Open AccessDose‐Dependent, Therapeutic Potential of Angiotensin‐(1–7) for the Treatment of Pulmonary Arterial Hypertension
Author(s) -
Breitling Siegfried,
Krauszman Adrienn,
Parihar Richa,
Walther Thomas,
Friedberg Mark K.,
Kuebler Wolfgang M.
Publication year - 2015
Publication title -
pulmonary circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.791
H-Index - 40
ISSN - 2045-8940
DOI - 10.1086/683696
Subject(s) - medicine , ambrisentan , pulmonary hypertension , angiotensin ii , pharmacology , therapeutic effect , lung , vasodilation , hemodynamics , renin–angiotensin system , pulmonary artery , receptor , blood pressure , cardiology , endothelin receptor , bosentan
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 μ g 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 μ g 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.