Doggrell Sheila A, Nand Vinita
Cardiovascular Pharmacology Group, Faculty of Medicine and Health Science, The University of Auckland, New Zealand.
J Pharm Pharmacol. 2002 May;54(5):707-15. doi: 10.1211/0022357021778862.
The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at < or = 3 x 10(-5) M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10(-6) to 3 x 10(-5) M relaxed the KCl-contracted aorta. Dofetilide at 10(-9)-10(-7) M augmented the force of contraction of leftventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17-21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12- and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10(-7)-10(-5) M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.
目的是测试多非利特是否具有用于治疗心力衰竭的潜力。浓度≤3×10⁻⁵ M的多非利特对静息的Wistar Kyoto（WKY）大鼠主动脉、肠系膜动脉和叶内动脉或WKY大鼠门静脉的自发收缩没有影响。浓度为10⁻⁶至3×10⁻⁵ M的多非利特可使氯化钾收缩的主动脉舒张。浓度为10⁻⁹至10⁻⁷ M的多非利特可增强12月龄和18月龄WKY大鼠左心室条带在2 Hz频率下的收缩力。12月龄和17至21月龄的自发性高血压大鼠（SHR）分别是心脏肥大和心力衰竭的模型。多非利特在2 Hz频率下增强收缩力的作用在12月龄和18月龄的WKY大鼠以及12月龄的SHR中相似，但在18月龄的SHR左心室中减弱。在更高的生理频率4 Hz下，增强21月龄SHR左心室力反应所需的多非利特阈值浓度显著增加，最大增强作用降低。浓度为10⁻⁷至10⁻⁵ M的多非利特可降低17月龄WKY大鼠右心房的心率，对年龄匹配的SHR右心房也有类似作用。总之，多非利特在大鼠中是一种正性肌力药和负性变时性药物。然而，由于在心力衰竭的生理频率下，临床相关浓度未观察到正性肌力作用，多非利特不太可能作为正性肌力药用于治疗心力衰竭。
