Our study indicates that all patients with ALS have the potential to suffer from pain, the intensity of which increases with decreased functional status.
Nitric oxide (NO), a known relaxant, is produced in cells from L-arginine (L-Arg). Because the relaxation of retinal pericytes alters the microcirculatory hemodynamics, it is important to understand the manner of NO production in retinal pericytes. The purpose of this study was to clarify the molecular mechanism(s) of uptake of L-Arg in retinal pericytes using a conditionally immortalized rat retinal pericyte cell line (TR-rPCT1 cells) which expresses the mRNAs of endothelial NO synthase and inducible NO synthase. L-Arg uptake by TR-rPCT1 cells exhibited Na -independence and concentration-dependence with a K m of 28.9 µM. This process was strongly inhibited by substrates of cationic amino acid transporters (CAT), such as L-ornithine and L-lysine. In contrast, L-valine, L-leucine, and L-glutamine, which are substrates of cation/ neutral amino acid transport systems, such as system y L, system B 0, , and system b 0, , did not strongly inhibit L-Arg uptake by TR-rPCT1 cells. In addition, the expression of mRNA and protein of CAT1 in TRrPCT1 cells was observed by reverse transcription-polymerase chain reaction and immunoblot analyses. Taking these results into consideration, it appears that CAT1 is involved in L-Arg uptake by retinal pericytes and this is expected to play an important role in the relaxation of retinal pericytes, thereby modulating the microcirculatory hemodynamics in the retina.
L-Glutamate (L-Glu) is known to be a relaxant of pericytes and to induce changes in microcirculatory hemodynamics. Since the concentration of L-Glu which induces the dilation of retinal capillaries is reported to be high compared with the estimated concentration in the retinal interstitial fluid, it is hypothesized that some systems involving concentrative L-Glu release are present in retinal pericytes. The purpose of this study was to investigate the existence of L-Glu-storing systems, which contribute to autocrine L-Glu release, in retinal pericytes using conditionally immortalized rat retinal pericytes (TR-rPCT1 Key words excitatory amino acid transporter; L-glutamate; retinal pericyte; alanine-serine-cysteine transporter; L-glutamine Retinal pericytes reside within the basal lamina of retinal capillaries and communicate with the retinal capillary endothelial cells which form the blood-retinal barrier (BRB).
1,2)It is known that the contraction and relaxation of pericytes which are induced by physiological factors leads to a change in the diameter of the capillaries. [3][4][5] Because it has been reported that the diameter of capillaries in the central nervous system (CNS) affects the blood flow rate in the capillaries and, thus, the exchange of some compounds between the circulating blood and retina, 6) it is very important to identify the regulatory mechanisms governing the contraction and relaxation of retinal pericytes.L-Glutamate (L-Glu) is known as a relaxant of pericytes and Peppiatt et al. have reported that L-Glu treatment induces dilation of the retinal capillaries. 7) Regarding the mechanism for the L-Glu-induced dilation of retinal capillaries, it has been proposed that L-Glu induces the production of nitric oxide (NO), a relaxant of the cells, and inhibits Ca 2+ influx in retinal pericytes, thereby relaxing the pericytes. 7,8) An in vitro analysis has indicated that this L-Glu-induced NO production occurs in the presence of L-Glu at a concentration of more than 1 mM. 8) In addition, the dilation of retinal capillaries accompanied with pericytes was induced by treatment with 500 µM L-Glu.7) The compounds between the retinal interstitial fluid (ISF) and vitreous humor are considered to be freely exchangeable, and the concentration of L-Glu in the vitreous humor has been reported to be 444 µM in rats.9) Because the L-Glu level in the retinal ISF seems to be low compared with the concentration which induces dilation of the retinal capillaries and relaxation in the pericytes, it is possible that some mechanisms for concentrative L-Glu release are present in retinal pericytes and/or the cells surrounded by the pericytes. In neuronal cells, the packing of L-Glu into synaptic vesicles up to concentrations as high as 100 mM and exocytotic release of L-Glu in the vesicles into the synaptic cleft have been reported. [10][11][12] It has also been reported that the uptake of L-Glu from the cytoplasm of neurons into synaptic vesicles involves the vesicular L-Glu transporters (VGLUTs) which belong to the so...
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