Richard V, Berdeaux A, Giudicelli J F
Département de Pharmacologie, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.
J Cardiovasc Pharmacol. 1993 Jul;22(1):52-7. doi: 10.1097/00005344-199307000-00009.
The effects of EXP3174 (0.03-0.3 mg/kg), the active metabolite of the angiotensin II (AII) receptor antagonist losartan, on systemic and coronary hemodynamics as well as on regional myocardial blood flow (radioactive microspheres) were evaluated in anesthetized, open-chest dogs with or without preactivated renin-angiotensin system (RAS) (furosemide treatment). These effects were compared with those of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat (0.1-1 mg/kg). In dogs without preactivated RAS, EXP3174 or enalaprilat did not exert marked hemodynamic effects other did not exert marked hemodynamic effects other than a significant decrease in mean arterial blood pressure (MAP) at the highest doses. In dogs with preactivated RAS, EXP3174 induced a marked, dose-dependent decrease in MAP (maximum decrease -23 +/- 7%), associated with a significant decrease in total peripheral resistance (TPR), whereas cardiac output (CO), heart rate (HR), and left ventricular dP/dt remained unchanged. At the coronary level, EXP3174 induced a decrease in mean coronary resistance that paralleled that of AP. Similar systemic and coronary hemodynamic effects were obtained with enalaprilat administered at doses three times higher. However, regional myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural) or its transmural distribution (endo/epi ratios) was not affected by EXP3174 or enalaprilat. Thus, these results indicate that blockade of the AT1 receptor of AII by EXP3174 induces hemodynamic modifications similar to those evoked by the ACE inhibitor enalaprilat. The lack of effect of EXP3174 or enalaprilat on regional myocardial blood flow (RMBF) suggests, however, that the RAS does not play a role in regulation of myocardial tissue perfusion.
在麻醉开胸犬中，评估了血管紧张素II（AII）受体拮抗剂氯沙坦的活性代谢产物EXP3174（0.03 - 0.3毫克/千克）对全身和冠状动脉血流动力学以及局部心肌血流量（放射性微球）的影响，这些犬分为肾素 - 血管紧张素系统（RAS）预激活（速尿治疗）和未预激活两组。将这些影响与血管紧张素转换酶（ACE）抑制剂依那普利拉（0.1 - 1毫克/千克）的影响进行比较。在未预激活RAS的犬中，EXP3174或依那普利拉除了在最高剂量时使平均动脉血压（MAP）显著降低外，未产生明显的血流动力学影响。在预激活RAS的犬中，EXP3174引起MAP显著的剂量依赖性降低（最大降低 - 23±7%），同时总外周阻力（TPR）显著降低，而心输出量（CO）、心率（HR）和左心室dP/dt保持不变。在冠状动脉水平，EXP3174引起平均冠状动脉阻力降低，与MAP降低平行。给予高三倍剂量的依那普利拉可获得类似的全身和冠状动脉血流动力学效应。然而，通过微球技术评估的局部心肌组织灌注（无论是心内膜下、心外膜下还是透壁）或其透壁分布（内膜/外膜比率）不受EXP3174或依那普利拉的影响。因此，这些结果表明，EXP3174对AII的AT1受体的阻断诱导了与ACE抑制剂依那普利拉引起的类似的血流动力学改变。然而，EXP3174或依那普利拉对局部心肌血流量（RMBF）缺乏影响表明，RAS在心肌组织灌注调节中不起作用。
