These results suggest that the presence of male sex steroid hormones in male rabbits helps to suppress rate- and drug-induced delays in cardiac repolarization. DHT action produces increased current densities for I(K1) and I(Kr) and a left-shift in the V(1/2) for I(Kr) that could account, at least in part, for the observed QTc differences between males and females. Since little change was seen in ventricular RERG gene expression, DHT action in the heart may influence I(Kr) via post-transcriptional and/or post-translational mechanisms.

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.

Tegaserod (HTF 919) is a new drug being developed for gastrointestinal motility disorders. Because other gastrointestinal prokinetic agents, such as cisapride and erythromycin, cause slowing of cardiac repolarization and have been implicated in the development of the potentially fatal ventricular arrhythmia, torsades de pointes, a study was initiated to determine whether tegaserod and its main human metabolite adversely influence cardiac repolarization. By using isolated Langendorff-perfused rabbit hearts, we show that QT intervals remain unchanged at concentrations of tegaserod from 0.5 to 10 microM. It was not until the tegaserod concentration was increased to 50 microM (roughly 500-5,000 times more concentrated than those typically found in human plasma after administration of recommended clinical dosages), that a small, but significant increase in the QT interval (12+/-4%; p < 0.05; n = 4) was observed. No significant changes in QT occurred in the presence of the tegaserod metabolite at any of the concentrations tested (0.5-50 microM). In contrast, cisapride caused QT lengthening at concentrations as low as 0.1 microM, with significant QT increases occurring when 5-50 microM cisapride was used (22+/-4% to >70%, respectively; p < 0.01; n = 4). Erythromycin also caused significant lengthening of QT intervals (11+/-2%; p < 0.001; n = 4), although 100 microM concentrations of this drug were required to achieve this effect. These results demonstrate that both cisapride and erythromycin can slow cardiac repolarization at therapeutic doses and that tegaserod's lack of QT prolongation at therapeutic doses suggests that it has the potential to be a safer alternative to cisapride as a gastrointestinal prokinetic agent.

No abstract