L-ARGININE REDUCES HEART COLLAGEN ACCUMULATION IN THE DIABETIC DB DB MOUSE/

Background Diabetic cardiomyopathy presents with significant collagen accumulation; decreased solubility, increased glucose-mediated abnorma l cross-linking, free radical crosslinking, or glucose-induced increas ed transcription of collagen is incriminated. In a previous study, we reduced collagen accumulation in the kidneys of diabetic mice by treat ment with oral arginine. This observation led us to examine the effect of arginine on cardial fibrosis. Methods and Results Twenty-nine db/d b spontaneously diabetic mice were used in the experiments. Sixteen we re given L-arginine (free base, in tap water, 50 mg/kg body wt per day ) for 4 months. At the end of the experiment, we determined total coll agen content of total ventricular tissue, acid solubility, carboxymeth yllysine, O-tyrosine, glutathione, blood glucose, and fructosamine as parameters for glycemic control. Heart collagen level was significantl y (P=.0001) reduced in the experimental group (mean, 0.24+/-0.05) comp ared with the control group (mean, 0.49+/-0.10 mu mol hydroxyproline p er 100 mg heart tissue). Significantly more collagen could be eluted f rom heart samples of the experimental group (P=.02). Carboxymethyllysi ne and O-tyrosine did not differ when related to heart weight. Glutath ione level was significantly higher in the untreated group (P=.003). P arameters of glycemic control did not differ between the groups. Concl usions Our findings clearly indicate that L-arginine reduced total hea rt collagen and increased acid solubility of heart collagen. Both find ings are compatible with the cross-linking hypothesis. The data for ca rboxymethyllysine, O-tyrosine, and glutathione would rule out the glyc oxidation hypothesis and, therefore, free radical cross-Linking. The p ostulated mechanism of action is most likely the blocking of reactive carbonyl functions by L-arginine in analogy to aminoguanidine activity . Correlations of collagen with glycemic control, however, point to an association of glucose with collagen metabolism, a phenomenon documen ted in cell cultures at the transcriptional level.