Abstract P133: Treating Hypertension With An Anti-inflammatory Formyl Peptide Receptor Agonist

Abstract

Background: Inflammation can play an important role in the progression of hypertension and end organ damage, yet anti-inflammatory drugs remain relatively underexplored as antihypertensive therapeutic options. Formyl peptide receptors (FPR) are integral to the regulation and resolution of inflammation and may be an attractive target for the treatment of hypertension-induced end organ damage, especially given our previous observation that a small molecule FPR prototype molecule reduced cardiac inflammation and fibrosis in a model of myocardial infarction and exhibited vasodilator effects in isolated blood vessels. Objective: The aim of the present study is to determine whether Cmpd17b has antihypertensive and antifibrotic effects in a mouse model of spontaneous hypertension. Methods: Hypertensive BPH/2J (n=14) and normotensive BPN/3J mice (n=12) were treated daily with Cmpd17b (50mg/kg/day, i.p.) or vehicle (8% tween80 and 10% dimethyl sulfoxide in saline, i.p.) for 4 weeks. Mean arterial pressure (MAP) was measured via pre-implanted radiotelemetry probes at baseline and throughout the treatment period. Sirius red staining of left ventricle tissue was used as a marker of cardiac fibrosis. Results: MAP in BPH/2J mice was markedly greater than BPN/3J mice at baseline (126±2 vs 106±1mmHg respectively, P <0.001). Cmpd17b resulted in a 6±1mmHg reduction in MAP from baseline in the BPH/2J mice ( P <0.001), whereas MAP was unchanged from baseline in Cmpd17B treated BPN/3J mice (1±1mmHg, P =0.533) and vehicle treated BPH/2J mice (1±1mmHg, P =0.316). Collagen content in the left ventricle (%LV) was greater in vehicle treated BPH/2J compared with BPN/3J mice ( P <0.05). BPH/2J mice treated with Cmpd17b had lower collagen content compared with vehicle treated BPH/2J (0.7±0.1 vs 1.2±0.2% respectively, P <0.05) whereas collagen content was comparable in BPN/3J treated with Cmpd17b versus vehicle (0.5±0.1 vs 0.5±0.1%). Conclusion: These findings suggest that targeting FPR with the agonist Cmpd17b, has both antihypertensive and antifibrotic effects in hypertensive mice, thus supporting further assessment of FPR based therapeutics for the treatment of hypertension and end organ damage.