Diminished L-arginine bioavailability in hypertension

L-Arginine is the precursor of NO (nitric oxide), a key endogenous mediator involved in endothelium-dependent vascular relaxation and platelet function. Although the concentration of intracellular L-arginine is well above the K_m for NO synthesis, in many cells and pathological conditions the transport of L-arginine is essential for NO production (L-arginine paradox). The present study was designed to investigate the modulation of L-arginine/NO pathway in systemic arterial hypertension. Transport of L-arginine into RBCs (red blood cells) and platelets, NOS (NO synthase) activity and amino acid profiles in plasma were analysed in hypertensive patients and in an animal model of hypertension. Influx of L-arginine into RBCs was mediated by the cationic amino acid transport systems y⁺ and y⁺L, whereas, in platelets, influx was mediated only via system y⁺L. Chromatographic analyses revealed higher plasma levels of L-arginine in hypertensive patients (175±19 μmol/l) compared with control subjects (137±8 μmol/l). L-Arginine transport via system y⁺L, but not y⁺, was significantly reduced in RBCs from hypertensive patients (60±7 μmol·l⁻¹·cells⁻¹·h⁻¹; n=16) compared with controls (90±17 μmol·l⁻¹·cells⁻¹·h⁻¹; n=18). In human platelets, the V_max for L-arginine transport via system y⁺L was 86±17 pmol·10⁹ cells⁻¹·min⁻¹ in controls compared with 36±9 pmol·10⁹ cells⁻¹·min⁻¹ in hypertensive patients (n=10; P<0.05). Basal NOS activity was decreased in platelets from hypertensive patients (0.12±0.02 pmol/10⁸ cells; n=8) compared with controls (0.22±0.01 pmol/10⁸ cells; n=8; P<0.05). Studies with spontaneously hypertensive rats demonstrated that transport of L-arginine via system y⁺L was also inhibited in RBCs. Our findings provide the first evidence that hypertension is associated with an inhibition of L-arginine transport via system y⁺L in both humans and animals, with reduced availability of L-arginine limiting NO synthesis in blood cells.