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.