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In vivo and in vitro evidence for ACh-stimulated L-arginine uptake

Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, Melbourne, Victoria 8008, Australia

Submitted 20 November 2003 ; accepted in final form 4 March 2004

Whereas L-arginine is clearly recognized as the precursor for nitric oxide synthesis, and its entry into endothelial cells via system y⁺ transport is established, few data exist regarding the acute regulation of this transport process. We specifically investigated the effect of ACh and isoprenaline (Iso) on L-arginine uptake in the human forearm and in cultured bovine aortic endothelial cells (BAEC). Sixteen healthy males were studied. During a steady-state intra-arterial infusion of [³H]L-arginine (100 nCi/min), the effects of ACh (9.25 and 37 µg/min), Iso (25–50 and 200 µg/min), and sodium nitroprusside (SNP) (1–2 and 8 µg/min) on forearm plasma flow (FPF), L-[³H]arginine uptake, and L-[³H]citrulline release were determined. In parallel experiments, the effects of ACh, Iso, and SNP on L-[³H]arginine uptake were studied in BAEC. L-Arginine uptake was inversely related to FPF (r = –0.50; P < 0.005). At a similar FPF (ACh 56.82 ± 9.25, Iso 58.49 ± 5.56, SNP 57.92 ± 4.96 ml/min; P = ns), intra-arterial ACh significantly increased forearm uptake of L-[³H]arginine (54,655 ± 8,018 dpm/min), compared with that observed with either Iso (40,517.23 ± 6,841 dpm/min; P = 0.01) or SNP (36,816 ± 4,650 dpm/min; P = 0.011). This was associated with increased ACh-induced L-[³H]citrulline release compared with Iso and SNP (P = 0.046). Similarly, in BAEC, ACh significantly increased L-[³H]arginine uptake compared with control, Iso, or SNP (ACh 12.0 x 10⁷ ± 1.83 x 10⁷ vs. control 6.67 x 10⁷ ± 1.16 x 10⁷ vs. Iso 7.35 x 10⁷ ± 1.63 x 10⁷ vs. SNP 6.01 x 10⁷ ± 1.11 x 10⁷ fmol·min^–1·mg^–1 at 300 µmol/l L-arginine; P = 0.043). Taken together, these data indicate that ACh stimulates L-arginine uptake in cultured endothelial cells and in human forearm circulation, indicating the potential for acute modulation of endothelial L-arginine uptake.

endothelial function; membrane transport; nitric oxide; substrate availability

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