TY - JOUR
T1 - Retinal transfer of nicotinate by H +-monocarboxylate transporter at the inner blood-retinal barrier
AU - Tachikawa, Masanori
AU - Murakami, Koji
AU - Martin, Pamela M.
AU - Hosoya, Ken Ichi
AU - Ganapathy, Vadivel
N1 - Funding Information:
We would like to thank S. Akanuma for technical assistance. This study was supported, in part, by the National Institutes of Health Grant EY018053 and the Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture , and from the Japan Society for the Promotion of Science, Japan .
PY - 2011/11
Y1 - 2011/11
N2 - Nicotinic acid is a constituent of the coenzymes NAD and NADP. It also serves as an agonist for the G-protein-coupled receptor GPR109A. Nicotinic acid is widely used at high doses as a lipid-lowering drug, which is associated with an ocular side effect known as niacin maculopathy. Here we investigated the mechanism by which nicotinate is transferred into retina across the inner blood-retinal barrier (BRB). In vivo the blood-to-retina transport of [ 3H]-nicotinate was studied using the carotid artery injection technique. The characteristics of nicotinate transport at the inner BRB were examined in a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2), an in vitro model of inner BRB. The expression of transporters in TR-iBRB2 cells was determined by reverse transcription-polymerase chain reaction. In vivo [ 3H]-nicotinate uptake by the retina was 5.4-fold greater than that of [ 14C]-sucrose, a BRB impermeable vascular space marker. Excess amounts of unlabeled nicotinate and salicylate significantly decreased the in vivo retinal uptake of [ 3H]-nicotinate. [ 3H]-Nicotinate was taken up by TR-iBRB2 cells via an H +-dependent saturable process with a Michaelis constant of ~7mM. Na + had minimal effect on the uptake. The H +-dependent uptake was significantly inhibited by endogenous monocarboxylates such as lactate and pyruvate, and monocarboxylic drugs such as valproate, salicylate, and ibuprofen. These characteristics are consistent with those of H +-coupled monocarboxylate transporters (MCTs). MCT1, MCT2, and MCT4 mRNAs were expressed in TR-iBRB2 cells. The Na +-dependent monocarboxylate transporters SMCT1 and SMCT2 were not expressed in these cells. In conclusion, transfer of nicotinate from blood to retina across the inner BRB occurs primarily via H +-coupled monocarboxylate transporters.
AB - Nicotinic acid is a constituent of the coenzymes NAD and NADP. It also serves as an agonist for the G-protein-coupled receptor GPR109A. Nicotinic acid is widely used at high doses as a lipid-lowering drug, which is associated with an ocular side effect known as niacin maculopathy. Here we investigated the mechanism by which nicotinate is transferred into retina across the inner blood-retinal barrier (BRB). In vivo the blood-to-retina transport of [ 3H]-nicotinate was studied using the carotid artery injection technique. The characteristics of nicotinate transport at the inner BRB were examined in a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2), an in vitro model of inner BRB. The expression of transporters in TR-iBRB2 cells was determined by reverse transcription-polymerase chain reaction. In vivo [ 3H]-nicotinate uptake by the retina was 5.4-fold greater than that of [ 14C]-sucrose, a BRB impermeable vascular space marker. Excess amounts of unlabeled nicotinate and salicylate significantly decreased the in vivo retinal uptake of [ 3H]-nicotinate. [ 3H]-Nicotinate was taken up by TR-iBRB2 cells via an H +-dependent saturable process with a Michaelis constant of ~7mM. Na + had minimal effect on the uptake. The H +-dependent uptake was significantly inhibited by endogenous monocarboxylates such as lactate and pyruvate, and monocarboxylic drugs such as valproate, salicylate, and ibuprofen. These characteristics are consistent with those of H +-coupled monocarboxylate transporters (MCTs). MCT1, MCT2, and MCT4 mRNAs were expressed in TR-iBRB2 cells. The Na +-dependent monocarboxylate transporters SMCT1 and SMCT2 were not expressed in these cells. In conclusion, transfer of nicotinate from blood to retina across the inner BRB occurs primarily via H +-coupled monocarboxylate transporters.
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U2 - 10.1016/j.mvr.2011.06.009
DO - 10.1016/j.mvr.2011.06.009
M3 - Article
C2 - 21741392
AN - SCOPUS:81055157870
SN - 0026-2862
VL - 82
SP - 385
EP - 390
JO - Microvascular Research
JF - Microvascular Research
IS - 3
ER -