Biomedical subjects

M L Quarum

Publications and source records attributed to M L Quarum.

3 recordsLinked to original sources

PubMed1990

(+)-[3H]MK-801 binding sites in postmortem human brain.

The pharmacological specificity and the regional distribution of the N-methyl-D-aspartate receptor-associated 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) binding sites in human postmortem brain tissue were determined by binding studies using (+)-[3H]MK-801. Scatchard analysis revealed a high-affinity (KD = 0.9 +/- 0.2 nM, Bmax = 499 +/- 33 fmol/mg of protein) and a low-affinity (KD = 3.6 +/- 0.9 nM, Bmax = 194 +/- 44 fmol/mg of protein) binding site. The high-affinity site showed a different regional distribution of receptor density (cortex greater than hippocampus greater than striatum) compared to the low-affinity binding site (cerebellum greater than brainstem). The rank order pharmacological specificity and stereoselectivity of the high-(cortex) and low-(cerebellar) affinity binding sites were identical. However, all compounds tested showed greater potency at the high-affinity site in cortex. The results indicate that (+)-[3H]MK-801 binding in human postmortem brain tissue shows pharmacological and regional specificity.

Aged↗

PubMed1989

Interaction of 6-cyano-7-nitroquinoxaline-2,3-dione with the N-methyl-D-aspartate receptor-associated glycine binding site.

The interaction of newly described antagonist of the non-NMDA glutamate receptor 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) with the glycine site of the NMDA receptor complex has been investigated. In whole-cell patch recordings from hippocampal neurons maintained in culture, currents induced by N-methyl-D-aspartate (NMDA) were dependent on extracellular glycine. Responses to both NMDA (30 microM) and kainate (20 microM) were reduced by CNQX (10-30 microM). The antagonism by CNQX of NMDA, but not kainate, receptor-mediated responses could be reversed by increasing the concentration of glycine in the external medium. Glycine concentration-response curves constructed in the presence of 30 microM NMDA were shifted to the right by CNQX, suggesting that CNQX was competing with glycine for the glycine binding site. However, even at high concentrations of glycine (300 microM) the maximal NMDA current obtained in the presence of CNQX (10-30 microM) was not restored to control levels. Because CNQX had no effect on responses produced by supramaximal concentrations of NMDA (500 microM) and glycine (300 microM), it is suggested that CNQX also interacts with the NMDA recognition site. The antagonism of currents induced by NMDA was not dependent on the membrane potential, and the rapid onset and offset of the block suggested that there was little or no use dependence. Radioligand binding experiments were performed using [3H]glycine to label the strychnine-insensitive glycine regulatory site of the NMDA receptor complex in guinea pig brain frontal cortex membranes. CNQX displaced [3H]glycine binding in a concentration-dependent manner (IC50 = 5.7 microM). Scatchard analysis of the inhibition showed a decrease in the affinity (increase in Kd) of [3H]glycine binding, but no change in the number of binding sites (Bmax) in the presence of 5 microM CNQX, suggesting a competitive interaction. These data provide evidence that CNQX antagonizes NMDA receptor-mediated responses by competing with glycine for a modulatory site associated with the NMDA receptor complex. Furthermore, the results indicate that CNQX may not be as selective an antagonist for non-NMDA receptors as initially described, although its selectivity will depend on the concentration of the NMDA receptor ligand and may be enhanced by increasing the extracellular concentration of glycine.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1984

Increasing dietary calcium moderates experimental gentamicin nephrotoxicity.

Because calcium has been reported to modify gentamicin binding to its proximal tubular brush border membrane receptor, we studied the effects of dietary calcium loading and subsequent hypercalciuria on experimental gentamicin nephrotoxicity. Male Fischer 344 rats were fed one of two diets that were identical except for calcium carbonate content: normal (0.5%) and high (4%). The high-calcium diet made rats hypercalciuric but there were no differences between the two groups in inulin clearance, sodium or osmolar excretion, or serum calcium prior to gentamicin administration. Animals on both diets were treated with gentamicin, 20 mg/kg b.i.d., for periods of 3 to 21 days. Both groups developed acute renal failure, but animals on the high-calcium diet had less severe acute toxic injury, as evidenced by studies of inulin clearance, renal histology, and in vitro cortical uptake of NMN and PAH. Furthermore, calcium-loaded animals tended to have lower peak renal cortical gentamicin levels during the period of acute toxicity. The mechanism by which increased dietary calcium protects against gentamicin nephrotoxicity remains speculative. Calcium and gentamicin may compete for the same brush border receptor or alternatively parathyroid suppression may result in diminution in tubular cell membrane drug binding sites. The possibility that high-calcium diets exert a nonspecific salutory effect on proximal tubular cell integrity has not been excluded.

Animals↗