Cerebral arteriolar dilations by KATP channel activators needl-lysine orl-arginine

1998 ◽  
Vol 274 (3) ◽  
pp. H974-H981 ◽  
Author(s):  
Hermes A. Kontos ◽  
Enoch P. Wei
Keyword(s):  
Amino Acids ◽  
Stationary Solution ◽  
Katp Channel ◽  
Sulfonylurea Receptor ◽  
Rapid Flow ◽  
Cerebral Arterioles

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

Abstract 1515: Regional Effects of Katp Channel Openers Reflect Distinct Atrial and Ventricular Katp Channel Structure in the Murine Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Alexey V Glukhov ◽  
Thomas P Flagg ◽  
Vadim V Fedorov ◽  
Igor R Efimov ◽  
Colin G Nichols
Keyword(s):  
Left Ventricle ◽  
Right Ventricle ◽  
Potassium Channel ◽  
Katp Channel ◽  
Channel Structure ◽  
Receptor Type ◽  
Optical Data ◽  
Sulfonylurea Receptor ◽  
Spatiotemporal Resolution ◽  
Intact Mouse

Classically, cardiac sarcolemmal KATP channels are thought to be composed of Kir6.2 (inward-rectifier potassium channel 6.2, KCNJ11) and SUR2A (sulfonylurea receptor type 2A, ABCC9) subunits. However, the evidence is strong that SUR1 (sulfonylurea receptor type 1, ABCC8) subunits are also expressed in the heart and that they play a significant functional role in the atria. To examine this further, we have estimated the effects of potassium channel-opening drugs diazoxide (specific to SUR1 > SUR2A) and pinacidil (SUR2A > SUR1) in intact hearts from wild type (WT, n=6) and SUR1−/− mice (KO, n=3) that lack SUR1 subunits. Action potential duration (APD) in both atria and ventricles were estimated by optical mapping of posterior surface of Langendorff-perfused hearts using the voltage sensitive dye RH237 and high spatiotemporal resolution CMOS camera (100x100 pixels; 3,000 frames/sec). In WT hearts, diazoxide (300 μM) decreased APD in atria (from 33.6±2.1 ms to 25.5±1.0 ms, p<0.001) and did not change it in ventricles (60.0±8.5 ms vs 61.2±8.3 ms, NS). The absence of SUR1 in KO mice resulted in loss of efficacy of diazoxide in atria (37.5±0.7 ms vs 36.5±0.7 ms, NS). In contrast, pinacidil (300 μM) significantly decreased ventricular APD in both type of mice (from 60.0±8.5 ms to 30.5±4.2 ms in WT, p<0.001; and from 62.0±1.4 ms to 30.5±6.4 ms in KO, p<0.001) and did not change atrial APD in either WT or KO hearts. Glass microelectrode recordings from isolated superfused atria confirmed the optical data. In both WT and KO hearts, the APD in left ventricle was significantly longer and the effect of pinacidil was significantly greater than in right ventricle (APD decreasing by 56.3±4.2% and 62.3±12.0% in left ventricle vs 49.4±3.4% and 50.9±4.1% in right ventricle for WT and KO mice respectively, p<0.05). Similar differences between APDs in right and left atria were not observed. Collectively, these results indicate that in the intact mouse heart, significant differential KATP pharmacology in atria and ventricles results from SUR1 predominance in forming the atrial channel, highlighting an unappreciated heterogeneity of KATP function in the heart.

scholarly journals Regulation of Cloned Atp-Sensitive K Channels by Adenine Nucleotides and Sulfonylureas

2001 ◽  
Vol 118 (4) ◽  
pp. 391-406 ◽  
Author(s):  
Scott A. John ◽  
James N. Weiss ◽  
Bernard Ribalet
Keyword(s):  
Katp Channel ◽  
Adenine Nucleotides ◽  
Katp Channels ◽  
Functional Coupling ◽  
Sulfonylurea Receptor ◽  
K Channels ◽  
Channel Regulation ◽  
Channel Opening ◽  
Insight Into ◽  
Positively Charged

KATP channels, comprised of the pore-forming protein Kir6.x and the sulfonylurea receptor SURx, are regulated in an interdependent manner by adenine nucleotides, PIP2, and sulfonylureas. To gain insight into these interactions, we investigated the effects of mutating positively charged residues in Kir6.2, previously implicated in the response to PIP2, on channel regulation by adenine nucleotides and the sulfonylurea glyburide. Our data show that the Kir6.2 “PIP2-insensitive” mutants R176C and R177C are not reactivated by MgADP after ATP-induced inhibition and are also insensitive to glyburide. These results suggest that R176 and R177 are required for functional coupling to SUR1, which confers MgADP and sulfonylurea sensitivity to the KATP channel. In contrast, the R301C and R314C mutants, which are also “PIP2-insensitive,” remained sensitive to stimulation by MgADP in the absence of ATP and were inhibited by glyburide. Based on these findings, as well as previous data, we propose a model of the KATP channel whereby in the presence of ATP, the R176 and R177 residues on Kir6.2 form a specific site that interacts with NBF1 bound to ATP on SUR1, promoting channel opening by counteracting the inhibition by ATP. This interaction is facilitated by binding of MgADP to NBF2 and blocked by binding of sulfonylureas to SUR1. In the absence of ATP, since KATP channels are not blocked by ATP, they do not require the counteracting effect of NBF1 interacting with R176 and R177 to open. Nevertheless, channels in this state remain activated by MgADP. This effect may be explained by a direct stimulatory interaction of NBF2/MgADP moiety with another region of Kir6.2 (perhaps the NH2 terminus), or by NBF2/MgADP still promoting a weak interaction between NBF1 and Kir6.2 in the absence of ATP. The region delimited by R301 and R314 is not involved in the interaction with NBF1 or NBF2, but confers additional PIP2 sensitivity.

scholarly journals KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Polin Haghvirdizadeh ◽  
Zahurin Mohamed ◽  
Nor Azizan Abdullah ◽  
Pantea Haghvirdizadeh ◽  
Monir Sadat Haerian ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Katp Channel ◽  
Pancreatic Beta Cells ◽  
Current Evidence ◽  
Nucleotide Polymorphisms ◽  
Sulfonylurea Receptor ◽  
Risk Variants ◽  
Kcnj11 Gene ◽  
Dm Type 2

Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM.

scholarly journals Capillary Pericyte KATP Channel Activation Drives the Dilation of Upstream Cerebral Arterioles

2021 ◽  
Vol 120 (3) ◽  
pp. 326a
Author(s):  
Ashwini Hariharan ◽  
Colin Robertson ◽  
Christer Betsholtz ◽  
Thomas A. Longden
Keyword(s):  
Katp Channel ◽  
Channel Activation ◽  
Cerebral Arterioles

The Size of a Single Residue of the Sulfonylurea Receptor Dictates the Effectiveness of KATP Channel Openers

2004 ◽  
Vol 67 (4) ◽  
pp. 1026-1033 ◽  
Author(s):  
Christophe Moreau ◽  
Fabienne Gally ◽  
Heélène Jacquet-Bouix ◽  
Michel Vivaudou
Keyword(s):  
Katp Channel ◽  
Sulfonylurea Receptor ◽  
Katp Channel Openers

Nitric oxide contributes to dilatation of cerebral arterioles during seizures

1993 ◽  
Vol 265 (6) ◽  
pp. H2209-H2212 ◽  
Author(s):  
F. M. Faraci ◽  
K. R. Breese ◽  
D. D. Heistad
Keyword(s):  
Nitric Oxide ◽  
Amino Acids ◽  
Arterial Pressure ◽  
Excitatory Amino Acids ◽  
No Synthase ◽  
Cerebral Microcirculation ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Endogenous Release ◽  
Arteriolar Diameter

Endogenous release of excitatory amino acids during seizures produces marked increases in neuronal activity and guanosine 3',5'-cyclic monophosphate levels in brain tissue, which are mediated by nitric oxide (NO). We tested the hypothesis that dilatation of the cerebral microcirculation during seizures is mediated by NO. Diameters of cerebral arterioles were measured using a closed cranial window in anesthetized rabbits. Three, five, nine, and eleven minutes after the onset of pentylenetetrazole-induced seizure (which releases endogenous excitatory amino acids), arteriolar diameter increased by 42 +/- 6, 30 +/- 3, 20 +/- 2, and 16 +/- 2% (means +/- SE), respectively, from a control diameter of 86 +/- 6 microns. Arterial pressure was maintained at control levels during seizures. In the presence of NG-nitro-L-arginine (L-NNA, 300 microM), an inhibitor of NO synthase, vasodilatation during seizures was not affected at 3 min (40 +/- 8%) but was significantly reduced at 5, 9, and 11 min (17 +/- 5, 6 +/- 3, and 1 +/- 3%, respectively, P < 0.05 vs. control). Vasodilatation in response to topical application of acetylcholine (1 microM) was also inhibited by L-NNA (33 +/- 5 vs. 3 +/- 2%, P < 0.05). Dilatation of cerebral arterioles in response to nitroprusside (1 and 10 microM) was not inhibited by L-NNA. Thus sustained, but not initial, dilatation of cerebral arterioles during seizures appears to be mediated in part by NO.

scholarly journals Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: A mechanistic study

2014 ◽  
Vol 144 (5) ◽  
pp. 469-486 ◽  
Author(s):  
Peter Proks ◽  
Heidi de Wet ◽  
Frances M. Ashcroft
Keyword(s):  
Katp Channel ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Nucleotide Binding ◽  
Mechanistic Study ◽  
Xenopus Laevis Oocytes ◽  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Stimulatory Action ◽  
Channel Inhibition

Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas.

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