Desjardins S, Cauchy M J
Biopharmaceutics and Pharmacodynamics Division, Bureau of Drug Research, Health Protection Branch, Ottawa, Ontario, Canada.
Drug Chem Toxicol. 1995 Feb;18(1):43-59. doi: 10.3109/01480549509017857.
The rat has been shown to be resistant to the inotropic action of milrinone. We compared in conscious rats, the effects of an i.v. infusion of milrinone (0.3 mg/kg/min), a phosphodiesterase (PDE) inhibitor to those of nitroprusside (50 micrograms/kg/min), a pure vasodilator, on blood pressure and dP/dtmax to determine whether or not an inherent positive inotropic effect of milrinone is offset by its powerful hypotensive action. For the first 10 min of infusion, we found no differences in dP/dtmax, (the first derivative of the left ventricular pressure (LVP), an index of contractility) for equihypotensive doses of milrinone or nitroprusside. A second objective of this study was to determine if milrinone-induced ventricular fibrillation (VF) is due to cardiac ischemia which could be associated with the profound hypotension induced by the drug. Milrinone infusion was accompanied by a significant QTc interval (QT corrected for heart rate) prolongation. VF and death occurred in 5/6 rats at total doses varying from 3.6 to 20.1 mg/kg infused over 12 to 67 min respectively. Premature ventricular contractions (PVCs) were noted in all 6 milrinone infused rats during the first min. of infusion. No arrhythmias were noted during the 2 hour i.v. infusion with nitroprusside. A direct action on the heart is postulated to explain, at least partially, the milrinone-induced VF since nitroprusside had a similar hypotensive action but no effect on the ECG. We conclude that the rat, in analogy to patients with severe cardiac failure, might be resistant to the inotropic action of milrinone but is sensitive to its vasodilatory and arrhythmogenic effects.
已证明大鼠对米力农的正性肌力作用具有抗性。我们在清醒大鼠中比较了静脉输注米力农（0.3毫克/千克/分钟）（一种磷酸二酯酶（PDE）抑制剂）和硝普钠（50微克/千克/分钟）（一种纯血管扩张剂）对血压和dP/dtmax的影响，以确定米力农固有的正性肌力作用是否被其强大的降压作用所抵消。在输注的前10分钟，我们发现等降压剂量的米力农或硝普钠在dP/dtmax（左心室压力（LVP）的一阶导数，收缩性指标）方面没有差异。本研究的第二个目的是确定米力农诱导的室性心动过速（VF）是否归因于心脏缺血，这可能与该药物引起的严重低血压有关。输注米力农伴随着显著的QTc间期（校正心率后的QT）延长。分别在12至67分钟内输注总剂量为3.6至20.1毫克/千克时，6只大鼠中有5只发生VF和死亡。在输注米力农的所有6只大鼠中，在输注的第一分钟内均记录到室性早搏（PVCs）。在硝普钠静脉输注2小时期间未观察到心律失常。推测米力农对心脏有直接作用，至少部分地解释了米力农诱导的VF，因为硝普钠有类似的降压作用，但对心电图无影响。我们得出结论，与严重心力衰竭患者类似，大鼠可能对米力农的正性肌力作用具有抗性，但对其血管扩张和致心律失常作用敏感。
