The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I HERG in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC 50 Ͻ 0.1 M) included lidoflazine, terfenadine, and haloperidol; moderatepotency blockers (0.1 M Ͻ IC 50 Ͻ 1 M) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC 50 Ͼ 1 M) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC 50 Ͼ 300 M) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (Ͻ30 min of drug exposure per measurement). Since two of the drugs that were ineffective I HERG blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I HERG .

Nicotinic acetylcholine receptors are pentameric, typically being composed of two or more different subunits. To investigate which receptor subtypes are active in the heart, we initiated a series of experiments using an isolated perfused rat heart (Langendorff) preparation. Nicotine administration (100 M) caused a brief decrease (Ϫ7 Ϯ 2%) followed by a much larger increase (17 Ϯ 5%) in heart rate that slowly returned to baseline within 10 to 15 min. The nicotine-induced decrease in heart rate could be abolished by an ␣7-specific antagonist, ␣-bungarotoxin (100 nM). In contrast, the nicotine-induced increase in heart rate persisted in the presence of ␣-bungarotoxin. These results suggest that the nicotinic acetylcholine receptors (nAChRs) that mediate the initial decrease in heart rate probably contain ␣7 subunits, whereas those that mediate the increase in heart rate probably do not contain ␣7 subunits. To investigate which subunits may contribute to the nicotine-induced increase in heart rate, we repeated our experiments with cytisine, an agonist at nAChRs that contain ␤4 subunits. The cytisine results were similar to those obtained with nicotine, thereby suggesting that the nAChRs on sympathetic nerve terminals in the heart probably contain ␤4 subunits. Thus, the results of this study show that pharmacologically distinct nAChRs are responsible for the differential effects of nicotine on heart rate. More specifically, our results suggest that ␣7 subunits participate in the initial nicotine-induced heart rate decrease, whereas ␤4 subunits help to mediate the subsequent nicotine-induced rise in heart rate.