium channel activator pinacidil for the short ischaemia caused comparable reductions in infarct size [28(4)%, p < or = 0.05 v non-preconditioned hearts]. This protection, however, could be blocked by concomitant administration of the adenosine receptor blocker 8-(p-sulphophenyl)theophylline (SPT) [44(3)% infarction]. CONCLUSIONS: When ketamine-xylazine anaesthesia was employed, the protective effects of ischaemic preconditioning in the rabbit heart could be blocked by glibenclamide, and pinacidil could mimic the protection of ischaemic preconditioning. Because the protection afforded by pinacidil could be blocked by SPT, however, there is still some question whether the KATP channel is the end effector of preconditioning.

Animals↗