BACKGROUND: Block of ultrarapid delayed rectified potassium current (I(Kur)), present in atria but not in ventricles, is thought to be a promising approach for atrial-specific therapy of atrial fibrillation (AF). However, it has been shown that I(Kur) block may abbreviate atrial repolarization and that loss-of-function mutations in KCNA5, which encodes K(v) 1.5 channels responsible for I(Kur), is associated with familial AF. OBJECTIVE: Our objective in this study was to use low concentrations of 4-aminopyridine (4-AP, 10 to 50 microM), known to selectively block I(Kur), to assess the proarrhythmic and antiarrhythmic effects of I(Kur) block in healthy and remodeled atria. METHODS: Isolated canine coronary-perfused right atrial preparations were used. Acetylcholine or ischemia/reperfusion was used to acutely remodel the atria. Transmembrane action potentials and a pseudo-electrocardiogram were simultaneously recorded. RESULTS: Normal (healthy) atria typically displayed action potentials (AP) with a prominent plateau, whereas remodeled atria displayed triangular-shaped APs (remodeled). In healthy atria, in which AF could not be induced with programmed stimulation, 4-AP abbreviated action potential measured at 90% repolarization (APD(90)) and effective refractory period (ERP), permitting the induction of AF in 4 of 12 preparations (33%). In remodeled atria, 4-AP produced little (50 microM) to no (10 to 25 microM) prolongation of APD(90) or ERP and was either ineffective or poorly effective in terminating AF or preventing its induction. CONCLUSION: Our findings suggest that block of I(Kur) can provide the substrate for development of AF in healthy canine atria, presumably via abbreviation of APD and ERP.
BACKGROUND: Block of ultrarapid delayed rectified potassium current (I(Kur)), present in atria but not in ventricles, is thought to be a promising approach for atrial-specific therapy of atrial fibrillation (AF). However, it has been shown that I(Kur) block may abbreviate atrial repolarization and that loss-of-function mutations in KCNA5, which encodes K(v) 1.5 channels responsible for I(Kur), is associated with familial AF. OBJECTIVE: Our objective in this study was to use low concentrations of 4-aminopyridine (4-AP, 10 to 50 microM), known to selectively block I(Kur), to assess the proarrhythmic and antiarrhythmic effects of I(Kur) block in healthy and remodeled atria. METHODS: Isolated canine coronary-perfused right atrial preparations were used. Acetylcholine or ischemia/reperfusion was used to acutely remodel the atria. Transmembrane action potentials and a pseudo-electrocardiogram were simultaneously recorded. RESULTS: Normal (healthy) atria typically displayed action potentials (AP) with a prominent plateau, whereas remodeled atria displayed triangular-shaped APs (remodeled). In healthy atria, in which AF could not be induced with programmed stimulation, 4-AP abbreviated action potential measured at 90% repolarization (APD(90)) and effective refractory period (ERP), permitting the induction of AF in 4 of 12 preparations (33%). In remodeled atria, 4-AP produced little (50 microM) to no (10 to 25 microM) prolongation of APD(90) or ERP and was either ineffective or poorly effective in terminating AF or preventing its induction. CONCLUSION: Our findings suggest that block of I(Kur) can provide the substrate for development of AF in healthy canine atria, presumably via abbreviation of APD and ERP.
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