title: 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.
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada ; Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Breitling
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada ; Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Krauszman
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Richa
authors.initials: R
authors.lastname: Parihar
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.affiliation: Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Friedberg
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada ; Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany ; Departments of Surgery and Physiology, University of Toronto, Toronto, Ontario, Canada; and German Heart Institute Berlin, Berlin, Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
keywords: pulmonary hypertension; renin-angiotensin system; vascular remodeling