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(Hypertension. 2001;37:72.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Angiotensin-(1-7)–Stimulated Nitric Oxide and Superoxide Release From Endothelial Cells

Holger Heitsch; Svitlana Brovkovych; Tadeusz Malinski; Gabriele Wiemer

From the Medicinal Chemistry/DG Cardiovascular (H.H., G.W.), Aventis Pharma Deutschland GmbH, Frankfurt/Main, Germany; and Department of Chemistry and Biochemistry (S.B., T.M.), Ohio University, Athens, Ohio.

Correspondence to Dr Holger Heitsch, Aventis Pharma Deutschland GmbH, DI&A, Medicinal Chemistry, Building G 838, D-65926 Frankfurt am Main, Germany. E-mail holger.heitsch{at}aventis.com

Abstract—The stimulation of endothelium-dependent NO release by angiotensin-(1-7) [Ang-(1-7)] has been indirectly shown in terms of vasodilation, which was diminished by NO synthase inhibition or removal of the endothelium. However, direct measurement of endothelium-derived NO has not been analyzed. With a selective porphyrinic microsensor, NO release was directly assessed from single primary cultured bovine aortic endothelial cells. Ang-(1-7) caused a concentration-dependent release of NO of 1 to 10 µmol/L, which was attenuated by NO synthase inhibition. [D-Ala⁷]Ang-(1-7) (5 µmol/L), described as a selective antagonist of Ang-(1-7) receptors, inhibited Ang-(1-7)–induced NO release only by 50%, whereas preincubation of bovine aortic endothelial cells with the angiotensin II subtype 1 and 2 receptor antagonists EXP 3174 and PD 123,177 (both at 0.1 µmol/L) led to an inhibition of 60% and 90%, respectively. A complete blockade of the Ang-(1-7)–induced NO release was observed on preincubation of the cells with 1 µmol/L concentration of the bradykinin subtype 2 receptor antagonist icatibant (HOE 140), suggesting an important role of local kinins in the action of Ang-(1-7). Simultaneous direct measurement of superoxide (O₂^-) detected by an O₂^--sensitive microsensor revealed that the moderately Ang-(1-7)–stimulated NO release was accompanied by a very slow concomitant O₂^- production with a relative low peak concentration in comparison to the O₂^- production of the strong NO releasers bradykinin and, especially, calcium ionophore. Thus, Ang-(1-7) might preserve the vascular system, among others, due to its low formation of cytotoxic peroxynitrite by the reaction between NO and O₂^-.

Key Words: angiotensin-(1-7) • nitric oxide • superoxide • endothelial cells • kinins

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