Serelaxin has greater anti-fibrotic potential than perindopril but maintains its anti-fibrotic efficacy in the presence of perindopril in normotensive mouse models of heart disease

AIMS: Serelaxin (RLX), the drug form of human gene-2 relaxin, has potent anti-fibrotic properties that are currently being clinically-evaluated for the treatment of heart failure (HF). Whilst these effects can potentially be antagonised by angiotensin receptor blocker co-administration, this study determined if RLX was a suitable adjunct therapy to angiotensin converting enzyme inhibitor (ACEi) treatment. In particular, the anti-fibrotic effects of RLX were compared to or combined with the clinically-used ACEi, perindopril, in murine models of isoprenaline (ISO)-induced cardiomyopathy and surgically-induced myocardial infarction (MI). METHODS: The dose-response effects of perindopril (1, 2 or 4 mg/kg/day) on systolic blood pressure (SBP) and left ventricular (LV) fibrosis were first assessed in ISO-injured mice, after 7- or 14-days of treatment. The therapeutic effects of RLX (0.5 mg/kg/day) on SBP, LV fibrosis and LV functional parameters (ejection fraction, fractional shortening, stroke volume, cardiac output) were then compared to or combined with perindopril (2 mg/kg/day) pre-treatment (7-days prior) or co-administration (over 7-days) in ISO-injured mice; or perindopril co-administration (over 21-days) in MI-injured mice. KEY FINDINGS: Perindopril attenuated the ISO-induced LV fibrosis at 2 or 4 mg/kg/day, but induced significant hypotension at 4 mg/kg/day. RLX reduced the ISO- or MI-induced LV fibrosis, and restored measures of LV dysfunction, to a greater extent than perindopril (2 mg/kg/day), in the absence of BP regulation. These effects were maintained in the presence of perindopril pre-treatment or co-administration. SIGNIFICANCE: These findings confirmed that RLX had greater anti-fibrotic potential than perindopril, but could be applied as a rapidly-acting adjunct therapy to ACEi.