title: Retinal transfer of nicotinate by H+ -monocarboxylate transporter at the inner blood-retinal barrier.
abstract: 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 [(3)H]-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 [(3)H]-nicotinate uptake by the retina was 5.4-fold greater than that of [(14)C]-sucrose, a BRB impermeable vascular space marker. Excess amounts of unlabeled nicotinate and salicylate significantly decreased the in vivo retinal uptake of [(3)H]-nicotinate. [(3)H]-Nicotinate was taken up by TR-iBRB2 cells via an H(+)-dependent saturable process with a Michaelis constant of ~7 mM. 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.
authors: Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Masanori
authors: M
authors: Tachikawa
authors: Koji
authors: K
authors: Murakami
authors: Pamela M
authors: PM
authors: Martin
authors: Ken-ichi
authors: K
authors: Hosoya
authors: Vadivel
authors: V
authors: Ganapathy
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects / Q000378:metabolism*; D017536:Carotid Artery, Common; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000378:metabolism*; D007269:Injections, Intra-Arterial; D007700:Kinetics; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D009525:Niacin / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000960:Hypolipidemic Agents; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D009525:Niacin; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C516342:Slc16a3 protein, rat; C091633:Slc16a7 protein, rat