Does L-arginine increase heart rate independent of nitric oxide?

Background: The beneficial effects of L-Arginine (L-Arg) supplementation in patients with hypertension or heart failure have been ascribed to an increase in the synthesis of NO. It is, however, controversial whether NO synthesis can be enhanced by supplying exogenous L-Arg since intracellular concentrations of L-Arg are already very high (∼mM in endothelial cells). We have recently shown that NO donors have a direct chronotropic effect. The aim of this study was to determine whether L-Arg can affect heart rate (HR) through a No-dependent mechanism. Methods and Results: In isolated guinea-pig atria, with a basal (B/L) HR of 176±5 bpm (mean±SEM), we evaluated the chronotropic effect of increasing concentrations (1μM to 10 mM) of L-Arg alone (n=8), L-Arg after pre-treatment (30 min) with the inhibitor of NO synthase L-NMMA (100-500 μM, n=9), or D-Arg (which is not a biological precursor of NO, n=7). L-NMMA decreased B/L HR by 8±1% (p<0.05, ANOVA). Application of L-Arg, L-Arg on top of L-NMMA, or D-Arg caused a progressive, dose-dependent, positive chronotropic response at concentrations ≥ 0.5 mM (see Fig, * p<0.05). The increase in HR was similar in each group (at 10 mM +64±7 bpm with L-Arg, +66±6 bpm with L-Arg on top of L-NMMA, and +68±6 bpm with D-Arg) and could be reversed upon wash-out. In Conclusion:, (i) the 8% decrease in HR in response to L-NMMA is consistent with a small tonic positive chronotropic effect of endogenous NO, (ii) the increase in HR with L-Arg appears to be independent of NO. Our results point out the importance of excluding non-specific effects of L-Arg in studies where this amino acid is used as a substrate for NO synthesis. (Graph Presented).