Nsa Allogho S, Gobeil F, Perron S I, Hess J F, Regoli D
Department of Pharmacology, Medical School, Université de Sherbrooke, Québec, Canada.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Mar;357(3):191-6. doi: 10.1007/pl00005157.
The aim of this study was to investigate the pharmacological profile of the kinin B1 and B2 receptors in isolated stomachs from wild-type control and B2 receptor knockout mice. Isometric contractions evoked by bradykinin (BK) (9 nM) and desArg9BK (28 nM) were shown to be different. The contraction induced by desArg9BK had a longer duration than that evoked by BK and increased during incubation in vitro in stomachs of wild-type controls, while in the transgenic B2 receptor knockout mice, the contractions evoked by desArg9BK and BK were similar and followed the B1 receptor agonist pattern. BK but not the carboxypeptidase-resistant analog, [Phe8psi(CH2-NH)Arg9]BK, was found to be active in the stomach of B2 receptor knockout mice. BK-induced contractions were prevented by mergetpa (a carboxypeptidase M inhibitor) (10 microM) and by a the B receptor antagonist, AcLys[DbetaNal7,Ile8]desArg9BK (R 715) (0.88 microM), while not being influenced by the B2 receptor antagonist HOE 140 (0.38 microM). BK and [Phe8psi(CH2-NH)Arg9]BK were potent contractants of the wild-type mice stomach and their effects were not influenced by mergetpa or by the B receptor antagonist: they were reduced by HOE 140. After incubation in vitro for 3-4 hours, the tissues were treated with HOE 140 (4 microM) and FR-173657 (17 microM) to eliminate B2 receptor function. In these tissues, BK evoked a B1-like contraction which was inhibited by mergetpa (10 microM) and antagonized by R 715 (8 microM). The results indicate that BK acts primarily on B2 receptors. However, after intramural conversion to desArg9BK, activation of B1 receptors of the mice stomach occurs. In the tissues of B2 receptor knockout mice, BK behaves as a pure B1 receptor agonist while in stomachs of control animals, the B2 receptor contribution is overwhelming. After complete blockade of the B2 receptor, BK is able to evoke B1-mediated responses similar to those observed in tissues of B2 receptor knockout mice. It is concluded that the disruption of the B2 receptor gene eliminates the B2 receptor without influencing the B1 receptor system.
本研究的目的是研究野生型对照小鼠和B2受体基因敲除小鼠离体胃中激肽B1和B2受体的药理学特性。结果显示，缓激肽（BK）（9 nM）和去精氨酸9-缓激肽（desArg9BK）（28 nM）诱发的等长收缩有所不同。desArg9BK诱发的收缩持续时间比BK诱发的更长，并且在野生型对照小鼠胃的体外孵育过程中增强，而在转基因B2受体基因敲除小鼠中，desArg9BK和BK诱发的收缩相似，并遵循B1受体激动剂模式。在B2受体基因敲除小鼠的胃中，发现BK具有活性，但羧肽酶抗性类似物[Phe8ψ(CH2-NH)Arg9]BK则无活性。BK诱发的收缩可被mergetpa（一种羧肽酶M抑制剂）（10 μM）和B受体拮抗剂AcLys[DβNal7，Ile8]去精氨酸9-缓激肽（R 715）（0.88 μM）阻断，而不受B2受体拮抗剂HOE 140（0.38 μM）影响。BK和[Phe8ψ(CH2-NH)Arg9]BK是野生型小鼠胃的强效收缩剂，它们的作用不受mergetpa或B受体拮抗剂影响：它们的作用被HOE 140减弱。体外孵育3 - 4小时后，用HOE 140（4 μM）和FR-173657（17 μM）处理组织以消除B2受体功能。在这些组织中，BK诱发类似B1的收缩，该收缩被mergetpa（10 μM）抑制，并被R 715（8 μM）拮抗。结果表明，BK主要作用于B2受体。然而，在壁内转化为desArg9BK后，小鼠胃的B1受体被激活。在B2受体基因敲除小鼠的组织中，BK表现为纯B1受体激动剂，而在对照动物的胃中，B2受体的作用占主导。在B2受体被完全阻断后，BK能够诱发与在B2受体基因敲除小鼠组织中观察到的类似的B1介导的反应。结论是，B2受体基因的破坏消除了B2受体，而不影响B1受体系统。
