Nolly H, Miatello R, Damiani M T, Abate C D
Laboratory of Experimental Hypertension and Vasoactive Substances, School of Medicine and National Council of Research, Mendoza, Argentina.
Immunopharmacology. 1997 Jun;36(2-3):185-91. doi: 10.1016/s0162-3109(97)00020-9.
The main objective of this study was to determine if the components of the kallikrein-kinin system are released into the venous effluent from isolated perfused rat hearts. To assess the contribution of kinins and the vascular and cardioprotective effects of the ACE inhibitor ramipril, we determined the status of cardiac kallikrein (CKK), potent kinin-generating enzyme, in rats with right ventricular hypertrophy induced by chronic volume overload and left ventricular hypertrophy by aortic banding. CKK was measured as previously described (Nolly, H.L., Carbini, L., Carretero, O.A., Scicli, A.G., 1994). Kininogen by a modification of the technique of Dinitz and Carvalho (1963) and kinins were extracted with a Sep-Pak C18 cartridge and measured by RIA. CKK (169 +/- 9 pg Bk/30 min), kininogen (670 +/- 45 pg Bk/30 min) and immunoreactive kinins (62 +/- 10 pg Bk/30 min) were released into the perfusate. The release was almost constant over a 120 min period. Pretreatment with the protein synthesis inhibitor puromycin (10 mg i.p.) lowered the release of kallikrein (42 +/- 12 pg Bk/30 min, p < 0.001) and kininogen (128 +/- 56 pg Bk/30 min, p < 0.001). Addition of ramiprilat (10 micrograms/ml) increased kinin release from 54 +/- 18 to 204 +/- 76 pg Bk/30 min (p < 0.001). Aortic banding of rats increased their blood pressure (BP) (p < 0.001), relative heart weight (RHW) (p < 0.001) and CKK (p < 0.001). Ramipril treatment induced a reduction in BP (p < 0.05) and RHW (p < 0.005) while CKK remained elevated. Aortocaval shunts increased their ANF plasma levels (p < 0.05), RHW (p < 0.001) and CKK (p < 0.01). Ramipril treatment induced a reduction in RHW (p < 0.05), while CKK and ANF increased significantly (p < 0.05). The present data show that the components of the kallikrein-kinin system are continuously formed in the isolated rat heart and that ramipril reduces bradykinin breakdown with subsequent increase in bradykinin outflow. The experiments with aorta caval shunt and aortic banding show that cardiac tissues increase their kinin-generating activity and this was even higher in ramipril-treated animals. This may suggest that the actual level of kinins is finely tuned to the local metabolic demands. In this experimental model of cardiac hypertrophy. ACE inhibitors potentiate the actions of kinins and probably try to normalise endothelial cell function.
本研究的主要目的是确定激肽释放酶-激肽系统的成分是否会释放到离体灌注大鼠心脏的静脉流出液中。为了评估激肽的作用以及血管紧张素转换酶（ACE）抑制剂雷米普利的血管和心脏保护作用，我们测定了慢性容量超负荷诱导右心室肥厚和主动脉缩窄诱导左心室肥厚大鼠心脏激肽释放酶（CKK）的状态，CKK是一种高效的激肽生成酶。CKK的测定方法如前所述（诺利，H.L.，卡尔比尼，L.，卡雷tero，O.A.，西克利，A.G.，1994）。采用对迪尼茨和卡瓦略（1963）技术的改良方法测定激肽原，并用Sep-Pak C18柱提取激肽，通过放射免疫分析法（RIA）进行测定。CKK（169±9皮克缓激肽/30分钟）、激肽原（670±45皮克缓激肽/30分钟）和免疫反应性激肽（62±10皮克缓激肽/30分钟）被释放到灌注液中。在120分钟内，释放量几乎保持恒定。用蛋白质合成抑制剂嘌呤霉素（腹腔注射10毫克）预处理可降低激肽释放酶（42±12皮克缓激肽/30分钟，p<0.001）和激肽原（128±56皮克缓激肽/30分钟，p<0.001）的释放。加入雷米普利拉（10微克/毫升）可使激肽释放量从54±18皮克缓激肽/30分钟增加到204±76皮克缓激肽/30分钟（p<0.001）。大鼠主动脉缩窄会使其血压（BP）升高（p<0.001）、相对心脏重量（RHW）增加（p<0.001）以及CKK升高（p<0.001）。雷米普利治疗可使血压降低（p<0.05）、RHW降低（p<0.005），而CKK仍保持升高。主动脉腔静脉分流可使大鼠心房钠尿肽（ANF）血浆水平升高（p<0.05）、RHW增加（p<0.001）以及CKK升高（p<0.01）。雷米普利治疗可使RHW降低（p<0.05），而CKK和ANF显著增加（p<0.05）。目前的数据表明，激肽释放酶-激肽系统的成分在离体大鼠心脏中持续形成，雷米普利可减少缓激肽的降解，随后缓激肽流出增加。主动脉腔静脉分流和主动脉缩窄实验表明，心脏组织的激肽生成活性增加，在雷米普利治疗的动物中这种增加更为明显。这可能表明激肽的实际水平会根据局部代谢需求进行精细调节。在这个心脏肥大的实验模型中，ACE抑制剂增强了激肽的作用，可能试图使内皮细胞功能恢复正常。
