匹莫苯丹（UD-CG 115 BS）及其O-去甲基代谢物UD-CG 212 Cl在清醒猪体内的全身血流动力学作用。

Systemic haemodynamic actions of pimobendan (UD-CG 115 BS) and its O-demethylmetabolite UD-CG 212 Cl in the conscious pig.

作者信息

Duncker D J, Hartog J M, Levinsky L, Verdouw P D

出版信息

Br J Pharmacol. 1987 Jul;91(3):609-15. doi: 10.1111/j.1476-5381.1987.tb11254.x.

DOI:10.1111/j.1476-5381.1987.tb11254.x

PMID:3607369

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1853547/

Abstract

The cardiovascular effects of the pyridazinone-derivatives pimobendan and its O-demethylmetabolite UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole HCl) were studied in conscious pigs, employing consecutive intravenous 10 min infusions of 10, 25, 50 and 100 micrograms kg-1 min-1 and 2, 4 and 8 micrograms kg-1 min-1 respectively. Pimobendan caused dose-dependent increases in LVdP/dtmax (up to 115%) and heart rate (up to 30%), while cardiac output was slightly elevated (up to 15%) and stroke volume decreased by 12%. Left ventricular end-diastolic pressure decreased in a dose-related manner from 8.7 +/- 1.0 mmHg to 2.7 +/- 1.7 mmHg. Mean arterial blood pressure was not significantly affected because systemic vascular resistance decreased dose-dependently up to 15%. After beta-adrenoceptor blockade, the pimobendan-induced increases in heart rate and cardiac output were attenuated and the increase in LVdP/dtmax almost abolished. The responses of left ventricular end-diastolic and mean arterial blood pressure, systemic vascular resistance and stroke volume were not modified. UD-CG 212 Cl caused dose-related increases in LVdP/dtmax (up to 100%) and heart rate (up to 25%). Cardiac output was minimally elevated (up to 8%) as stroke volume decreased dose-dependently up to 15%. As systemic vascular resistance decreased up to 12%, mean arterial blood pressure was slightly reduced (5%). Left ventricular end-diastolic blood pressure decreased dose-dependently from 9.0 +/- 0.8 mmHg to 3.8 +/- 1.3 mmHg. After beta-adrenoceptor blockade, the UD-CG 212 Cl-induced increases in heart rate and LVdP/dtmax were attenuated and almost abolished and amounted up to 15% and 20%, respectively. The responses of the other systemic haemodynamic parameters were not significantly modified. We conclude that pimobendan and UD-CG 212 Cl are compounds with marked positive inotropic and venodilator properties in the conscious pig. The attenuation of the inotropic effects by pretreatment with propranolol strongly suggests that, in the conscious pig, the beta-adrenergic system is significantly involved in the positive inotropic actions. The lack of effect of beta-adrenoceptor blockade on the vasodilator responses to both compounds suggest a mechanism not related to beta-adrenergic activity.

摘要

在清醒猪身上研究了哒嗪酮衍生物匹莫苯丹及其O-去甲基代谢物UD-CG 212 Cl（2-(4-羟基苯基)-5-(5-甲基-3-氧代-4,5-二氢-2H-哒嗪-6-基)苯并咪唑盐酸盐）的心血管效应，分别以10、25、50和100微克/千克·分钟-1以及2、4和8微克/千克·分钟-1的剂量连续静脉输注10分钟。匹莫苯丹使左心室压力最大上升速率（LVdP/dtmax）呈剂量依赖性增加（高达115%），心率升高（高达30%），而心输出量略有升高（高达15%），每搏输出量下降12%。左心室舒张末期压力以剂量相关方式从8.7±1.0 mmHg降至2.7±1.7 mmHg。平均动脉血压未受到显著影响，因为全身血管阻力剂量依赖性降低高达15%。β-肾上腺素能受体阻断后，匹莫苯丹引起的心率和心输出量增加减弱，LVdP/dtmax的增加几乎消失。左心室舒张末期和平均动脉血压、全身血管阻力和每搏输出量的反应未改变。UD-CG 212 Cl使LVdP/dtmax呈剂量相关增加（高达100%），心率升高（高达25%）。心输出量略有升高（高达8%），每搏输出量剂量依赖性降低高达15%。由于全身血管阻力降低高达12%，平均动脉血压略有降低（5%）。左心室舒张末期血压以剂量相关方式从9.0±0.8 mmHg降至3.8±1.3 mmHg。β-肾上腺素能受体阻断后，UD-CG 212 Cl引起的心率和LVdP/dtmax增加减弱并几乎消失，分别高达15%和20%。其他全身血流动力学参数的反应未显著改变。我们得出结论，在清醒猪中，匹莫苯丹和UD-CG 212 Cl是具有显著正性肌力和静脉扩张特性的化合物。用普萘洛尔预处理使正性肌力作用减弱，强烈提示在清醒猪中，β-肾上腺素能系统显著参与正性肌力作用。β-肾上腺素能受体阻断对这两种化合物的血管舒张反应无影响，提示其机制与β-肾上腺素能活性无关。