Bikhazi A B, Haddad R E, Nahle Z A, Bitar K M
Departments of Physiology, Surgery, and Physics, American University of Beirut, Lebanon.
J Pharm Sci. 1998 Nov;87(11):1363-7. doi: 10.1021/js980061j.
Peptide delivery toward its targets in an intact organ is equally as important as its routing from the systemic circulation to cell surface receptor sites. A physical model pertinent to a heart perfusion technique in Sprague-Dawley rats is presented describing reversible binding of angiotensin II and/or antagonist (DUP 753, losartan) with the microvascular endothelial receptor subtypes as well as with the cardiac myocyte receptor subtypes that are exposed to the perfusate by CHAPS-treatment. Analysis of the collected effluents are curve-fitted with a conservation equation and a first-order Bessel function. The results suggest that angiotensin II delivery and binding to the pool of receptor subtypes both at the level of the microvascular endothelium and cardiac myocyte sites differ marginally in binding affinities. The findings postulate that angiotensin II can have access to the myocyte site in an intact heart by an endothelial angiotensin II-receptor-internalization process. In addition, considering that the AT1- and AT2-receptor subtypes are present in equal proportions and have equal binding affinities with angiotensin II, the results of the 3H-DUP 753 binding indicated approximately 3-3.5 times higher affinity to the AT1-receptors subtype than angiotensin II at both the endothelial and myocyte sites. In the presence of losartan, angiotensin II binding showed higher affinity with the exposed unopposed AT2-receptor subtype than with the receptor pool, which could be due to alterations in the AT2-receptor structure and configuration. This increase in the binding affinity of angiotensin II with the AT2-receptor subtype may be categorized under the direct effect of the AT1-antagonist modality in producing cardioprotective effects.
肽向完整器官中的靶标递送与其从体循环到细胞表面受体位点的途径同样重要。本文提出了一个与Sprague-Dawley大鼠心脏灌注技术相关的物理模型，描述了血管紧张素II和/或拮抗剂（DUP 753，氯沙坦）与微血管内皮受体亚型以及经CHAPS处理后暴露于灌注液中的心肌细胞受体亚型的可逆结合。对收集的流出物进行分析，并使用守恒方程和一阶贝塞尔函数进行曲线拟合。结果表明，血管紧张素II在微血管内皮和心肌细胞位点向受体亚型池的递送和结合在结合亲和力上略有不同。研究结果推测，血管紧张素II可以通过内皮血管紧张素II受体内化过程进入完整心脏中的心肌细胞位点。此外，考虑到AT1和AT2受体亚型以相等的比例存在，并且与血管紧张素II具有相等的结合亲和力，3H-DUP 753结合结果表明，在内皮和心肌细胞位点，其对AT1受体亚型的亲和力比血管紧张素II高约3-3.5倍。在氯沙坦存在的情况下，血管紧张素II与暴露的未被占据的AT2受体亚型的结合亲和力高于与受体池的结合亲和力，这可能是由于AT2受体结构和构象的改变。血管紧张素II与AT2受体亚型结合亲和力的这种增加可能属于AT1拮抗剂产生心脏保护作用的直接效应范畴。
