Dose-dependence of 4-aminopyridine plasma - Concentrations and electrophysiological effects in dogs potential relevance to ionic mechanisms in vivo

Background-Previous investigators have administered 4-aminopyridine (4AP) to dogs to evaluate the role of transient outward current (I-to) in vivo; however, plasma concentrations of 4AP were not measured, and it is therefore uncertain which cardiac ion channels were blocked at the concentrations achieved. Methods and Results-We applied high-performance liquid chromatography to measure 4AP concentrations produced by intravenous 4AP administration to dogs. A previously described dose regimen produced plasma concentrations that increased during the maintenance infusion but never exceeded 250 mu mol/L and caused significant mortality. Whole-cell patch-clamp experiments on isolated canine myocytes showed that even the maximum 4AP concentrations achieved in vivo:failed to alter ventricular I-to and had very small effects on atrial I-to; however, concentrations achieved in vivo had a strong inhibitory effect on the dog ultrarapid delayed rectifier (I-Kur.d) present only in atrial cells, We designed a loading and maintenance infusion regimen to produce stable 4AP plasma concentrations. At concentrations in the range of 25 and 50 mu mol/L, 4AP had no effect on ventricular refractory period but increased atrial refractoriness significantly, consistent: with the results of voltage clamp studies. Conclusions-The interpretation of previous studies using intravenous 4AP administration to inhibit I-to in dogs in vivo needs to be reevaluated in Light of the fact that the infusion regimens used produce plasma concentrations that are inadequate to affect ventricular I-to Our findings also support the concept that selective inhibition of ultrarapid delayed rectifier current can prolong atrial refractory periods without affecting ventricular refractoriness.