Blockade of the pre- and postjunctional effects of angiotensin in vivo with a non-peptide angiotensin receptor antagonist.
Blockade of the pre- and postjunctional effects of angiotensin in vivo with a non-peptide angiotensin receptor antagonist.
复制标题
用非肽血管紧张素受体拮抗剂阻断体内血管紧张素的连接前和连接后作用。
DOI：
10.1016/0024-3205(90)90096-a
复制
发表时间：
1990
期刊：
影响因子：
6.1
通讯作者：
Inagami,T
中科院分区：
文献类型：
--
作者：
Jackson,EK;Inagami,T
最近的报道表明，一些咪唑-5-乙酸衍生物是血管紧张素II受体的竞争性拮抗剂。然而，据我们所知，没有关于以下方面的公开信息：1）这些非肽血管紧张素受体阻断剂的恒定输注速率对于有效拮抗体内血管紧张素受体是必需的，2）咪唑-5-乙酸衍生物是否拮抗连接前和连接后血管紧张素受体，和3）这些化合物的有效水平是否发挥非特异性作用和/或部分激动剂活性。为了解决这些问题，将溶媒2-丁基-4-氯-1-（2-硝基苄基）咪唑-5-乙酸（CV-2961; 30和100 μg/min）或标准血管紧张素受体阻滞剂1 Sar 8Ile-血管紧张素II（100 ng/min）静脉输注至准备进行肠系膜血管床原位灌注的卡托普利处理大鼠中。CV-2961输注2.5小时未改变动脉血压、肠系膜灌注压、血浆醛固酮水平或肠系膜血管对交感神经刺激或外源性去甲肾上腺素的反应。较高剂量的CV-2961（100 μg/min）完全阻断血管紧张素II诱导的交感神经刺激血管反应增强，并使血管紧张素II诱导的肠系膜灌注压升高的血管紧张素剂量-反应曲线向右移动10倍。较低剂量CV-2961（30 μg/min）对血管紧张素II的这些作用的影响无统计学意义。1 Sar 8Ile-血管紧张素II消除了血管紧张素II的连接前和连接后作用。我们得出结论，在完整大鼠中，以100 μg/min输注CV-2961，拮抗连接前和连接后血管紧张素II受体，但对血管紧张素II的连接前作用有更大的影响。CV-2961无部分激动剂活性，CV-2961无明显的非特异性作用。咪唑-5-乙酸衍生物可作为药理学探针和治疗剂发现相当大的实用性。
Recent reports indicate that some imidazole-5-acetic acid derivatives are competitive antagonists of angiotensin II receptors. However, to our knowledge, there is no published information regarding: 1) what constant infusion rate of these non-peptide angiotensin receptor blockers is necessary to effectively antagonize angiotensin receptorsin vivo, 2) whether imidazole-5-acetic acid derivatives antagonize both prejunctional and postjunctional angiotensin receptors, and 3) whether effective levels of these compounds exert non-specific actions and/or partial agonist activity. To address these issues, either vehicle, 2-butyl-4-chloro-1-(2-nitrobenzyl) imidazole-5-acetic acid (CV-2961; 30 and 100 μg/min) or a standard angiotensin receptor blocker,1Sar8Ile-angiotensin II (100 ng/min), was infused intravenously into captopril-treated rats that were prepared forin situperfusion of their mesenteric vascular beds. Infusion of CV-2961 for two and one-half hours did not alter arterial blood pressure, mesenteric perfusion pressure, plasma aldosterone level, or mesenteric vascular responses to sympathetic nerve stimulation or exogenous norepinephrine. The higher dose of CV-2961 (100 μg/min) completely blocked angiotensin II-induced enhancement of vascular responses to sympathetic nerve stimulation and shifted the angiotensin dose-response curve 10-fold to the right with respect to angiotensin II-induced increases in mesenteric perfusion pressure. The effects of the lower dose of CV-2961 (30 μg/min) on these actions of angiotensin II were not statistically significant.1Sar8Ile-angiotensin II abolished both the prejunctional and postjunctional effects of angiotensin II. We conclude that in intact rats CV-2961, infused at 100 μg/min, antagonizes both prejunctional and postjunctional angiotensin II receptors, yet has a somewhat greater effect on the prejunctional actions of angiotensin II. CV-2961 is devoid of partial agonist activity, and no non-specific actions of CV-2961 are evident. Imidazole-5-acetic acid derivatives may find considerable utility as pharmacological probes and as therapeutic agents.