Intrauterine growth restriction (IUGR) represents an important risk factor for perinatal complications and for adult disease. IUGR is associated with a down-regulation of placental amino acid transporters; however, whether these changes are primary events directly contributing to IUGR or a secondary consequence is unknown. We investigated the time course of changes in placental and fetal growth, placental nutrient transport in vivo and the expression of placental nutrient transporters in pregnant rats subjected to protein malnutrition, a model for IUGR. Pregnant rats were given either a low protein (LP) diet (n = 64) or an isocaloric control diet (n = 66) throughout pregnancy. Maternal insulin, leptin and IGF-I levels decreased, whereas maternal amino acid concentrations increased moderately in response to the LP diet. Fetal and placental weights in the LP group were unaltered compared to control diet at gestational day (GD) 15, 18 and 19 but significantly reduced at GD 21. Placental system A transport activity was reduced at GD 19 and 21 in response to a low protein diet. Placental protein expression of SNAT2 was decreased at GD 21. In conclusion, placental amino acid transport is down-regulated prior to the development of IUGR, suggesting that these placental transport changes are a cause, rather than a consequence, of IUGR. Reduced maternal levels of insulin, leptin and IGF-1 may link maternal protein malnutrition to reduced fetal growth by down-regulation of key placental amino acid transporters.

Omission of extracellular Ca2؉ for 15 min from the incubation medium of cultured hippocampal slices stimulated the efflux of glutathione, phosphoethanolamine, hypotaurine, and taurine. The efflux was reduced by several blockers of gap junctions, i.e. carbenoxolone, flufenamic acid, and endothelin-1, and by the connexin43 hemichannel blocking peptide Gap26 but was unchanged by the P2X 7 receptor inhibitor oxidized ATP, a pannexin1 hemichannel blocking peptide and an inactive analogue of carbenoxolone. Pretreatment of the slices with the neurotoxin N-methyl-D-aspartate left the efflux by Ca 2؉ omission unchanged, indicating that the stimulated efflux primarily originated from glia. Elevated glutamate efflux was detected when Ca 2؉ omission was combined with the glutamate uptake blocker L-trans-pyrrolidine-2,4-dicarboxylate and when both Ca 2؉ and Mg 2؉ were omitted from the medium. Omission of Ca 2؉ for 15 min alone did not induce delayed toxicity, but in combination with blocked glutamate uptake, significant cell death was observed 24 h later. Our results indicate that omission of extracellular Ca 2؉ stimulates efflux of glutathione and specific amino acids including glutamate via opening of glial hemichannels.

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In an earlier study, using hippocampal slice cultures from rat, we showed that N-methyl-Daspartate (NMDA) 1 receptor activation caused release of N-acetylaspartate (NAA), an organic anion of predominantly neuronal origin that is frequently used as a marker of neuronal death and/or dysfunction [1,2]. A specific number of other organic anions, including the antioxidant GSH, were also released after NMDA receptor activation. The efflux of these anions was Ca 2+ dependent and correlated with delayed nerve cell death measured 24 h later, indicating a role of the efflux in the nerve cell death. Interestingly, the efflux of NAA, as determined by reversed-phase HPLC coupled to UV detection, was accompanied by the release of a few unknown UV-absorbing components. The tight correlation between the efflux and delayed nerve cell death prompted us to try to identify the unknown components. In this work, we identified one of the earlier unknown and released substances as creatine (Cr) and further developed the previously used reversed-phase HPLC method [1].