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Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on L-arginine transport in cardiac myocytes.

ABSTRACT: Nitric oxide (NO) plays a central role as a cellular signaling molecule in health and disease. In the heart, NO decreases the rate of spontaneous beating and the velocity and extent of shortening and accelerates the velocity of relengthening. Since the cationic amino acid l-arginine (l-Arg) is the substrate for NO production by NO synthases (NOS), we tested whether the transporters that mediate l-Arg import in cardiac muscle cells represent an intervention point in the regulation of NO synthesis. Electrical currents activated by l-Arg with low apparent affinity in whole cell voltage-clamped rat cardiomyocytes were found to be rapidly and reversibly inhibited by NO donors. Radiotracer uptake studies performed on cardiac sarcolemmal vesicles revealed the presence of high-affinity/low-capacity and low-affinity/high-capacity components of cationic amino acid transport that were inhibited by the NO donor S-nitroso-N-acetyl-dl-penicillamine. NO inhibited uptake in a noncompetitive manner with K(i) values of 275 and 827 nM for the high- and low-affinity component, respectively. Fluorescence spectroscopy experiments showed that millimolar concentrations of l-Arg initially promoted and then inhibited the release of endogenous NO in cardiomyocytes. Likewise, l-Arg currents measured in cardiac myocytes voltage clamped in the presence of 460 nM free intracellular Ca(2+), a condition in which a Ca-CaM complex should activate endogenous NO production, showed fast activation followed by inhibition of l-Arg transport. The NOS inhibitor N-nitro-l-arginine methyl ester, but not blockers of downstream reactions, specifically removed this inhibitory component. These results demonstrate that NO acutely regulates its own biosynthesis by modulating the availability of l-Arg via cationic amino acid transporters.

SUBMITTER: Zhou J

PROVIDER: S-EPMC2928638 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on L-arginine transport in cardiac myocytes.

Zhou Jiaguo J Kim David D DD Peluffo R Daniel RD

American journal of physiology. Cell physiology 20100526 2

Nitric oxide (NO) plays a central role as a cellular signaling molecule in health and disease. In the heart, NO decreases the rate of spontaneous beating and the velocity and extent of shortening and accelerates the velocity of relengthening. Since the cationic amino acid l-arginine (l-Arg) is the substrate for NO production by NO synthases (NOS), we tested whether the transporters that mediate l-Arg import in cardiac muscle cells represent an intervention point in the regulation of NO synthesis ...[more]

PMID: 20505044

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Project description:L-Arginine (L-Arg), the precursor of nitric oxide (NO), plays an important role in muscle function. Fast-twitch glycolytic fibres are more susceptible to age-related atrophy than slow-twitch oxidative fibres. The effect of L-Arg/NO on protein metabolism of fast- and slow-twitch muscle fibres was evaluated in chickens. In Exp. 1, 48 chicks at 1 day old were divided into 4 groups of 12 birds and subjected to 4 treatments: basal diet without supplementation or supplemented with 1% L-Arg, and water supplemented with or without L-nitro-arginine methyl ester (L-NAME, 18.5 mM). In Exp. 2, 48 chicks were divided into 4 groups of 12 birds fed with the basal diet and subjected to the following treatments: tap water (control), tap water supplemented with L-NAME (18.5 mM), or molsidomine (MS, 0.1 mM), or 18.5 mM L-NAME + 0.1 mM MS (NAMS). The regulatory effect of L-Arg/NO was further investigated in vitro with myoblasts obtained from chicken embryo pectoralis major (PM) and biceps femoris (BF). In vivo, dietary L-Arg supplementation increased breast (+14.94%, P < 0.05) and thigh muscle mass (+23.40%, P < 0.05); whereas, MS treatment had no detectable influence. However, L-NAME treatment blocked the beneficial influence of L-Arg on muscle development. L-Arg decreased (P < 0.05) protein synthesis rate, phosphorylated mTOR and ribosomal protein S6 kinase beta-1 (p70S6K) levels in breast muscle, which was recovered by L-NAME treatment. In vitro, L-Arg or sodium nitroprusside (SNP) reduced protein synthesis rate, suppressed phosphorylated mTOR/p70S6K and decreased atrogin-1 and muscle RING finger 1 (MuRF1) in myoblasts from PM muscle (P < 0.05). L-NAME abolished the inhibitory effect of L-Arg on protein synthesis and the mTOR/p70S6K pathway. However, myoblasts from BF muscle showed the weak influence. Moreover, blocking the mTOR/p70S6K pathway with rapamycin suppressed protein synthesis of the 2 types of myoblasts; whereas, the protein expression of atrogin-1 and MuRF1 levels were restricted only in myoblasts from PM muscle. In conclusion, L-Arg/NO/mTOR/p70S6K pathway enhances protein accumulation and muscle development in fast-twitch glycolytic muscle in chickens. L-Arg/NO regulates protein turnover in a muscle fibre specific way, which highlights the potential clinical application in fast-twitch glycolytic muscle fibres.

Dataset Information

Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on L-arginine transport in cardiac myocytes.

Publications

Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on L-arginine transport in cardiac myocytes.

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