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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 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 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. (Circulation.

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Pentobarbital and alpha-chloralose are widely used for experimental anesthesia, but their direct electrophysiological actions at anesthetic concentrations are unknown. Trough and peak concentrations measured by high-performance liquid chromatography averaged 27 +/- 3 and 45 +/- 13 mg/l (means +/- SD) for pentobarbital and 41 +/- 15 and 103 +/- 13 mg/l for alpha-chloralose in dogs receiving them for general anesthesia. The direct effects of each agent on papillary muscle action potentials obtained from guinea pigs killed by decapitation were studied in vitro. Pentobarbital increased action potential duration to 95% by 24 +/- 6 and 33 +/- 4% at 25 and 50 mg/l (P less than 0.001 for each), respectively, and caused corresponding increases in effective refractory period. Furthermore, pentobarbital reduced maximum rate of voltage change (Vmax) of phase 0 in a voltage-, rate-, and concentration-dependent fashion, suggesting use-dependent sodium channel blocking actions. The voltage dependence of Vmax was shifted by 3.7 +/- 1.7 (P less than 0.01) and 6.5 +/- 1.8 mV (P less than 0.001) by 25 and 50 mg/l pentobarbital, respectively. In canine ventricular muscle, pentobarbital caused rate- and concentration-dependent decreases in Vmax and increases in action potential duration and refractory period over a concentration range of 5-100 mg/l. alpha-Chloralose was devoid of direct electrophysiological effects in both species. We conclude that pentobarbital has potentially important electrophysiological actions on ventricular tissues at concentrations required for general anesthesia and may confound the results of in vivo studies.