scholarly journals Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

2007 ◽  
Vol 283 (3) ◽  
pp. 1518-1524 ◽  
Author(s):  
Roman V. Frolov ◽  
Ilya G. Berim ◽  
Satpal Singh
Keyword(s):  
Potassium Channels ◽  
Acetylsalicylic Acid ◽  
Selective Inhibition ◽  
Cardiac Effect ◽  
Delayed Rectifier ◽  
Heart Cells ◽  
Cox Inhibitors ◽  
Cox 2 ◽  
Rat Heart Cells ◽  
Cox 1

Selective inhibitors of cyclooxygenase-2 (COX-2), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have been developed for treating arthritis and other musculoskeletal complaints. Selective inhibition of COX-2 over COX-1 results in preferential decrease in prostacyclin production over thromboxane A2 production, thus leading to less gastric effects than those seen with nonselective COX inhibitors such as acetylsalicylic acid (aspirin). Here we show a novel effect of celecoxib via a mechanism that is independent of COX-2 inhibition. The drug inhibited the delayed rectifier (Kv2) potassium channels from Drosophila, rats, and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture. These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid, a potent inhibitor of both COX-1 and COX-2, to inhibit rat Kv2.1 channels. A genetically null mutant of Drosophila Shab (Kv2) channels reproduced the cardiac effect of celecoxib, and the drug was unable to further enhance the effect of the mutation. These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats, implicating the inhibition of Kv2 channels as the mechanism underlying this effect.

Key role for constitutive cyclooxygenase-2 of MDCK cells in basal signaling and response to released ATP

2001 ◽  
Vol 281 (2) ◽  
pp. C524-C531 ◽  
Author(s):  
Rennolds S. Ostrom ◽  
Caroline Gregorian ◽  
Ryan M. Drenan ◽  
Kathryn Gabot ◽  
Brinda K. Rana ◽  
...  
Keyword(s):  
Cell Function ◽  
Mdck Cells ◽  
Second Messengers ◽  
Atp Release ◽  
Cox Inhibitors ◽  
Cox 2 ◽  
Factor Α ◽  
Biochemical Activation ◽  
Camp Formation ◽  
Cox 1

Madin-Darby canine kidney (MDCK) cells release ATP upon mechanical or biochemical activation, initiating P2Y receptor signaling that regulates basal levels of multiple second messengers, including cAMP ( J Biol Chem 275: 11735–11739, 2000). Data shown here document inhibition of cAMP formation by Gd3+ and niflumic acid, channel inhibitors that block ATP release. cAMP production is stimulated via Ca2+-dependent activation of cytosolic phospholipase A2, release of arachidonic acid (AA), and cyclooxygenase (COX)-dependent production of prostaglandins, which activate prostanoid receptors coupled to Gs and adenylyl cyclase. In the current investigation, we assessed the expression and functional role of the two known isoforms of COX, COX-1 and COX-2. Treatment of cells with either a COX-1-selective inhibitor, SC-560, or COX-2-selective inhibitors, SC-58125 or NS-398, inhibited basal and UTP-stimulated cAMP levels. COX inhibitors also decreased forskolin-stimulated cAMP formation, implying this response is in part attributable to an action of AA metabolites. These findings imply an important role for the inducible form of COX, COX-2, under basal conditions. Indeed, COX-2 expression was readily detectable by immunoblot, and treatments that induce or reduce COX-2 expression in other cells (interleukin-1β, tumor necrosis factor-α, phorbol ester, or dexamethasone) had minimal or no effect on the levels of COX-2 immunoreactivity. RT-PCR using isoform-specific primers detected COX-2 mRNA. We conclude that COX-2 is constitutively expressed in MDCK-D1 cells and participates in basal and P2Y2-mediated signaling, implying a key role for COX-2 in regulation of epithelial cell function.

scholarly journals Cyclooxygenases Inhibitors Efficiently Induce Cardiomyogenesis in Human Pluripotent Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 554 ◽  
Author(s):  
Harshal Nemade ◽  
Aviseka Acharya ◽  
Umesh Chaudhari ◽  
Erastus Nembo ◽  
Filomain Nguemo ◽  
...  
Keyword(s):  
Wnt Signaling Pathway ◽  
Calcium Transient ◽  
Cardiac Differentiation ◽  
Cyclooxygenase Inhibitors ◽  
Cox Inhibitors ◽  
Screening Model ◽  
Cox 2 ◽  
Transient Measurements ◽  
Cox 1

Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model.

Sa1096 SELECTIVE INHIBITION OF COX-1, BUT NOT COX-2, DECREASED THE COLONIC EPITHELIAL INTEGRITY IN THE TNBS-INDUCED COLITIS IN RATS.

2020 ◽  
Vol 158 (6) ◽  
pp. S-274
Author(s):  
Humberto B. da Costa ◽  
Thiago M. Sales ◽  
Suliana M. Paula ◽  
Rodrigo C. Mourão ◽  
Maria Klayre A. Sousa ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Epithelial Integrity ◽  
Cox 2 ◽  
Cox 1

scholarly journals Comparative Analysis of Pharmacologic and/or Genetic Disruption of Cyclooxygenase-1 and Cyclooxygenase-2 Function in Female Reproduction in Mice*

Endocrinology ◽  
2001 ◽  
Vol 142 (7) ◽  
pp. 3198-3206 ◽  
Author(s):  
Jeff Reese ◽  
Xuemei Zhao ◽  
Wen-Ge Ma ◽  
Naoko Brown ◽  
Timothy J. Maziasz ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Synergistic Effects ◽  
Female Reproduction ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Simultaneous Inhibition ◽  
Cox 2 ◽  
Alternative Sources ◽  
First Time ◽  
Cox 1

Abstract Cyclooxygenase (COX)-derived prostaglandins are critical in female reproduction. Gene targeting studies show that ovulation, fertilization, implantation, and decidualization are defective in COX-2 deficient mice. We used genetic and pharmacologic approaches to perturb COX function and examine the differential and synergistic effects of inhibition of COX-1, COX-2, or of both isoforms on reproductive outcomes during early pregnancy in mice. The results demonstrate that simultaneous inhibition of COX-1 and COX-2 produces more severe effects on early pregnancy events than inhibition of either isoform alone. The effects of pharmacological inhibition of COX-2 on female reproductive functions were less severe than the null mutation of the COX-2 gene. A combined approach showed that COX-2 inhibition in COX-1−/− mice induced complete reproductive failure, suggesting a lack of alternative sources of prostaglandin synthesis. This investigation raises caution regarding the indiscriminate use of COX inhibitors and shows for the first time the distinct and overlapping pathways of the cyclooxygenase systems in female reproduction.

Synthesis and evaluation of new benzimidazole-based COX inhibitors: a naproxen-like interaction detected by STD-NMR

RSC Advances ◽  
2015 ◽  
Vol 5 (61) ◽  
pp. 49098-49109 ◽  
Author(s):  
Luísa C. R. Carvalho ◽  
Daniela Ribeiro ◽  
Raquel S. G. R. Seixas ◽  
Artur M. S. Silva ◽  
Mariana Nave ◽  
...  
Keyword(s):  
Pharmacological Activity ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Std Nmr ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Non-steroidal anti-inflammatory drugs exert their pharmacological activity through inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2).

scholarly journals Kinetic basis for selective inhibition of cyclo-oxygenases

1999 ◽  
Vol 339 (3) ◽  
pp. 607-614 ◽  
Author(s):  
James K. GIERSE ◽  
Carol M. KOBOLDT ◽  
Mark C. WALKER ◽  
Karen SEIBERT ◽  
Peter C. ISAKSON
Keyword(s):  
Inhibitory Activity ◽  
Tight Binding ◽  
Selective Inhibition ◽  
Time Dependent ◽  
Experimental Conditions ◽  
Kinetic Behaviour ◽  
Competitive Kinetics ◽  
Binding Time ◽  
Cox 2 ◽  
Cox 1

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins by cyclo-oxygenases (COX). The discovery of a second COX isoform (COX-2) associated with inflammation led to agents that selectively inhibit COX-2, e.g. celecoxib. We evaluated the kinetics of inhibition of celecoxib and several NSAIDs. Celecoxib displays classic competitive kinetics on COX-1 (Ki = 10-16 μM). An initial competitive interaction with COX-2 can also be discerned with celecoxib (Ki = 11-15 μM), followed by a time-dependent interaction leading to potent inhibition, characterized as inactivation (Kinact = 0.03-0.5 s-1). Half-maximal inhibition (IC50) using end-point assays reflects the competitive component on COX-1 (IC50 = 4-19 μM) and the inactivation component on COX-2 (IC50 = 0.003-0.006 μM). NSAIDs exhibit four distinct modes of COX inhibition based on kinetic behaviour: (1) competitive, e.g. ibuprofen; (2) weak binding, time-dependent, e.g. naproxen, oxicams; (3) tight binding, time-dependent, e.g. indomethacin; (4) covalent, e.g. aspirin. In addition, most NSAIDs display different kinetic behaviour for each isoform. Weakly binding inhibitors show variable behaviour in enzyme assays, with apparent inhibitory activity being markedly influenced by experimental conditions; determination of kinetic constants with this class is unreliable and IC50 values are strongly dependent on assay conditions. Although IC50 determinations are useful for structure/activity analyses, the complex and distinct mechanisms of enzyme inhibition of each COX isoform by the NSAIDs renders comparison of inhibitory activity on COX-1 and COX-2 using IC50 ratios of questionable validity.

Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys

2006 ◽  
Vol 290 (4) ◽  
pp. F897-F904 ◽  
Author(s):  
Lori Warford-Woolgar ◽  
Claudia Yu-Chen Peng ◽  
Jamie Shuhyta ◽  
Andrew Wakefield ◽  
Deepa Sankaran ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Relative Difference ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Relative Contribution ◽  
Prostanoid Production ◽  
Prostaglandin F ◽  
Cox 2 ◽  
Cox 1

Renal prostanoids are important regulators of normal renal function and maintenance of renal homeostasis. In diseased kidneys, renal cylooxygenase (COX) expression and prostanoid formation are altered. With the use of the Han:Sprague-Dawley- cy rat, the aim of this study was to determine the relative contribution of renal COX isoforms (protein, gene expression, and activity) on renal prostanoid production [thromboxane B2 (TXB2, stable metabolite of TXA2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1α (6-keto-PGF1α, stable metabolite of PGI2)] in normal and diseased kidneys. In diseased kidneys, COX-1-immunoreactive protein and mRNA levels were higher and COX-2 levels were lower compared with normal kidneys. In contrast, COX activities were higher in diseased compared with normal kidneys for both COX-1 [0.05 ± 0.02 vs. 0.45 ± 0.11 ng prostanoids·min−1·mg protein−1 ( P < 0.001)] and COX-2 [0.64 ± 0.10 vs. 2.32 ± 0.22 ng prostanoids·min−1·mg protein−1 ( P < 0.001)]. As the relative difference in activity was greater for COX-1, the ratio of COX-1/COX-2 was higher in diseased compared with normal kidneys, although the predominant activity was still due to the COX-2 isoform in both genotypes. Endogenous and steady-state in vitro levels of prostanoids were ∼2–10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB2 > 6-keto-PGF1α > PGE2, as determined by higher renal prostanoid levels and COX activity ratios of TXB2/6-keto-PGF1α, TXB2/PGE2, and 6-keto-PGF1α/PGE2. This specificity in both the COX isoform type and for the prostanoids produced has implications for normal and diseased kidneys in treatments involving selective inhibition of COX isoforms.

scholarly journals Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression—Evoked cerebral oligemia

2016 ◽  
Vol 37 (3) ◽  
pp. 1060-1068 ◽  
Author(s):  
Helaine Gariepy ◽  
Jun Zhao ◽  
Dan Levy
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Selective Inhibition ◽  
Doppler Flowmetry ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Synthase Inhibitor ◽  
Later Phase ◽  
Cox 1

Cortical spreading depression (CSD) is considered a significant phenomenon for human neurological conditions and one of its key signatures is the development of persistent cortical oligemia. The factors underlying this reduction in cerebral blood flow (CBF) remain incompletely understood but may involve locally elaborated vasoconstricting eicosanoids. We employed laser Doppler flowmetry in urethane-anesthetized rats, together with a local pharmacological blockade approach, to test the relative contribution of cyclooxygenase (COX)-derived prostanoids to the oligemic response following CSD. Administration of the non-selective COX inhibitor naproxen completely inhibited the oligemic response. Selective inhibition of COX-1 with SC-560 preferentially reduced the early reduction in CBF while selective COX-2 inhibition with NS-398 affected only the later response. Blocking the action of thromboxane A2 (TXA2), using the selective thromboxane synthase inhibitor ozagrel, reduced only the initial CBF decrease, while inhibition of prostaglandin F2alpha action, using the selective FP receptor antagonist AL-8810, blocked the later phase of the oligemia. Our results suggest that the long-lasting oligemia following CSD consists of at least two distinct temporal phases, mediated by preferential actions of COX-1- and COX-2-derived prostanoids: an initial phase mediated by COX-1 that involves TXA2 followed by a later phase, mediated by COX-2 and PGF2alpha.

Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo

2000 ◽  
Vol 278 (6) ◽  
pp. R1496-R1505 ◽  
Author(s):  
Yasushi Takahashi ◽  
Christine Roman ◽  
Sylvain Chemtob ◽  
Mary M. Tse ◽  
Emil Lin ◽  
...  
Keyword(s):  
Ductus Arteriosus ◽  
Plasma Concentrations ◽  
Additional Increase ◽  
Cox Inhibitors ◽  
Fetal Plasma ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE2 and 6ketoPGF1α production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 ± 0.6 μg/ml, mean ± standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE2 and 6ketoPGF1α. Indomethacin (0.7 ± 0.2 μg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.

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