L-arginine supplementation reduces cardiac noradrenergic neurotransmission in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) are known to have cardiac noradrenergic hyperactivity due to an impaired nitric oxide (NO)-cGMP pathway. We hypothesized that dietary L-arginine supplementation may correct this autonomic phenotype. Male SHR and Wistar Kyoto rats (WKY) aged 16-18 weeks were given L-arginine (10 g/L in drinking water) for 1 week. Separate control groups received no supplementation. The SHR control had a significantly lower plasma L-arginine than WKY control, but this was increased to a comparable level following L-arginine. Atrial cGMP was lower in the SHR control compared with the WKY control (2.4 +/- 0.4 pmol/mg vs 3.9 +/- 0.5 pmol/mg, p<0.05), but increased to 4.1 +/- 0.5 pmol/mg protein (n=8, p<0.05) with L-arginine. Evoked [H-3]norepinephrine release in isolated spontaneously beating right atria from the SHR control (328 +/- 19%, n=19) was 28% higher than the WKY control (256 +/- 20%, n=14, p<0.05), but was reduced to 258 +/- 11% with L-arginine feeding (n=24, p<0.01). Soluble guanylyl cyclase (sGC) inhibition caused a greater increase of evoked norepinephrine release in the L-arginine fed SHR compared with the non-fed SHR. L-arginine feeding did not reduce evoked norepinephrine release in the WKY. In-vitro heart rate response to exogenous norepinephrine (0.1-5 mu mol/L) was similar between arginine fed (n=13) and non-fed SHR (n=10), suggesting that L-arginine supplementation worked presynaptically. Myocardial tyrosine hydroxylase protein was decreased in SHR following L-arginine supplementation, providing a link to reduced synthesis of norepinephrine. In conclusion, L-arginine supplementation corrects local cardiac noradrenergic hyperactivity in the SHR, probably via increased presynaptic substrate availability of NOS-sGC-cGMP pathway and reduced tyrosine hydroxylase levels. (C) 2009 Elsevier Inc. All rights reserved.