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1 Research Center, Montreal Heart Institute
2 Faculty of Pharmacy, University of Montreal, Montréal, Québec, Canada
3 Department of Physiology and Biophysics, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada T2N 4 N1
4 Department of Bioengineering, University of California, San Diego, CA, 92093-0412, USA
Although the K+ currents expressed in hearts of adult mice have been studied extensively, detailed information concerning their relative sizes and biophysical properties in ventricle and atrium is lacking. Here we describe and validate pharmacological and biophysical methods that can be used to isolate the three main time- and voltage-dependent outward K+ currents which modulate action potential repolarization. A Ca2+-independent transient outward K+ current, Ito, can be separated from total outward current using an ‘inactivating prepulse’. The rapidly activating, slowly inactivating delayed rectifier K+ current, IKur, can be isolated using submillimolar concentrations of 4-aminopyridine (4-AP). The remaining K+ current, Iss, can be obtained by combining these two procedures: (i) inactivating Ito and (ii) eliminating IKur by application of low concentration of 4-AP. Iss activates relatively slowly and shows very little inactivation, even during depolarizations lasting several seconds. Our findings also show that the rate of reactivation of Ito is more than 20-fold faster than that of IKur. These results demonstrate that the outward K+ currents in mouse ventricles can be separated based on their distinct time and voltage dependence, and different sensitivities to 4-AP. Data obtained at both 22 and 32°C demonstrate that although the duration of the inactivating prepulse has to be adapted for the recording temperature, this approach for separation of K+ current components is also valid at more physiological temperatures. To demonstrate that these methods also allow separation of these K+ currents in other cell types, we have applied this same approach to myocytes from mouse atria. Molecular approaches have been used to compare the expression levels of different K+ channels in mouse atrium and ventricle. These findings provide new insights into the functional roles of IKur, Ito and Iss during action potential repolarization.
(Received 10 May 2004;
accepted after revision 19 July 2004;
first published online 22 July 2004)
Corresponding author C. Fiset: Research Center, Montreal Heart Institute, 5000 Bélanger Est, Montréal, Québec, Canada H1T 1C8. Email: celine.fiset{at}icm-mhi.org
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