EFFECTS OF HYPOKALEMIA ON ARRHYTHMOGENIC RISK OF QUINIDINE IN RATS

Plasma potassium concentration plays an important role in the inductio n of arrhythmia and is closely related to the arrhythmogenicity of var ious drugs. We quantitatively analyzed the influence of plasma potassi um concentration on QT intervals before drug administration and on dru g-induced QT prolongation, to estimate the risk of drug-induced arrhyt hmia under hypokalaemic conditions. The hypokalaemic models were produ ced by intraperitoneal administration of furosemide and hydrochlorothi azide in male Sprague-Dawley rats. The relationship between the change s in QT intervals and time profiles of plasma quinidine (QND) concentr ation were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The pl asma QND concentration reached the therapeutic range (3-7 mu g/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences be tween normal and hypokalaemic rats were observed. QND induced QT prolo ngation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hy pokalaemia, the QT intervals before drug administration were significa ntly prolonged in hypokalaemic rats (65.90 +/- 1.40 vs 56.60 +/- 0.748 msec, mean +/- SEM, p < 0.0001). Thus, the prolongation of QT interva ls before drug administration may act as a risk factor of arrhythmia u nder hypokalaemic conditions.