Abstract
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cardiovascular Research |
| Vol/bind | 79 |
| Udgave nummer | 1 |
| Sider (fra-til) | 61-69 |
| Antal sider | 8 |
| ISSN | 0008-6363 |
| DOI | |
| Status | Udgivet - 2008 |
Bibliografisk note
Keywords: Animals; Anti-Arrhythmia Agents; Atrioventricular Block; Bradycardia; Cresols; Delayed Rectifier Potassium Channels; Disease Models, Animal; Electrocardiography; Female; Long QT Syndrome; Myocytes, Cardiac; Patch-Clamp Techniques; Phenethylamines; Phenylurea Compounds; Rabbits; Sulfonamides; Torsades de PointesAdgang til dokumentet
Citationsformater
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
I: Cardiovascular Research, Bind 79, Nr. 1, 2008, s. 61-69.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome.
AU - Diness, Thomas G
AU - Yeh, Yung-Hsin
AU - Qi, Xiao Yan
AU - Chartier, Denis
AU - Tsuji, Yukiomi
AU - Hansen, Rie S
AU - Olesen, Søren-Peter
AU - Grunnet, Morten
AU - Nattel, Stanley
N1 - Keywords: Animals; Anti-Arrhythmia Agents; Atrioventricular Block; Bradycardia; Cresols; Delayed Rectifier Potassium Channels; Disease Models, Animal; Electrocardiography; Female; Long QT Syndrome; Myocytes, Cardiac; Patch-Clamp Techniques; Phenethylamines; Phenylurea Compounds; Rabbits; Sulfonamides; Torsades de Pointes
PY - 2008
Y1 - 2008
N2 - AIMS: Impaired repolarization in cardiac myocytes can lead to long QT syndrome (LQTS), with delayed repolarization and increased susceptibility to Torsades de Pointes (TdP) arrhythmias. Current pharmacological treatment of LQTS is often inadequate. This study sought to evaluate the antiarrhythmic effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, I(Kr), in two rabbit models of acquired LQTS. METHODS AND RESULTS: We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: (i) three-week atrioventricular block with ventricular bradypacing; (ii) dofetilide-induced I(Kr) inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with I(Kr) suppressed by bradycardia remodelling or dofetilide exposure. Bradypaced rabbits developed QT interval prolongation, spontaneous ventricular ectopy, and TdP. Infusion of NS1643 completely suppressed arrhythmic activity and shortened the QT interval; vehicle had no effect. NS1643 also suppressed ventricular tachyarrhythmias caused by infusion of dofetilide to methoxamine-sensitized rabbits, and reversed dofetilide-induced QT prolongation. NS1643 increased I(Kr) in cardiomyocytes isolated from normal and bradycardia-remodelled rabbits by approximately 75% and 50%, respectively (P < 0.001 for each). Similarly, NS1643 restored I(Kr) suppressed by 5 nmol/L dofetilide (tail current 0.28 +/- 0.03 pA/pF pre-dofetilide, 0.20 +/- 0.01 pA/pF in the presence of dofetilide, 0.27 +/- 0.02 pA/pF after adding NS1643 to dofetilide-containing solution, P < 0.01). CONCLUSION: Pharmacological activation of I(Kr) reverses acquired LQTS and TdP caused by bradycardic remodelling and I(Kr)-blocking drugs. I(Kr)-activating drug therapy could be a potentially interesting treatment approach for LQTS.
AB - AIMS: Impaired repolarization in cardiac myocytes can lead to long QT syndrome (LQTS), with delayed repolarization and increased susceptibility to Torsades de Pointes (TdP) arrhythmias. Current pharmacological treatment of LQTS is often inadequate. This study sought to evaluate the antiarrhythmic effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, I(Kr), in two rabbit models of acquired LQTS. METHODS AND RESULTS: We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: (i) three-week atrioventricular block with ventricular bradypacing; (ii) dofetilide-induced I(Kr) inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with I(Kr) suppressed by bradycardia remodelling or dofetilide exposure. Bradypaced rabbits developed QT interval prolongation, spontaneous ventricular ectopy, and TdP. Infusion of NS1643 completely suppressed arrhythmic activity and shortened the QT interval; vehicle had no effect. NS1643 also suppressed ventricular tachyarrhythmias caused by infusion of dofetilide to methoxamine-sensitized rabbits, and reversed dofetilide-induced QT prolongation. NS1643 increased I(Kr) in cardiomyocytes isolated from normal and bradycardia-remodelled rabbits by approximately 75% and 50%, respectively (P < 0.001 for each). Similarly, NS1643 restored I(Kr) suppressed by 5 nmol/L dofetilide (tail current 0.28 +/- 0.03 pA/pF pre-dofetilide, 0.20 +/- 0.01 pA/pF in the presence of dofetilide, 0.27 +/- 0.02 pA/pF after adding NS1643 to dofetilide-containing solution, P < 0.01). CONCLUSION: Pharmacological activation of I(Kr) reverses acquired LQTS and TdP caused by bradycardic remodelling and I(Kr)-blocking drugs. I(Kr)-activating drug therapy could be a potentially interesting treatment approach for LQTS.
U2 - 10.1093/cvr/cvn075
DO - 10.1093/cvr/cvn075
M3 - Journal article
C2 - 18367457
SN - 0008-6363
VL - 79
SP - 61
EP - 69
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -