Background and purpose: Bradykinin [BK-(1-9)] is an endogenous peptide involved in many physiological and pathological processes, such as cardiovascular homeostasis and inflammation. The central dogma of the kallikrein-kinin system is that BK-(1-9) fragments are biologically inactive. In this manuscript, we proposed to test whether these fragments were indeed inactive. Experimental Approach: Nitric oxide (NO) was quantified in human, mouse and rat cells loaded with DAF-FM after stimulation with BK-(1-9), BK-(1-7), BK-(1-5) and BK-(1-3). We used adult male rat aortic ring preparation to test vascular reactivity mediated by BK-(1-9) fragments. Changes in blood pressure and heart rate was measured in conscious adult male rats by intraarterial catheter method. Key results: BK-(1-9) induced NO production in all cell types tested by B2 receptor activation. BK-(1-7), BK-(1-5) and BK-(1-3) also induced NO production in all tested cell types but this response was independent of the activation of B1 receptor and/or B2 receptor. BK-(1-7), BK-(1-5) or BK-(1-3) induced only vasorelaxant effect and in a concentration-dependent fashion. Vasorelaxant effects for BK-(1-7), BK-(1-5) or BK-(1-3) were independent of the kinin receptors. Different administration routes (i.e., intravenous or intra-arterial) did not affect the observed hypotension induced by BK-(1-7), BK-(1-5) or BK-(1-3). Importantly, these observations diverged from the BK-(1-9) results, highlighting that indeed the BK-(1-9) fragments do not seem to act via the classical kinin receptors. Conclusions and implications: In conclusion, BK-(1-7), BK-(1-5) and BK-(1-3) are biologically active components of the kallikrein-kinin system. Importantly, observed pathophysiological outcomes of these peptides are independent of B1R and/or B2R activation.

中文翻译：

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激肽释放酶激肽系统被分解：缓激肽片段是生物活性肽

背景与目的：缓激肽[BK-（1-9）]是一种内源性肽，参与许多生理和病理过程，例如心血管稳态和炎症。激肽释放酶激肽系统的中心教条是BK-（1-9）片段在生物学上没有活性。在本手稿中，我们建议测试这些片段是否确实无效。实验方法：用BK-（1-9），BK-（1-7），BK-（1-5）和BK刺激后，在装有DAF-FM的人，小鼠和大鼠细胞中对一氧化氮（NO）进行定量-（1-3）。我们使用成年雄性大鼠主动脉环制剂来测试由BK-（1-9）片段介导的血管反应性。通过动脉内导管法测量了成年雄性成年大鼠的血压和心率变化。主要结果：BK-（1-9）诱导通过B2受体活化测试的所有细胞类型均产生NO。BK-（1-7），BK-（1-5）和BK-（1-3）在所有测试的细胞类型中均诱导NO生成，但该反应与B1受体和/或B2受体的激活无关。BK-（1-7），BK-（1-5）或BK-（1-3）仅诱导血管舒张作用，且呈浓度依赖性。BK-（1-7），BK-（1-5）或BK-（1-3）的血管舒张作用独立于激肽受体。不同的给药途径（即静脉内或动脉内）不影响观察到的由BK-（1-7），BK-（1-5）或BK-（1-3）引起的低血压。重要的是，这些观察结果与BK-（1-9）的结果背道而驰，突出表明确实BK-（1-9）片段似乎并不通过经典激肽受体起作用。结论与启示：总之，BK-（1-7），BK-（1-5）和BK-（1-3）是激肽释放酶激肽系统的生物活性成分。重要的是，观察到的这些肽的病理生理结果与B1R和/或B2R激活无关。