Role of Potassium Channels in Isoflurane- and Sevoflurane-induced Attenuation of Hypoxic Pulmonary Vasoconstriction in Isolated Perfused Rabbit Lungs

2001 ◽  
Vol 95 (4) ◽  
pp. 939-946 ◽  
Author(s):  
Renyu Liu ◽  
Mayumi Ueda ◽  
Naoto Okazaki ◽  
Yuichi Ishibe
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Minimum Alveolar Concentration ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Inhibitory Effect ◽  
Ca Channel ◽  
Kv Channels ◽  
Pulmonary Vasoconstriction ◽  
Channel Inhibition ◽  
Channel Opening

Background Although potassium channels are thought to be responsible for the initiation of hypoxic pulmonary vasoconstriction (HPV), their role in the HPV-inhibitory effect of volatile anesthetics is unclear. The current study tested if the HPV-inhibitory effect of isoflurane and sevoflurane can be affected by changing the potassium-channel opening status with specific potassium-channel inhibitors in isolated rabbit lungs. Methods Isolated rabbit lungs were divided into eight groups (n = 6 each in isoflurane groups and n = 8 in sevoflurane groups): those receiving no inhibitor treatment = control-isoflurane and control-sevoflurane groups; those treated with an adenosine triphosphate-sensitive potassium (K(ATP))-channel inhibitor, glibenclamide = glibenclamide-isoflurane and glibenclamide-sevoflurane groups; those treated with a high-conductance calcium-activated potassium (K(Ca))-channel inhibitor, iberiotoxin = iberiotoxin-isoflurane and iberiotoxin-sevoflurane groups; and those treated with a voltage-sensitive potassium (Kv)-channel inhibitor, 4-aminopyridine = 4-aminopyridine-isoflurane and 4-aminopyridine-sevoflurane groups. The effect of anesthetic on HPV was tested by exposure of the lungs to isoflurane at a concentration of 0, 0.5, 1, or 2 minimum alveolar concentration, or to sevoflurane at a concentration of 0, 0.5, 1, or 1.62 minimum alveolar concentration. The relation between anesthetic concentrations and the HPV response was analyzed by the Wagner equation. Results The inhibition of Kv channels by 4-aminopyridine and K(Ca) channels by iberiotoxin augmented the HPV response. The isoflurane-induced attenuation of HPV was attenuated by voltage-sensitive potassium-channel inhibition with 4-aminopyridine, potentiated by K(Ca)-channel inhibition with iberiotoxin, but not affected by K(ATP)-channel inhibition with glibenclamide. The sevoflurane-induced attenuation of HPV was not affected by any of the potassium-channel inhibitors. Conclusions Isoflurane may modulate the HPV response partially through K(Ca) and Kv channels, but sevoflurane may attenuate the HPV response through other pathways rather than through the currently investigated potassium channels in isolated rabbit lungs.

Ketamine Preserves and Propofol Potentiates Hypoxic Pulmonary Vasoconstriction Compared with the Conscious State in Chronically Instrumented Dogs 

1999 ◽  
Vol 91 (3) ◽  
pp. 760-760 ◽  
Author(s):  
Masayasu Nakayama ◽  
Paul A. Murray
Keyword(s):  
Potassium Channel ◽  
Adenosine Triphosphate ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Conscious State ◽  
Pressure Flow ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction ◽  
Channel Inhibition ◽  
Ketamine Anesthesia ◽  
Pathway Inhibition

Background The authors tested the hypothesis that ketamine and propofol anesthesia would alter the magnitude of hypoxic pulmonary vasoconstriction compared with the conscious state. In addition, they assessed the extent to which cyclooxygenase pathway inhibition and adenosine triphosphate-sensitive potassium channel inhibition modulate hypoxic pulmonary vasoconstriction in the conscious state, and whether these pathways are altered during propofol anesthesia. Methods Twenty conditioned, male mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow relationship. Pressure-flow plots were measured during normoxia and hypoxia (systemic arterial PO2 reduced to about 60 and about 50 mm Hg) on separate days in the conscious state, during ketamine anesthesia, and during propofol anesthesia. The effects of indomethacin and glibenclamide on the magnitude of hypoxic pulmonary vasoconstriction were also assessed in the conscious and propofol-anesthetized states. Results Neither ketamine nor propofol had an effect on the baseline pressure-flow relationship during normoxia compared with the conscious state. Hypoxia resulted in stimulus-dependent pulmonary vasoconstriction (P<0.01) in the conscious state. Compared with the conscious state, the magnitude of hypoxic pulmonary vasoconstriction was preserved during ketamine but was potentiated (P<0.01) during propofol anesthesia. Indomethacin enhanced (P<0.01) hypoxic pulmonary vasoconstriction in both the conscious and propofol-anesthetized states. In contrast, glibenclamide only enhanced (P<0.01) hypoxic pulmonary vasoconstriction in the conscious state and had no effect during propofol anesthesia. Conclusion Hypoxic pulmonary vasoconstriction is preserved during ketamine anesthesia but is potentiated during propofol anesthesia. The potentiated response during propofol anesthesia appears to be caused by inhibition of adenosine triphosphate-sensitive potassium channel-mediated pulmonary vasodilation.

scholarly journals Role of ATP-sensitive potassium channels on hypoxic pulmonary vasoconstriction in endotoxemia

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Maurizio Turzo ◽  
Julian Vaith ◽  
Felix Lasitschka ◽  
Markus A. Weigand ◽  
Cornelius J. Busch
Keyword(s):  
Potassium Channels ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasoconstriction

Kv7 channel inhibition increases hypoxic pulmonary vasoconstriction in endotoxemic mouse lungs

2020 ◽  
pp. 1-13
Author(s):  
Maurizio Turzo ◽  
Fabian A. Spöhr ◽  
Lasitschka Felix ◽  
Markus A. Weigand ◽  
Cornelius J. Busch
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasoconstriction ◽  
Channel Inhibition ◽  
Mouse Lungs ◽  
Endotoxemic Mouse

Desflurane Inhibits Hypoxic Pulmonary Vasoconstriction in Isolated Rabbit Lungs

1995 ◽  
Vol 83 (3) ◽  
pp. 552-556. ◽  
Author(s):  
Stephan A. Loer ◽  
Thomas W. L. Scheeren ◽  
Jorg Tarnow
Keyword(s):  
Minimum Alveolar Concentration ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Constant Flow ◽  
Inhibiting Effect ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Inspiratory Oxygen

Background Inhalational anesthetics inhibit hypoxic pulmonary vasoconstriction (HPV) in vivo and in vitro with a half-maximum inhibiting effect (ED50) within concentrations applied for general anesthesia. Because it is unknown whether desflurane acts likewise, we studied its effect on HPV in isolated blood-perfused rabbit lungs and compared its ED50 with that of halothane. Methods Isolated blood-perfused rabbit lungs were randomly allocated to treatment with either desflurane (n = 6) or halothane (n = 6). HPV, defined as an increase in pulmonary arterial pressure (PAP) at constant flow, was elicited by decreasing inspiratory oxygen concentration from 20% to 3% for 4 min. This effect was determined without (control HPV) and with increasing concentrations of the anesthetics (fraction of inspired carbon dioxide kept constant at 4.8 +/- 0.2%, perfusate temperature at 37 degrees C, and blood flow at 100 ml.min-1). Results Before exposure to the anesthetics, PAP increased by 8.6 +/- 1.9 cmH2O for all lungs within 4 min of hypoxia (control PAP for all lungs 19.6 +/- 2.5 cmH2O). Desflurane decreased this effect in a concentration-dependent fashion with an ED50 of 14.5%, compared with that of halothane, with an ED50 of 1.7%. Conclusions Assuming that 1 minimum alveolar concentration (MAC) values of desflurane and halothane for rabbits are 8.9% and 1.39%, respectively, this study yields ED50 values for the inhibition of HPV of approximately 1.6 MAC for desflurane and 1.2 MAC for halothane (P not statistically significant).

scholarly journals Reversible Silencing of CFTR Chloride Channels by Glutathionylation

2005 ◽  
Vol 125 (2) ◽  
pp. 127-141 ◽  
Author(s):  
Wei Wang ◽  
Claudia Oliva ◽  
Ge Li ◽  
Arne Holmgren ◽  
Christopher Horst Lillig ◽  
...  
Keyword(s):  
Chloride Channels ◽  
Single Channel ◽  
Bound State ◽  
Inhibitory Effect ◽  
Transmembrane Conductance Regulator ◽  
Mixed Disulfide ◽  
Channel Inhibition ◽  
Channel Opening ◽  
Mixed Disulfides ◽  
Signature Sequence

The cystic fibrosis transmembrane conductance regulator (CFTR) is a phosphorylation- and ATP-dependent chloride channel that modulates salt and water transport across lung and gut epithelia. The relationship between CFTR and oxidized forms of glutathione is of potential interest because reactive glutathione species are produced in inflamed epithelia where they may be modulators or substrates of CFTR. Here we show that CFTR channel activity in excised membrane patches is markedly inhibited by several oxidized forms of glutathione (i.e., GSSG, GSNO, and glutathione treated with diamide, a strong thiol oxidizer). Three lines of evidence indicate that the likely mechanism for this inhibitory effect is glutathionylation of a CFTR cysteine (i.e., formation of a mixed disulfide with glutathione): (a) channels could be protected from inhibition by pretreating the patch with NEM (a thiol alkylating agent) or by lowering the bath pH; (b) inhibited channels could be rescued by reducing agents (e.g., DTT) or by purified glutaredoxins (Grxs; thiol disulfide oxidoreductases) including a mutant Grx that specifically reduces mixed disulfides between glutathione and cysteines within proteins; and (c) reversible glutathionylation of CFTR polypeptides in microsomes could be detected biochemically under the same conditions. At the single channel level, the primary effect of reactive glutathione species was to markedly inhibit the opening rates of individual CFTR channels. CFTR channel inhibition was not obviously dependent on phosphorylation state but was markedly slowed when channels were first “locked open” by a poorly hydrolyzable ATP analogue (AMP-PNP). Consistent with the latter finding, we show that the major site of inhibition is cys-1344, a poorly conserved cysteine that lies proximal to the signature sequence in the second nucleotide binding domain (NBD2) of human CFTR. This region is predicted to participate in ATP-dependent channel opening and to be occluded in the nucleotide-bound state of the channel based on structural comparisons to related ATP binding cassette transporters. Our results demonstrate that human CFTR channels are reversibly inhibited by reactive glutathione species, and support an important role of the region proximal to the NBD2 signature sequence in ATP-dependent channel opening.

Effects of the RBC membrane and increased perfusate viscosity on hypoxic pulmonary vasoconstriction

2000 ◽  
Vol 88 (5) ◽  
pp. 1520-1528 ◽  
Author(s):  
Steven Deem ◽  
John T. Berg ◽  
Mark E. Kerr ◽  
Erik R. Swenson
Keyword(s):  
Nitric Oxide ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Respir Crit ◽  
Inhibitory Effect ◽  
No Synthase ◽  
Small Reduction ◽  
Rbc Membrane ◽  
Pulmonary Vasoconstriction

Red blood cells (RBCs) augment hypoxic pulmonary vasoconstriction (HPV) in part by scavenging of nitric oxide (NO) by Hb (Deem S, Swenson ER, Alberts MK, Hedges RG, and Bishop MJ, Am J Respir Crit Care Med 157: 1181–1186, 1998). We studied the contribution of the RBC compartmentalization of Hb to augmentation of HPV and scavenging of NO in isolated perfused rabbit lungs. Lungs were initially perfused with buffer; HPV was provoked by a 5-min challenge with hypoxic gas (inspired O2 fraction 0.05). Expired NO was measured continuously. Addition of free Hb to the perfusate (0.25 mg/ml) resulted in augmentation of HPV and a fall in expired NO that were similar in magnitude to those associated with a hematocrit of 30% (intracellular Hb of 100 mg/ml). Addition of dextran resulted in a blunting of HPV after free Hb but no change in expired NO. Blunting of HPV by dextran was not prevented by NO synthase inhibition with N ω-nitro-l-arginine and/or cyclooxygenase inhibition. RBC ghosts had a mild inhibitory effect on HPV but caused a small reduction in expired NO. In conclusion, the RBC membrane provides a barrier to NO scavenging and augmentation of HPV by Hb. Increased perfusate viscosity inhibits HPV by an undetermined mechanism.

Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction

1992 ◽  
Vol 262 (4) ◽  
pp. C882-C890 ◽  
Author(s):  
J. M. Post ◽  
J. R. Hume ◽  
S. L. Archer ◽  
E. K. Weir
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
K Channel ◽  
Pulmonary Vasoconstriction ◽  
Channel Inhibition ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
K Currents

Cellular mechanisms responsible for hypoxic pulmonary vasoconstriction were investigated in pulmonary arterial cells, isolated perfused lung, and pulmonary artery rings. Three K+ channel antagonists, Leiurus quinquestriatus venom, tetraethylammonium, and 4-aminopyridine, mimicked the effects of hypoxia in isolated lung and arterial rings by increasing pulmonary artery pressure and tension and also inhibited whole cell K+ currents in isolated pulmonary arterial cells. Reduction of oxygen tension from normoxic to hypoxic levels directly inhibited K+ currents and caused membrane depolarization in isolated canine pulmonary arterial smooth muscle cells but not in canine renal arterial smooth muscle cells. Nisoldipine or high buffering of intracellular Ca2+ concentration with [1,2-bis(2)aminophenoxy] ethane-N,N,N',N'-tetraacetic acid prevented hypoxic inhibition of K+ current, suggesting that a Ca(2+)-sensitive K+ channel may be responsible for the hypoxic response. These results indicate that K+ channel inhibition may be a key event that links hypoxia to pulmonary vasoconstriction by causing membrane depolarization and subsequent Ca2+ entry.

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