Blockade of NMDA channels in acutely isolated rat hippocampal neurons by the Na+/Ca2+ exchange inhibitor KB-R7943

Neuropharmacology. 1999 Aug;38(8):1235-42. doi: 10.1016/s0028-3908(99)00040-4.


Neurons acutely isolated from the CA1 region of rat hippocampal slices using the 'vibrodissociation' method were voltage-clamped in the whole-cell configuration. The currents through NMDA channels were elicited by application of 100 microM aspartate (ASP) in a Mg2+-free solution in the presence of 3 microM glycine. The compound KB-R7943, (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate) known as a Na+/Ca2+ exchange inhibitor was able to block effectively the NMDA channels. At a holding potential of -100 mV, the measurement of the concentration dependence of the stationary current blockade revealed the existence of two populations of NMDA channels differing by a high (IC50 = 0.8 microM) and low (IC50 = 11 microM) affinity for KB-R7943. The Hill coefficients indicated that one blocking molecule can bind to NMDA channels which have a high affinity for KB-R7943 and at least two blocking molecules can bind to the NMDA channels which have a low affinity for KB-R7943. When applied externally, KB-R7943 can bind to the low-affinity NMDA channels irrespective of whether or not these channels are activated by the agonist. The KB-R7943-induced blockade of the NMDA channel was partly voltage-dependent. Within the framework of the Woodhull model, the apparent value of delta calculated for the voltage-dependent binding of KB-R7943 was in the range of 0.26-0.41. The blocking action of KB-R7943 on NMDA channels did not depend either on ASP or glycine concentrations which indicated that the binding sites for KB-R7943 and those for the agonist and the coagonist did not overlap.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartic Acid / pharmacology
  • Glycine / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / physiology
  • Neurons / drug effects*
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Sodium-Calcium Exchanger / antagonists & inhibitors*
  • Sodium-Calcium Exchanger / physiology
  • Thiourea / administration & dosage
  • Thiourea / analogs & derivatives*


  • 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
  • Receptors, N-Methyl-D-Aspartate
  • Sodium-Calcium Exchanger
  • Aspartic Acid
  • Thiourea
  • Glycine