Dose-dependent, therapeutic potential of angiotensin-(1–7) for the treatment of pulmonary arterial hypertension

Abstract

The effects of the heptapeptide angiotensin-(1–7) (Ang-(1–7)), via its receptor Mas, oppose many of the effects of the classic angiotensin II signaling pathway, and pharmacological exploitation of this effect is currently actively pursued for a wide range of cardiovascular, neoplastic, or immunological disorders. On the basis of its vasodilatory and antiproliferative properties, Ang-(1–7) has consequentially also been proposed as a novel therapeutic strategy for the treatment of pulmonary arterial hypertension (PAH). In this study, we tested the effectiveness of Ang-(1–7) and its stable, cyclic analog cAng-(1–7) over a range of doses for their therapeutic potential in experimental PAH. In the monocrotaline (MCT) rat model of PAH, Ang-(1–7) or cAng-(1–7) were injected in doses of 30, 100, 300, or 900 μg kg–1 day–1, and effects on pulmonary hemodynamics and vascular remodeling were assessed. Five weeks after MCT injection, right ventricular systolic pressure (RVSP) was significantly reduced for 3 dose groups treated with Ang-(1–7) (100, 300, and 900 μg kg–1 day–1) and for all dose groups treated with cAng-(1–7), as compared to untreated controls, yet the total reduction of RVSP was >50% at best and thus markedly lower than that with a positive treatment control with ambrisentan. Medial-wall thickness in pulmonary arterioles was only slightly reduced, without reaching significance, for any of the tested Ang-(1–7) compounds and doses. The reported moderate attenuation of PAH does not confirm the previously postulated high promise of this strategy, and the therapeutic usefulness of Ang-(1–7) may be limited in PAH relative to that in other cardiovascular diseases.

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Topics

Endothelin and Endothelium & Epithelium and Epithelial Transport
Pulmonary Hypertension
Pulmonary Vascular Remodeling

Authors

Siegfried Breitling, Adrienn Krauszman, Richa Parihar, Thomas Walther, Mark K. Friedberg, Wolfgang M. Kuebler

Published in:

Pulmonary Circulation Vol 5: No 4 cover image

December 2015

Pulmonary Circulation Vol 5: No 4

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