Bachert E L, Fung H L
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
J Cardiovasc Pharmacol. 1993 May;21(5):781-5. doi: 10.1097/00005344-199305000-00014.
We tested whether nicorandil (NCR), a nitrovasodilator which also possesses K+ channel action, will produce in vivo hemodynamic tolerance commonly observed with other nitrovasodilators such as nitroglycerin (NTG). NCR was infused at 50 micrograms/kg/min for 10 h through a femoral cannula into conscious rats (n = 5) with congestive heart failure (CHF). Left ventricular end-diastolic pressure (LVEDP), LV peak-systolic pressure (LVPSP), and heart rate (HR) were measured periodically through an implanted catheter. Under these conditions, NCR produced a 40% reduction (p < 0.05) in LVEDP from baseline at 40 min after the start of the infusion. This reduction lasted approximately 6 h, followed by a slow return to baseline between 6 and 10 h. LVPSP was reduced (p < 0.05) from 2 h and leveled at approximately 8 h. HR increased by 12% from baseline at 40 min (p < 0.05). Plasma NCR concentrations were identical at 5 h (pretolerant state) and at 10 h (tolerant state) in these animals, suggesting that plasma pharmacokinetics were unrelated to NCR pharmacodynamics. NCR kinetics were not changed by the presence of CHF. Thus, in this animal model, tolerance to NCR developed in LVEDP but not LVPSP, and the K+ channel action of NCR apparently could not prevent tolerance development to venodilation arising from nitrate action.
我们测试了尼可地尔（NCR），一种兼具钾通道作用的硝基血管扩张剂，是否会像硝酸甘油（NTG）等其他硝基血管扩张剂那样产生体内血流动力学耐受性。通过股动脉插管，以50微克/千克/分钟的速度向患有充血性心力衰竭（CHF）的清醒大鼠（n = 5）输注NCR，持续10小时。通过植入的导管定期测量左心室舒张末期压力（LVEDP）、左心室收缩压峰值（LVPSP）和心率（HR）。在这些条件下，输注开始后40分钟，NCR使LVEDP较基线水平降低了40%（p < 0.05）。这种降低持续了约6小时，随后在6至10小时之间缓慢恢复到基线水平。LVPSP从2小时开始降低（p < 0.05），并在约8小时趋于平稳。HR在40分钟时较基线水平增加了12%（p < 0.05）。这些动物在5小时（预耐受状态）和10小时（耐受状态）时血浆NCR浓度相同，表明血浆药代动力学与NCR药效学无关。CHF的存在并未改变NCR的动力学。因此，在该动物模型中，LVEDP出现了对NCR的耐受性，但LVPSP未出现，并且NCR的钾通道作用显然无法阻止因硝酸盐作用引起的静脉扩张耐受性的发展。
