The plateau outward current in canine ventricle, sensitive to 4-aminopyridine, is a constitutive contributor to ventricular repolarization

Background and purpose: I-Kur (Ultra-rapid delayed rectifier current) has mu M sensitivity to 4-aminopyridine (4-AP) and is an important modulator of the plateau amplitude and action potential duration in canine atria. Kv1.5 encodes I-Kur and is present in both atria and ventricles in canines and humans. We hypothesized that a similar plateau outward current with mM sensitivity to 4-AP is present in canine ventricle. Experimental approach: We used established voltage clamp protocols and used 4-AP (50 and 100 mM) to measure a plateau outward current in normal canine myocytes isolated from the left ventricular mid-myocardium. Key results: Action potential recordings in the presence of 4-AP showed significant prolongation of action potential duration at 50 and 90% repolarization at 0.5 and 1Hz (P < 0.05), while no prolongation occurred at 2 Hz. Voltage clamp experiments revealed a rapidly activating current, similar to current characteristics of canine atrial I-Kur, in similar to 70% of left ventricular myocytes. The IC50 of 4-AP for this current was 24.2 mM. The concentration of 4-AP used in our experiments resulted in selective blockade of an outward current that was not I-to or I-Kr. beta-Adrenergic stimulation with isoprenaline significantly increased the 4-AP sensitive outward current density (P < 0.05), suggesting a role for this current during increased sympathetic stimulation. In silico incorporation into a canine ventricular cell model revealed selective AP prolongation after current blockade. Conclusions and implications: Our results support the existence of a canine ventricular plateau outward current sensitive to micromolar 4-AP and its constitutive role in ventricular repolarization.