The kinin B_1 receptor antagonist des-Arg~9-[Leu~8]bradykinin: an antagonist of the angiotensin AT_1 receptor which also binds to the AT_2 receptor

摘要

1. Agonists and antagonists of kinin B_1 and B_2 receptors were evaluated in vitro for their effects against angiotensin II (All)-induced contractile responses in the rabbit aorta and for their binding properties to angiotensin AT_1 and AT_2 receptors from purified membrane of rat liver and lamb uterus respectively. 2. In aortic rings, the kinin B_1 receptor antagonist, des-Arg~9-[Leu~8]bradykinin (BK) (3-100 μM) caused a concentration-dependent decrease in sensitivity and a depression of the maximum response to AIL Des-Arg~(10)-[Leu~9]kallidin (KD), des-Arg~9-BK, des-Arg~(10)-KD, BK or KD at 3 μM had no effect against All-induced contractions. 3. Des-Arg~9-[Leu~8]BK (3 or 100 μM) did not affect contractions of aortic rings to histamine, potassium chloride, endothelin-1, 5-hydroxytryptamine, noradrenaline and the thromboxane A_2-mimetic, U46619. 4. Des-Arg~9-[Leu~8]BK displaced [~(125)I]-Sar~1-AII binding to the AT_1 subtype in rat liver membranes with a K_i value of 1.1 ± 0.4 μM. Values of K_i for des-Arg~9-BK and KD were 45 ± BUM and 25 ± 22 μM, respectively. The other kinin derivatives des-Arg~(10)-KD, BK and des-Arg~(10)-[Leu~9]KD at concentrations up to 100 μM did not bind to the AT_1 receptor. 5. All the kinin derivatives except BK bound to AT_2 receptors in lamb uterus membranes. Values of K_i for des-Arg~9-[Leu~8]BK, des-Arg~(10)-[Leu~9]KD, des-Arg~9-BK, des-Arg~(10)-KD and KD were 0.3 ± 0.1, 0.7 ± 0.1, 1.2 ± 0.3, 1.5 ± 0.3 and 7.0 ± 1.6 ±M, respectively. 6. In conclusion, des-Arg~9-[Leu~8]BK is an insurmountable antagonist of All-induced contractions in the rabbit aorta and also binds with a relatively high affinity to AT_1 and AT_2 receptors in isolated membrane fractions. These additional properties of des-Arg~9-[Leu~8]BK should be considered when it is used as an antagonist to characterize kinin B_1 receptors.