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Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve

Interaction of different potassium channels in cardiac repolarization in dog ventricular... The aim of this study was to investigate the possible role of the interaction of different potassium channels in dog ventricular muscle, by applying the conventional microelectrode and whole cell patch‐clamp techniques at 37°C. Complete block of IKr by 1 μM dofetilide lengthened action potential duration (APD) by 45.6±3.6% at 0.2 Hz (n=13). Chromanol 293B applied alone at 10 μM (a concentration which selectively blocks IKs) did not markedly lengthen APD (<7%), but when repolarization had already been prolonged by complete IKr block with 1 μM dofetilide, inhibition of IKs with 10 μM chromanol 293B substantially delayed repolarization by 38.5±8.2% at 0.2 Hz (n=6). BaCl2, at a concentration of 10 μM which blocks IKl without affecting other currents, lengthened APD by 33.0±3.1% (n=11), but when IKr was blocked with 1 μM dofetilide, 10 μM BaCl2 produced a more excessive rate dependent lengthening in APD, frequently (in three out of seven preparations) initiating early afterdepolarizations. These findings indicate that if only one type of potassium channels is inhibited in dog ventricular muscle, excessive APD lengthening is not likely to occur. Dog ventricular myocytes seem to repolarize with a strong safety margin (‘repolarization reserve’). However, when this normal ‘repolarization reserve’ is attenuated, otherwise minimal or moderate potassium current inhibition can result in excessive and potentially proarrhythmic prolongation of the ventricular APD. Therefore, application of drugs which are able to block more than one type of potassium channel is probably more hazardous than the use of a specific inhibitor of one given sort of potassium channel, and when simultaneous blockade of several kinds of potassium channel may be presumed, a detailed study is needed to define the determinants of ‘repolarization reserve’. British Journal of Pharmacology (2002) 137, 361–368. doi:10.1038/sj.bjp.0704881 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve

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References (28)

Publisher
Wiley
Copyright
2002 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0704881
pmid
12237256
Publisher site
See Article on Publisher Site

Abstract

The aim of this study was to investigate the possible role of the interaction of different potassium channels in dog ventricular muscle, by applying the conventional microelectrode and whole cell patch‐clamp techniques at 37°C. Complete block of IKr by 1 μM dofetilide lengthened action potential duration (APD) by 45.6±3.6% at 0.2 Hz (n=13). Chromanol 293B applied alone at 10 μM (a concentration which selectively blocks IKs) did not markedly lengthen APD (<7%), but when repolarization had already been prolonged by complete IKr block with 1 μM dofetilide, inhibition of IKs with 10 μM chromanol 293B substantially delayed repolarization by 38.5±8.2% at 0.2 Hz (n=6). BaCl2, at a concentration of 10 μM which blocks IKl without affecting other currents, lengthened APD by 33.0±3.1% (n=11), but when IKr was blocked with 1 μM dofetilide, 10 μM BaCl2 produced a more excessive rate dependent lengthening in APD, frequently (in three out of seven preparations) initiating early afterdepolarizations. These findings indicate that if only one type of potassium channels is inhibited in dog ventricular muscle, excessive APD lengthening is not likely to occur. Dog ventricular myocytes seem to repolarize with a strong safety margin (‘repolarization reserve’). However, when this normal ‘repolarization reserve’ is attenuated, otherwise minimal or moderate potassium current inhibition can result in excessive and potentially proarrhythmic prolongation of the ventricular APD. Therefore, application of drugs which are able to block more than one type of potassium channel is probably more hazardous than the use of a specific inhibitor of one given sort of potassium channel, and when simultaneous blockade of several kinds of potassium channel may be presumed, a detailed study is needed to define the determinants of ‘repolarization reserve’. British Journal of Pharmacology (2002) 137, 361–368. doi:10.1038/sj.bjp.0704881

Journal

British Journal of Pharmacology – Wiley

Published: Oct 1, 2002

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