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      Inhibition of Nitric Oxide Synthesis by Systemic N G-Monomethyl- L-Arginine Administration in Humans: Effects on Interstitial Adenosine, Prostacyclin and Potassium Concentrations in Resting and Contracting Skeletal Muscle


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          We examined whether the formation or the release of the vasodilators adenosine, prostacyclin (PGI<sub>2</sub>) and potassium (K<sup>+</sup>) increase in skeletal muscle interstitium in response to nitric oxide synthase (NOS) inhibition. Five subjects performed one-legged knee extensor exercise at 30 W without (controls) and with prior N<sup>G</sup>-nitro- L-arginine methyl ester (L-NAME) infusion (4 mg/kg, intravenously). Samples from the interstitial fluid were obtained at rest, during exercise and after exercise with the microdialysis technique. Interstitial adenosine in controls increased (p < 0.05) from 0.11 ± 0.03 μmol/l at rest to 0.48 ± 0.06 μmol/l during exercise. Interstitial adenosine during exercise in L-NAME was similar (p > 0.05) to controls. The 6-keto-prostaglandin F1α concentration in controls was 1.17 ± 0.20 ng/ml at rest and increased (p < 0.05) to 1.97 ± 0.30 ng/ml during exercise and was further elevated (p < 0.05) to 2.76 ± 0.38 ng/ml after exercise and these concentrations were not different (p > 0.05) in L-NAME. The interstitial K<sup>+</sup> concentration in controls increased (p < 0.05) from 4.1 ± 0.1 mmol/l at rest to 9.5 ± 0.5 mmol/l during exercise. The interstitial K<sup>+</sup> concentration during exercise (6.7 ± 0.4 mmol/l) was lower (p < 0.05) in L-NAME than in controls. The present findings demonstrate that the muscle interstitial concentrations of adenosine, PGI<sub>2</sub> and K<sup>+</sup> during exercise are not increased with systemic NOS inhibition. Thus, the lack of effect of NOS inhibition on the rate of blood flow to contracting human skeletal muscle does not appear to be due to compensatory formation or release of adenosine, PGI<sub>2</sub> and K<sup>+</sup> in the muscle interstitium. The present study also supports a role for PGI<sub>2</sub> in the regulation of blood flow during exercise.

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          Most cited references 7

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          Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle.

          Complementary DNA clones corresponding to human brain nitric oxide (NO) synthase have been isolated. The deduced amino acid sequence revealed an overall identity with rat brain NO synthase of about 93% and contained all suggested consensus sites for binding of the co-factors. The cDNA transfected COS-1 cells showed significant NO synthase activity with the typical co-factor requirements. Unexpectedly, messenger RNA levels of this isoform of NO synthase was more abundant in human skeletal muscle than human brain. Moreover, we detected high NO synthase activity and the expressed protein in human skeletal muscle by Western blot analysis, indicating a possible novel function of NO in skeletal muscle.
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            The internal reference technique in microdialysis: a practical approach to monitoring dialysis efficiency and to calculating tissue concentration from dialysate samples.

             D Scheller,  J. Kolb (1991)
            In microdialysis experiments, 'recovery' estimations are required to calculate extracellular concentrations of the compounds determined. Generally, relative recovery (RR) is determined in vitro as: RR = cd/cs, with (cd) being the concentration of a compound in a dialysate fraction and (cs) its known concentration within a sample solution. To determine recoveryin vivo, relative loss (RL) was defined RL = (cp-cd)/cp with (cp-cd) being the loss of a compound from the perfusate and (cp) its perfusate concentration. RL was determined in vitro and in vivo by adding an 'internal reference compound' to the perfusate. Here, 14C-labelled lactate was used as the compound of interest. Comparing RL and RR in vitro, we found both to be similar. In vivo, however, RL was 34% of RL(in) vitro (CSF) and 46% of RL(in) vitro in agar-containing CSF. During ischaemia, RL of lactate even decreased to only 35% of the pre-ischaemic control level. We conclude that RL and RR represent inverse measurements of 'recovery.' Whereas RR can only be determined in vitro, RL can be determined in vivo. We found recoveryin vivo to be different from recoveryin vitro. Moreover, recoveryin vivo decreased during ischaemia. By means of the measured recoveryin vivo extracellular lactate concentrations prior and during ischaemia were calculated. The results, therefore, validate the 'internal reference technique' as a practical method for estimating recoveryin vivo and for controlling dialysis efficacy in vivo even continuously.
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              Localization of nitric oxide synthase in human skeletal muscle.

              The present study investigated the cellular localization of the neuronal type I and endothelial type III nitric oxide synthase in human skeletal muscle. Type I NO synthase immunoreactivity was found in the sarcolemma and the cytoplasm of all muscle fibres. Stronger immunoreactivity was expressed in the sarcolemma as well as the cytoplasm of type I muscle fibres. NADPH diaphorase activity confirmed a higher level of NO synthase activity in the sarcolemma as well as the cytoplasm of type I muscle fibers. Histochemical staining for cytochrome oxidase showed a staining pattern similar to that observed for type I NO synthase immunoreactivity and NADPH diaphorase activity. Type III NO synthase immunoreactivity was observed both in the endothelium of larger vessels and of microvessels. The results establish that human skeletal muscle expresses two different constitutive isoforms of NO synthase in different cellular compartments and suggest that NO may have specific actions in relation to its site of production. The localization of type I NO synthase in the vicinity of mitochondria supports a specific action of NO on mitochondrial respiration, whereas the localization of type III NO synthase in vascular endothelium is consistent with a role for NO in the control of blood flow in human skeletal muscle.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                August 2000
                14 August 2000
                : 37
                : 4
                : 297-302
                Copenhagen Muscle Research Centre, University of Copenhagen, Denmark
                25743 J Vasc Res 2000;37:297–302
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 35, Pages: 6
                Research Paper


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