Brosnihan K B, Li P, Tallant E A, Ferrario C M
Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1032, USA.
Biol Res. 1998;31(3):227-34.
Angiotensin-(1-7) [Ang-(1-7)] possesses novel biological functions that are distinct from angiotensin II (Ang II). In coronary arteries, the octapeptide Ang II and the heptapeptide Ang-(1-7) exert opposing actions. Ang II elicits vasoconstriction and Ang-(1-7) is a vasodilator. Ang-(1-7) elicits vasodilation by an endothelium-dependent release of nitric oxide. Further, the vasorelaxant activity is markedly attenuated by the bradykinin (BK) B2 receptor antagonist icatibant and does not appear to be associated with the synthesis and release of prostaglandins. Ang-(1-7) vasodilation is mediated by a non-AT1/AT2 receptor, since [Sar1Thr8]-Ang II, but neither candesartan, an AT1 receptor antagonist, nor PD123319, an AT2 receptor antagonist, blocked the response. Specific and high affinity binding of 125I-Ang-(1-7) to the endothelial layer of canine coronary arteries was demonstrated using in vitro emulsion autoradiography. Binding was effectively competed for by either unlabeled Ang-(1-7) or the specific Ang-(1-7) antagonist [D-Ala7]-Ang-(1-7). Additionally, Ang-(1-7) potentiated synergistically BK-induced vasodilation. The EC50 of BK vasodilation (2.45 +/- 0.51 nmol/L vs 0.37 +/- 0.08 nmol/L) was shifted 6.6-fold left-ward in the presence of 2 mumol/L concentration of Ang-(1-7). The potentiated response was specific for BK, since Ang-(1-7) did not augment the vasodilation produced by either acetylcholine or sodium nitroprusside; further, it was specific for Ang-(1-7), since neither Ang I nor Ang II augmented the BK response. In contrast to the vasodilator actions of Ang-(1-7), the potentiated response was not blocked by candesartan, PD123319 or [Sar1Thr8]-Ang II. Novel studies from our group demonstrate that Ang-(1-7) is both a substrate and inhibitor for angiotensin converting enzyme (ACE). Ang-(1-7) was shown to retard the degradation of 125I-[Tyr0]-BK in coronary rings. These studies describe novel actions of Ang-(1-7) as a vasodilator and a local synergistic modulator of kinin-induced vasodilation in coronary arteries.
血管紧张素 -（1 - 7）[Ang -（1 - 7）]具有与血管紧张素II（Ang II）不同的新型生物学功能。在冠状动脉中，八肽Ang II和七肽Ang -（1 - 7）发挥相反的作用。Ang II引起血管收缩，而Ang -（1 - 7）是一种血管舒张剂。Ang -（1 - 7）通过内皮依赖性释放一氧化氮引起血管舒张。此外，缓激肽（BK）B2受体拮抗剂艾替班特可显著减弱血管舒张活性，且其似乎与前列腺素的合成和释放无关。Ang -（1 - 7）介导的血管舒张由非AT1/AT2受体介导，因为[Sar1Thr8]-Ang II，但AT1受体拮抗剂坎地沙坦和AT2受体拮抗剂PD123319均不能阻断该反应。使用体外乳胶放射自显影技术证明了125I - Ang -（1 - 7）与犬冠状动脉内皮细胞层具有特异性和高亲和力结合。未标记的Ang -（1 - 7）或特异性Ang -（1 - 7）拮抗剂[D - Ala7]-Ang -（1 - 7）均可有效竞争这种结合。此外，Ang -（1 - 7）协同增强BK诱导的血管舒张。在存在2 μmol/L浓度的Ang -（1 - 7）时，BK血管舒张的半数有效浓度（EC50）（2.45±0.51 nmol/L对0.37±0.08 nmol/L）向左移动了6.6倍。这种增强的反应对BK具有特异性，因为Ang -（1 - 7）不会增强乙酰胆碱或硝普钠产生的血管舒张；此外，它对Ang -（1 - 7）具有特异性，因为Ang I和Ang II均不会增强BK反应。与Ang -（1 - 7）的血管舒张作用相反，坎地沙坦、PD123319或[Sar1Thr8]-Ang II均不能阻断这种增强的反应。我们团队的新研究表明，Ang -（1 - 7）既是血管紧张素转换酶（ACE）的底物又是其抑制剂。Ang -（1 - 7）可延缓冠状动脉环中125I - [Tyr0]-BK的降解。这些研究描述了Ang -（1 - 7）作为血管舒张剂以及冠状动脉中激肽诱导的血管舒张的局部协同调节剂的新作用。
