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¹ Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK
² Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

Ventricular arrhythmogenesis in long QT 3 syndrome (LQT3) involves both triggered activity and re-entrant excitation arising from delayed ventricular repolarization. Effects of specific L-type Ca²⁺ channel antagonism were explored in a gain-of-function murine LQT3 model produced by a KPQ 1505–1507 deletion in the SCN5A gene. Monophasic action potentials (MAPs) were recorded from epicardial and endocardial surfaces of intact, Langendorff-perfused Scn5a+/ hearts. In untreated Scn5a+/ hearts, epicardial action potential duration at 90% repolarization (APD₉₀) was 60.0 ± 0.9 ms compared with 46.9 ± 1.6 ms in untreated wild-type (WT) hearts (P < 0.05; n = 5). The corresponding endocardial APD₉₀ values were 52.0 ± 0.7 ms and 53.7 ± 1.6 ms in Scn5a+/ and WT hearts, respectively (P > 0.05; n = 5). Epicardial early afterdepolarizations (EADs), often accompanied by spontaneous ventricular tachycardia (VT), occurred in 100% of MAPs from Scn5a+/ but not in any WT hearts (n = 10). However, EAD occurrence was reduced to 62 ± 7.1%, 44 ± 9.7%, 10 ± 10% and 0% of MAPs following perfusion with 10 nM, 100 nM, 300 nM and 1 µM nifedipine, respectively (P < 0.05; n = 5), giving an effective IC₅₀ concentration of 79.3 nM. Programmed electrical stimulation (PES) induced VT in all five Scn5a+/ hearts (n = 5) but not in any WT hearts (n = 5). However, repeat PES induced VT in 3, 2, 2 and 0 out of 5 Scn5a+/ hearts following perfusion with 10 nM, 100 nM, 300 nM and 1 µM nifedipine, respectively. Patch clamp studies in isolated ventricular myocytes from Scn5a+/ and WT hearts confirmed that nifedipine (300 nM) completely suppressed the inward Ca²⁺ current but had no effect on inward Na⁺ currents. No significant effects were seen on epicardial APD₉₀, endocardial APD₉₀ or ventricular effective refractory period in Scn5a+/ and WT hearts following perfusion with nifedipine at 1 nM, 10 nM, 100 nM, 300 nM and 1 µM nifedipine concentrations. We conclude that L-type Ca²⁺ channel antagonism thus exerts specific anti-arrhythmic effects in Scn5a+/ hearts through suppression of EADs.

(Received 1 October 2006; accepted after revision 13 November 2006; first published online 16 November 2006)
Corresponding author C. L.-H. Huang: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Email: clh11{at}cam.ac.uk

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