ANGIOTENSIN II AND BRADYKININ IN CARDIAC HYPERTROPHY

产品说明：（改编自研究者摘要）血管紧张素转换酶（ACE）抑制剂的心脏保护作用的机制最可能涉及血管紧张素II（ANG II）的产生减少和缓激肽（BK）的积累，而ANG II 1型（AT 1）受体拮抗剂（AT 1-ant）的有益作用是通过阻断AT 1受体介导的。越来越多的证据表明，在ACE抑制剂和AT 1-ant治疗期间增加的ANG肽可能产生通过BK形成介导的共同作用机制。此外，肾素-血管紧张素系统（RAS）和激肽释放酶-激肽系统（KKS）被血液动力学应激同时激活，在心脏中产生增加的ANG II和BK水平。使用微透析的新技术，在体内的狗心脏的间质液（ISF）空间采样，PI已经证明，输注卡托普利到正常狗心脏的ISF空间导致ISF BK水平增加2.5倍，为ACE抑制剂在体内增强BK提供了证据。此外，将ANG I和ANG-（1-7）输注到正常狗心脏的ISF空间中分别导致ISF BK增加15倍和60倍，这为ANG肽在体内增强BK提供了证据。目前提出的假设是ANG II通过激活AT 2受体或ANG-（1-7）形成与BK形成相关，并且该机制对犬心脏的心肌功能和结构具有重要影响。将在正常条件下、急性血流动力学应激和通过实验诱导的二尖瓣复流的慢性容量超负荷肥大下对犬进行研究。在本建议中使用犬模型的益处是RAS/糜酶ANG II形成机制与人类心脏的相似性，以及慢性MR犬模型中RAS/糜酶组分的充分记录的上调。利用微透析技术对心脏的ISF空间进行采样，提供了对肌细胞和成纤维细胞在体内暴露的环境的直接评估。在AT 1-ant、BK 2-ant和ACE抑制剂治疗期间，体内ISF ANG II、ANG-（1-7）和BK将与心肌功能、间质胶原以及RAS和KKS组分的表达相关。

DESCRIPTION: (Adapted from the Investigator's Abstract) The mechanisms responsible for the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors most likely involve both reduced production of angiotensin II (ANG II) and accumulation of bradykinin (BK), while the beneficial effect of ANG II type-1 (AT1) receptor antagonists (AT1-ant) is mediated by blockade of the AT1 receptor. There is mounting evidence that increased ANG peptides during ACE inhibitor and AT1-ant therapies may produce a common mechanism of action mediated via BK formation. Further, the renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are simultaneously activated by hemodynamic stress, producing increased ANG II and BK levels in the heart. Using the novel technique of microdialysis to sample the interstitial fluid (ISF) space of the dog heart in vivo, the PI has demonstrated that infusion of captopril into the ISF space of the normal dog heart resulted in a 2.5-fold increase in ISF BK levels, providing evidence for in vivo potentiation of BK by ACE inhibitor. Moreover, infusion of ANG I and ANG-(1-7) into the ISF space of the normal dog heart resulted in a 15-fold and 60-fold increase in ISF BK, respectively, providing evidence for in vivo potentiation of BK by ANG peptides. The hypothesis of the current proposal is that ANG II is linked to BK formation either by activation of the AT2 receptor or ANG-(1-7) formation and that this mechanism has important effects on myocardial function and structure in the dog heart. Studies will be performed in the dog under normal conditions, acute hemodynamic stress and chronic volume overload hypertrophy by experimentally induced mitral regurgiation. The benefits of using the dog model in this proposal are the similarities of RAS/chymase ANG II forming mechanisms to the human heart and the well documented upregulation of RAS/chymase components in the dog model of chronic MR. Utilization of the microdialysis technique to sample the ISF space of the heart provides a direct assessment of the milieu to which the myocytes and fibroblasts are exposed in vivo. In vivo ISF ANG II, ANG-(1-7), and BK will be related to myocardial function, interstitial collagen, and expression of RAS and KKS components during AT1-ant, BK2-ant, and ACE inhibitor treatments.