L-arginine supplementation reduces cardiac noradrenergic neurotransmission in spontaneously hypertensive rats.
J Mol Cell Cardiol. 2009 Jul;47(1):149-55. Epub 2009 Apr 9. PMID: 19362092
Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
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 [(3)H]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 mumol/L) was similar between l-arginine fed (n=13) and non-fed SHR (n=10), suggesting that l-arginine supplementation worked pre-synaptically. 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 pre-synaptic substrate availability of NOS-sGC-cGMP pathway and reduced tyrosine hydroxylase levels.