Homoarginine Treatment of Rats Improves Cardiac Function and Remodeling in Response to Pressure Overload

Abstract

\n Purpose\n\nLow serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on myocardial function and remodeling in rats undergoing aortic banding or given the nitric oxide synthesis inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME).\nMethods\n\nMale Wistar rats (n\u2009=\u2009136) underwent sham operation (SH) or aortic banding (AB) and were equally divided into fourteen subgroups, receiving different doses of HA alone or in combination with either lisinopril, spironolactone or L-NAME over a 4-week period.\nResults\n\nHA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg−\u20091·day−\u20091. Combining 800 mg·kg−\u20091·day−\u20091 HA with spironolactone or lisinopril yielded synergistic effects, showing a positive correlation with LV ejection fraction (+\u200927%, p\u2009<\u20090.05), fractional shortening (+\u200937%, p\u2009<\u20090.05) and an inverse association with collagen area fraction (-56%, p\u2009<\u20090.05), myocyte cross-sectional area (-22%, p\u2009<\u20090.05) and the molecular markers atrial natriuretic factor (-78%, p\u2009=\u20090.04), brain natriuretic peptide (-28%, p\u2009=\u20090.22), beta-myosin heavy chain (-42%, p\u2009=\u20090.19) and collagen type V alpha 1 chain (-73%, p\u2009=\u20090.06) compared to placebo treated AB animals. Even co-administration of HA and L-NAME was found to attenuate cardiac remodeling and to prevent NO-deficient hypertension following AB.\nConclusion\n\nHA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes of cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in synergistic beneficial effects boosting the direct impact of HA on heart failure pathophysiology.