Homoarginine treatment of rats improves cardiac function and remodeling in response to pressure overload.

Low 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 cardiac remodeling in rats undergoing either transaortic banding or inhibition of nitric oxide synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Male Wistar rats (n = 136) underwent sham operation (SH) or aortic banding (AB). Both groups were equally divided into 14 subgroups, receiving different doses of HA alone or in combination with lisinopril, spironolactone, or L-NAME for 4 weeks. HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg-1 ·day-1 . Combining 800 mg·kg-1 ·day-1 HA with spironolactone or lisinopril yielded additional effects, showing a positive correlation with LV ejection fraction (+33%, p = 0.0002) and fractional shortening (+41%, p = 0.0014). An inverse association was observed with collagen area fraction (-41%, p < 0.0001), myocyte cross-sectional area (-22%, p < 0.0001) and the molecular markers atrial natriuretic factor (-74%, p = 0.0091), brain natriuretic peptide (-42%, p = 0.0298), beta-myosin heavy chain (-46%, p = 0.0411), and collagen type V alpha 1 chain (-73%, p = 0.0257) compared to placebo-treated AB animals. Co-administration of HA and L-NAME was found to attenuate cardiac remodeling and prevent NO-deficient hypertension following AB. HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes in cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in additional beneficial effects boosting its direct impact on heart failure pathophysiology.

l-Homoarginine supplementation prevents diabetic kidney damage.

l-homoarginine is an endogenous, non-proteinogenic amino acid that has emerged as a new player in health and disease. Specifically, low l-homoarginine levels are associated with cardiovascular diseases, stroke, and reduced kidney function. However, the role of l-homoarginine in the pathogenesis of diabetic nephropathy (DN) is not known. Experiments were conducted in 6-week-old Ins2Akita mice supplemented with l-homoarginine via drinking water or mini osmotic pump for 12 weeks. Both plasma and kidney l-homoarginine levels were significantly reduced in diabetic mice compared to nondiabetic controls. Untreated Ins2Akita mice showed significant increases in urinary albumin excretion, histological changes, glomerular macrophage recruitment, the inflammatory cytokine KC-GRO/CXCL1, and urinary thiobarbituric acid reactive substances (TBARS) excretion as an indicator of oxidative stress, along with a significant reduction in kidney nitrate + nitrite levels compared to control mice at 18 weeks of age. In contrast, l-homoarginine supplementation for 12 weeks in Ins2Akita mice, via either drinking water or mini osmotic pump, significantly reduced albuminuria, renal histological changes, glomerular macrophage recruitment, KC-GRO/CXCL1 levels, urinary TBARS excretion, and largely restored kidney nitrate + nitrite levels. These data demonstrate that l-homoarginine supplementation attenuates specific features of DN in mice and could be a potential new therapeutic tool for treating diabetic patients.

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.

A prodrug of a selective inhibitor of inducible nitric oxide synthase is neuroprotective in the rat model of glaucoma.

PURPOSE: To test the hypothesis that nitric oxide, synthesized by inducible nitric oxide synthase, causes degeneration of retinal ganglion cells in an animal model of glaucoma. METHODS: Rats with unilateral, chronic, moderately elevated intraocular pressure were treated orally with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide, a prodrug of an inhibitor of inducible nitric oxide synthase. The loss of retinal ganglion cells was quantitated as an indicator of glaucomatous damage. RESULTS: At the end of seven months, rat eyes with chronic, moderately elevated intraocular pressure lost approximately 20,000 retinal ganglion cells. Treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide for seven months completely prevented the loss of retinal ganglion cells in eyes with chronic, moderately elevated intraocular pressure. When treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide was delayed and started after three months of chronic, moderately elevated intraocular pressure, further loss of retinal ganglion cells was prevented. CONCLUSION: Pharmacological neuroprotection with a selective inhibitor of inducible nitric oxide synthase may be useful for the treatment of glaucoma.