(Hypertension. 1997;29:394.)
© 1997 American Heart Association, Inc.
State-of-the-Art-Lecture |
Angiotensin-(1–7) Augments Bradykinin-Induced Vasodilation by Competing With ACE and Releasing Nitric Oxide
From The Hypertension Center, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.
Correspondence to K. Bridget Brosnihan, PhD, Hypertension Center, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1032. E-mail bbrosnih{at}bgsm.edu
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 µmol/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 µmol/L) or sodium nitroprusside (0.1 µmol/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
-nitro-L-arginine (L-NA; 100 µmol/L) completely abolished the effects of Ang-(1–7) on BK-induced vasodilation whereas pretreatment with indomethacin (10 µmol/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 µmol/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 µmol/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 µmol/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 µmol/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 µmol/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.
Key Words: angiotensin peptides • coronary artery • angiotensin-converting enzyme • endothelium-derived relaxing factors • nitric oxide • kinins • dog
Abbreviations: ACEI = angiotensin converting enzyme inhibitor • Ach = acetylcholine • Ang = angiotensin • BK = bradykinin • L-NA = N-nitro-L-arginine
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