Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome.

Abstract

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.

• Authors: Thomas G Diness, Yung-Hsin Yeh, Xiao Yan Qi, Denis Chartier, Yukiomi Tsuji, Rie S Hansen, Soren-Peter Olesen, Morten Grunnet, Stanley Nattel
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 79 Issue 1 Pg. 61-9 (Jul 01 2008) ISSN: 0008-6363 [Print] England
• PMID: 18367457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Cresols
• Delayed Rectifier Potassium Channels
• Phenethylamines
• Phenylurea Compounds
• Sulfonamides
• 1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea
• dofetilide

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Atrioventricular Block (complications)
• Bradycardia (etiology, physiopathology, prevention & control)
• Cresols (pharmacology)
• Delayed Rectifier Potassium Channels (agonists)
• Disease Models, Animal
• Electrocardiography
• Female
• Long QT Syndrome (chemically induced, physiopathology, prevention & control)
• Myocytes, Cardiac (drug effects, physiology)
• Patch-Clamp Techniques
• Phenethylamines
• Phenylurea Compounds (pharmacology)
• Rabbits
• Sulfonamides
• Torsades de Pointes (chemically induced, physiopathology, prevention & control)