Li P, Chappell M C, Ferrario C M, Brosnihan K B
Hypertension Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1032, USA.
Hypertension. 1997 Jan;29(1 Pt 2):394-400. doi: 10.1161/01.hyp.29.1.394.
Recent studies have shown that angiotensin-(1-7) [Ang-(1-7)] interacts with kinins and augments bradykinin (BK)-induced vasodilator responses by an unknown mechanism. In this study, we evaluated whether the potentiation of the BK-induced vasodilation by Ang-(1-7) may be attributable to inhibition of BK metabolism, release of nitric oxide, or both. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers. 125I-[Tyr0]-BK metabolism was determined in vascular rings by assessing the degradation of the peptide by high-performance liquid chromatography. Ang-(1-7) augmented the vasodilation induced by BK in a concentration-dependent manner in rings preconstricted with the thromboxane analog U46619. The EC50 of BK (2.45 +/- 0.51 nmol/L versus 0.37 +/- 0.08 nmol/L) was shifted leftward by 6.6-fold in the presence of 2 mumol/L concentration of Ang-(1-7). The response was specific for BK. since Ang-(1-7) did not augment the vasodilation induced by either acetylcholine (0.05 mumol/L) or sodium nitroprusside (0.1 mumol/L). Moreover, neither angiotensin I nor angiotensin II (Ang II) duplicated the augmented BK response of Ang-(1-7). Pretreatment of vascular rings with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NA; 100 mumol/L) completely abolished the effects of Ang-(1-7) on BK-induced vasodilation whereas pretreatment with indomethacin (10 mumol/L) was without effect. The potent specific BK B2 receptor antagonist, Hoe 140. nearly abolished the BK and the Ang-(1-7) potentiated responses at 2 mumol/L, whereas at a lower concentration (20 nmol/L) Hoe 140 shifted the response curve to the right for both Ang-(1-7) and vehicle; however, the augmented response to Ang-(1-7) persisted. Preincubation of vascular rings with 20 mumol/L of the AT1 (CV11974), AT2 (PD123319), or nonselective (Sar1 Thr8-Ang II) receptor antagonists had no significant effect on the Ang-(1-7)-enhanced vasodilator response to BK. Lisinopril (2 mumol/L) significantly enhanced the BK-induced vasodilator response while at the same time it abolished the synergistic action of Ang-(1-7) on BK. In addition, pretreatment with 2 mumol/L Ang-(1-7) significantly inhibited the degradation of 125I-[Tyr0]-BK and the appearance of the BK-(1-7) and BK-(1-5) metabolites in coronary vascular rings. Ang-(1-7) inhibited purified canine angiotensin converting enzyme activity with an IC50 of 0.65 mumol/L. In conclusion. Ang-(1-7) acts as a local synergistic modulator of kinin-induced vasodilation by inhibiting angiotensin converting enzyme and releasing nitric oxide.
最近的研究表明，血管紧张素 -（1 - 7）[Ang -（1 - 7）]与激肽相互作用，并通过未知机制增强缓激肽（BK）诱导的血管舒张反应。在本研究中，我们评估了Ang -（1 - 7）增强BK诱导的血管舒张是否归因于抑制BK代谢、释放一氧化氮或两者兼有。在器官浴槽中悬挂的完整犬冠状动脉环中测量等长张力。通过高效液相色谱法评估肽的降解，测定血管环中125I - [Tyr0] - BK的代谢。在预先用血栓素类似物U46619预收缩的环中，Ang -（1 - 7）以浓度依赖性方式增强BK诱导的血管舒张。在存在2 μmol/L浓度的Ang -（1 - 7）时，BK的半数有效浓度（EC50）（2.45±0.51 nmol/L对0.37±0.08 nmol/L）向左移动了6.6倍。该反应对BK具有特异性，因为Ang -（1 - 7）未增强乙酰胆碱（0.05 μmol/L）或硝普钠（0.1 μmol/L）诱导的血管舒张。此外，血管紧张素I和血管紧张素II（Ang II）均未复制Ang -（1 - 7）增强的BK反应。用一氧化氮合酶抑制剂Nω-硝基-L-精氨酸（L-NA；100 μmol/L）预处理血管环完全消除了Ang -（1 - 7）对BK诱导的血管舒张的作用，而用吲哚美辛（10 μmol/L）预处理则无效。强效特异性BK B2受体拮抗剂Hoe 140在2 μmol/L时几乎消除了BK和Ang -（1 - 7）增强的反应，而在较低浓度（20 nmol/L）时，Hoe 140使Ang -（1 - 7）和溶剂的反应曲线均向右移动；然而，对Ang -（1 - 7）增强的反应仍然存在。用20 μmol/L的AT1（CV11974）、AT2（PD123319）或非选择性（Sar1 Thr8 - Ang II）受体拮抗剂预孵育血管环对Ang -（1 - 7）增强的对BK的血管舒张反应无显著影响。赖诺普利（2 μmol/L）显著增强BK诱导的血管舒张反应，同时消除了Ang -（1 - 7）对BK的协同作用。此外，用2 μmol/L Ang -（1 - 7）预处理显著抑制了冠状动脉环中125I - [Tyr0] - BK的降解以及BK -（1 - 7）和BK -（1 - 5）代谢产物的出现。Ang -（1 - 7）抑制纯化的犬血管紧张素转换酶活性，半数抑制浓度（IC50）为0.65 μmol/L。总之，Ang -（1 - 7）通过抑制血管紧张素转换酶和释放一氧化氮，作为激肽诱导的血管舒张的局部协同调节剂。
