Hamlin Robert L, Kijtawornrat Anusak, Keene Bruce W, Hamlin David M
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
Toxicol Sci. 2003 Dec;76(2):437-42. doi: 10.1093/toxsci/kfg254. Epub 2003 Nov 4.
A facile system for obtaining electrocardiograms from conscious animals was used to conduct studies on 12 animals studied both conscious and anesthetized, on 4 conscious animals given vehicle (0.5% methylcellulose) and QT-lengthening test articles, and on 6 animals given test articles thought to not lengthen QTc. In 12 animals whose ECGs were monitored via a bipolar transthoracic ECG, heart rates were slowed with 1.0 mg/kg zatebradine, while they were conscious in their slings, and after being anesthetized with ketamine/xylazine. The following regression equations were obtained relating QT to RR: QT = 44.7 ln RR - 132.9, r2 = 0.7, for conscious animals; QT = 79.4 ln RR - 287.4, r2 = 0.8 for anesthetized animals, with RR intervals varying between 150 and 550 ms. The anesthetic increases QT at all RR intervals (p < 0.001), but does not change the slope of the relationship between QT and RR when compared with the conscious guinea pig. The Fridericia method was best for correcting QT for RR interval in conscious guinea pigs, but the Bazett method was best for correcting in anesthetized animals. QTc lengthened significantly in all conscious guinea pigs given, orally, cisapride, ketoconazole, and sotalol (positive test articles) and did not change with methylcellulose (the vehicle) or with propranolol, verapamil, or enalapril (negative controls). These techniques and relationships demonstrate that this methodology may be useful in exploring torsadogenic effects of novel pharmacological entities.
一种用于从清醒动物获取心电图的简易系统被用于对12只清醒和麻醉状态下均进行研究的动物、4只给予赋形剂（0.5%甲基纤维素）和QT延长测试品的清醒动物以及6只给予被认为不会延长QTc的测试品的动物进行研究。在12只通过双极经胸心电图监测心电图的动物中，给予1.0 mg/kg扎替雷定后，无论是在吊床中清醒时还是用氯胺酮/赛拉嗪麻醉后，心率均减慢。得到了以下将QT与RR相关联的回归方程：对于清醒动物，QT = 44.7 ln RR - 132.9，r2 = 0.7；对于麻醉动物，QT = 79.4 ln RR - 287.4，r2 = 0.8，RR间期在150至550毫秒之间变化。麻醉会使所有RR间期的QT增加（p < 0.001），但与清醒豚鼠相比，不会改变QT与RR之间关系的斜率。弗里德里西亚方法最适合校正清醒豚鼠RR间期的QT，但巴泽特方法最适合校正麻醉动物的QT。所有口服西沙必利、酮康唑和索他洛尔（阳性测试品）的清醒豚鼠QTc均显著延长，而给予甲基纤维素（赋形剂）或普萘洛尔、维拉帕米或依那普利（阴性对照）时QTc未改变。这些技术和关系表明，该方法可能有助于探索新型药理实体的致扭转型室性心动过速作用。
