ANGIOTENSIN II AND BRADYKININ IN CARDIAC HYPERTROPHY

血管紧张素转换酶(ACE)抑制剂的心脏保护作用的机制很可能既涉及血管紧张素II(Ang II)的减少，又涉及缓激肽(BK)的积累，而Ang II 1型(AT1)受体拮抗剂(AT1-ANT)的有益作用是通过阻断AT1受体介导的。越来越多的证据表明，在ACE抑制剂和AT1-ANT治疗过程中增加的Ang多肽可能通过BK的形成而产生共同的作用机制。此外，血流动力学应激同时激活肾素-血管紧张素系统(RAS)和激肽释放酶-激动素系统(KKS)，从而在心脏产生更高的Ang II和BK水平。应用微透析技术对犬心脏间质液(ISF)间隙进行活体取样，PI证实正常犬心脏ISF间隙注入卡托普利后，ISF BK水平增加2.5倍，为血管紧张素转换酶(ACE)抑制剂在体内增强BK活性提供了证据。此外，将Ang I和Ang-(1-7)注入正常犬心脏ISF间隙，可使ISF BK分别增加15倍和60倍，为Ang多肽在体内增强BK提供了证据。目前的假设是，Ang II通过激活AT2受体或Ang-(1-7)形成与BK的形成有关，这一机制对犬心脏的心肌功能和结构有重要影响。研究将在正常情况下，急性血流动力学应激和慢性容量超负荷肥厚的实验诱导的二尖瓣关闭。在这项建议中使用犬模型的好处是RAS/Chymase Ang II形成机制与人类心脏相似，以及在慢性MR犬模型中RAS/Chymase组分上调的充分证据。利用微透析技术采样心脏的ISF间隙提供了对心肌细胞和成纤维细胞在体内暴露的环境的直接评估。在体内，在AT1-ANT、BK2-ANT和ACE抑制剂治疗期间，ISF-Ang II、Ang-(1-7)和BK可能与心肌功能、间质胶原以及RAS和KKS组分的表达有关。

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.