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(Stroke. 1999;30:1687-1694.)
© 1999 American Heart Association, Inc.

Original Contributions

Pharmacological Inhibition of the Na⁺/Ca²⁺ Exchanger Enhances Depolarizations Induced by Oxygen/Glucose Deprivation but Not Responses to Excitatory Amino Acids in Rat Striatal Neurons

Paolo Calabresi, MD; Girolama A. Marfia, MD; Salvatore Amoroso, MD; Antonio Pisani, MD Giorgio Bernardi, MD

From Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata (P.C., G.A.M., A.P., G.B.), and IRCCS Ospedale Santa Lucia (P.C., G.B.), Rome, and Dipartimento di Neuroscienze, Università Federico II (S.A.), Naples, Italy.

Correspondence to Paolo Calabresi, Clinica Neurologica, Dipartimento di Neuroscienze, Università "Tor Vergata," via di Tor Vergata 135, 00133, Rome, Italy. E-mail calabre{at}uniroma2.it

Background and Purpose—Neuronal Na⁺/Ca²⁺ exchanger plays a relevant role in maintaining intracellular Ca²⁺ and Na⁺ levels under physiological and pathological conditions. However, the role of this exchanger in excitotoxicity and ischemia-induced neuronal injury is still controversial and has never been studied in the same neuronal subtypes.

Methods—We investigated the effects of bepridil and 3',4'-dichlorobenzamil (DCB), 2 blockers of the Na⁺/Ca²⁺ exchanger, in rat striatal spiny neurons by utilizing intracellular recordings in brain slice preparations to compare the action of these drugs on the membrane potential changes induced either by oxygen and glucose deprivation (OGD) or by excitatory amino acids (EAAs).

Results—Bepridil (3 to 100 µmol/L) and DCB (3 to 100 µmol/L) caused a dose-dependent enhancement of the OGD-induced depolarization measured in striatal neurons. The EC₅₀ values for these effects were 31 µmol/L and 29 µmol/L, respectively. At these concentrations neither bepridil nor DCB altered the resting membrane properties of the recorded cells (membrane potential, input resistance, and current-voltage relationship). The effects of bepridil and DCB on the OGD-induced membrane depolarization persisted in the presence of D-2-amino-5-phosphonovalerate (50 µmol/L) plus 6-cyano-7-nitroquinoxaline-2,3-dione (20 µmol/L), which suggests that they were not mediated by an enhanced release of EAAs. Neither tetrodotoxin (1 µmol/L) nor nifedipine (10 µmol/L) affect the actions of these 2 blockers of the Na⁺/Ca²⁺ exchanger, which indicates that voltage-dependent Na⁺ channels and L-type Ca²⁺ channels were not involved in the enhancement of the OGD-induced depolarization. Conversely, the OGD-induced membrane depolarization was not altered by 5-(N,N-hexamethylene) amiloride (1 to 3 µmol/L), an inhibitor of the Na⁺/H⁺ exchanger, which suggests that this antiporter did not play a prominent role in the OGD-induced membrane depolarization recorded from striatal neurons. Bepridil (3 to 100 µmol/L) and DCB (3 to 100 µmol/L) did not modify the amplitude of the excitatory postsynaptic potentials evoked by cortical stimulation. Moreover, these blockers did not affect membrane depolarizations caused by brief applications of glutamate (0.3 to 1 mmol/L), AMPA (0.3 to 1 µmol/L), and NMDA (10 to 30 µmol/L).

Conclusions—These results provide pharmacological evidence that the activation of the Na⁺/Ca²⁺ exchanger exerts a protective role during the early phase of OGD in striatal neurons, although it does not shape the amplitude and the duration of the electrophysiological responses of these cells to EAA.

Editorial Comment

Patricia D. Hurn, PhD, Guest Editor

Anesthesiology/Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland

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