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(Stroke. 1996;27:127-133.)
© 1996 American Heart Association, Inc.
Articles |
Effects of Cerebral Ischemia on N-Methyl-D-Aspartate and Dihydropyridine-Sensitive Calcium Currents
An Electrophysiological Study in the Rat Hippocampus In Situ
From the Departments of Neurology (T.D., M.D.) and Pharmacology (C.A., G.E., R.O.), Hacettepe University, Faculty of Medicine, Ankara, Turkey.
Correspondence to Turgay Dalkara, MD, PhD, Department of Neurology, Hacettepe University Hospital, Ankara, Turkey, TR 06100.
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Abstract |
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 Top Abstract IntroductionMaterials and Methods Results Discussion References |
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Background and Purpose During cerebral ischemia, both promoting and limiting factors are present for activation of the N-methyl-D-aspartate (NMDA) receptor ion channel and the dihydropyridine (DHP)-sensitive Ca2+ channels. We investigated the activity of these channels during ischemia and reperfusion in the rat hippocampus in situ.
Methods Reversible ischemia was induced by bilateral carotid artery ligation. NMDA and BAY K8644 were applied by iontophoresis or pneumatic ejection, and extracellular field potential and resistance changes were recorded from the CA1 region of the rat hippocampus. Resting membrane potentials of the CA1 neurons were also recorded.
Results DC potential shifts produced by NMDA and BAY K8644 were reduced when ischemia depressed the evoked activity more than 50%. They disappeared on total failure of synaptic transmission and recovered during reperfusion. When the evoked activity was depressed less than 50%, DC shifts were greater than their preischemic values; however, BAY K8644-induced potentiation did not reach statistical significance. CA1 neurons were depolarized during ischemia.
Conclusions These data suggest that ischemia severe enough to cause transmission failure inactivates NMDA and DHP-sensitive Ca2+ currents. During less intense ischemia and reperfusion, NMDA and DHP-sensitive Ca2+ channels are functional, and their overactivation may lead to neurotoxicity.
Key Words: calcium channels • cerebral ischemia • hippocampus • N-methyl-D-aspartate • rats
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Increased cytosolic Ca2+ is a major cause of cell damage in cerebral ischemia.1 2 The NMDA receptor ion channel and DHP-sensitive Ca2+ channels are considered among the possible routes of Ca2+ entry to neurons during ischemia.3 4 5 6 However, failure of NMDA receptor antagonists to prevent tissue damage in global ischemia led to the idea that there might be factors limiting NMDA receptor overactivation under ischemic conditions.7 8 9 10 Demonstration of phosphorylation dependency of DHP-sensitive Ca2+ channels and depression of their activity during anoxia also cast some doubt on their role in energy-deficient states.11 12 13 It is likely that ischemia triggers both facilitatory and inhibitory processes acting on these channels, and the overall effect may vary depending on the severity of ischemia. We investigated this possibility by following the activity of these channels during the course of cerebral ischemia and reperfusion. Channel activity was induced by local application of NMDA or the Ca2+ channel agonist BAY K8644 in the rat hippocampus and was monitored by recording population currents and Rt changes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Humane treatment of experimental animals was strictly applied throughout the housing and experimental periods. The procedures followed were within local institutional guidelines. The experiments were performed on 22 male Swiss albino rats weighing 200 to 300 g. Anesthesia was induced by urethane (1.4 to 1.6 g/kg IP). Both carotid arteries were exposed after a ventral median surgical incision on the neck and suspended with silk sutures. After completion of surgery on the neck, rats were placed in a stereotaxic apparatus. The rectal temperature was maintained at 37°C to 38°C. The heart rate was monitored.
Stimulating electrodes were placed in the fimbria/commissure at the
following coordinates: anterior 6.5, lateral 0.5, height +7.0,
according to the atlas of Albe-Fessard et al.14
Multibarreled glass microelectrodes were used for recording and
iontophoretic and pneumatic administration of drugs. Recording
barrels were routinely filled with 3 mol/L NaCl, and the other barrels
were filled with N-methyl-DL-aspartate (Sigma
Chemical Co; 50 mmol/L in 0.15 mol/L saline, pH 8) or BAY K8644 (Bayer
AG; 100 mol/L in 1% ethanol and 0.15 mol/L saline). NMDA was applied
by iontophoresis or pressure ejection, BAY K8644 only by pressure. The
specificity of the effects observed with these agents was determined by
antagonizing their effects by MK-801 (Merck Sharp & Dohme; 40 mmol/L in
0.15 mol/L saline, 15 to 100 nA) and nimodipine (Bayer AG; 50 mmol/L in
1% ethanol and 0.15 mol/L saline, 7 to 15 psi) (Fig 1
).
Pressure application of ethanol (1% in 0.15 mol/L saline) or 0.15
mol/L saline did not produce any effect except a 15% to 25% drop in
Rt, possibly due to expansion of extracellular space
by volume injection. Positioning of the recording electrode in
the CA1 region of the right hippocampus was guided by observation of
the characteristic field response evoked by fimbrial/commissural
stimulation and the stereotaxic coordinates (anterior 4.0,
lateral 2.0 to 2.5, height 
2). Extracellular DC potential changes
(DC shifts) during drug applications were recorded in addition to
the stimulus-evoked activity. The current applied for iontophoresis
was automatically balanced with a current having the same magnitude but
opposite polarity to minimize the potential shift due to iontophoretic
current. Borosilicate, glass microelectrodes without filament filled
with 3 mol/L KCl and having tip resistances of 40 to 60 M
were used
for intracellular recordings. RMP was taken as the difference
between the potential recorded before and immediately after the
cell was penetrated to avoid extracellular DC potential changes and
electrode tip potentials, which make the estimation of transmembrane
potential difference complicated during long-lasting intracellular
recordings and ischemia. Glia were easily identified
with their high membrane potential, absence of synaptic potentials, and
failure to fire with depolarizing pulses.
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Cellular swelling or shrinkage due to either ischemia or drug application was monitored by measuring the change in electrical resistance at the tip of microelectrode. A constant current pulse (10 to 50 nA, 10 milliseconds, 1 Hz) was applied between one barrel of the microelectrode and a remote silver plate placed subcutaneously in the neck, and another barrel was used to record the voltage drop, which is directly proportional to the resistance of the tissue between the tip of the voltage barrel and the remote electrode. However, because the current lines converge as they approach the tip of the electrode, the contribution of tissue to the resistance increases as it gets closer to the tip.15 16 17 Therefore, practically, the measured resistance is essentially determined by the tissue immediately surrounding the tip of the microelectrode.
Ischemia was produced by ligation of carotid arteries, which was previously shown to provide a suitable model to study the electrophysiological changes in the rat hippocampus during moderate ischemia.18 19 Briefly, carotid arteries were pulled into glass tubes by using silk sutures to interrupt the carotid blood flow and released for recirculation. First, the ipsilateral carotid was ligated and, if amplitude of the evoked activity was depressed by more than 10%, drugs were tested at this mildly ischemic level. Ischemia was subsequently deepened by ligating the contralateral carotid artery.19 Recirculation was commenced after total failure of the evoked response. In some animals, controlled bleeding was required after bilateral carotid ligation to completely abolish the field response. Since the severity of ischemia was highly variable during the first 20 minutes, possibly depending on the adequacy of collateral circulation, we used the depression of the evoked activity as a measure of the severity of ischemia.
Peak amplitudes of the signals were measured from the baseline. Values are expressed as mean±SEM.
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Results |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Effects of Ischemia on NMDA Responses
NMDA application by iontophoresis (30 to 70 nA, 10 seconds, n=21) or pressure (6 to 17 psi, 2 to 5 seconds, n=10) in the CA1 region of the hippocampus caused an extracellular negative DC potential shift of 8 to 12 mV (Fig 2
). This was accompanied by an increase
in local Rt (30% to 150%). Both effects were totally
reversed by MK-801 (15 to 100 nA) and therefore were attributed to
cation influx through the NMDA receptor ion channel and subsequent
cellular swelling20 21 22 (Fig
1
). Responses to NMDA were
reversible within 1 minute, and no desensitization was observed with
repeated applications of NMDA every 2 minutes. Regular applications
were continued during ischemia and reperfusion. On induction of
ischemia, NMDA-induced DC shifts were initially increased up to
332% of their preischemic amplitude (Figs 2 and
3 and
Table). NMDA-induced local Rt
increases were also enhanced up to 458% of their
preischemic values. Potentiation of the NMDA responses was
usually seen within the first 2 minutes of ischemia and was
associated with less than approximately 40% depression of the evoked
field potential. NMDA-induced DC shifts and Rt increases
were progressively inhibited as the evoked activity was further
depressed. NMDA responses could not be induced after disappearance of
the evoked activity even if the amount of NMDA applied was increased
(Figs 2 and 3). Both responses to NMDA recovered
concurrently with the
evoked potential during reperfusion (Figs 2 and
3) and, in three rats,
along with spontaneous partial recovery of the evoked activity during
ischemia.
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Effects of Ischemia on BAY K8644 Responses
Pressure
application of BAY K8644 for 1 to 5 seconds induced
extracellular negative DC potential shifts of 3 to 20 mV that were
antagonized by nimodipine (Fig 1). On ligation of the carotid
arteries,
BAY K8644-induced DC shifts were increased up to 183% of their
preischemic amplitude, although this effect did not reach
statistical significance (P=.07, Table; Figs
4 and 5). Potentiation was seen within the
first 2 minutes of ischemia when depression of the evoked
activity was less than 50%. BAY K8644-induced DC shifts were
progressively inhibited with further depression of the field response
and abolished when the stimulation-evoked activity disappeared
(Figs 4 and 5). Increasing the pressure or
duration of application
failed to restore BAY K8644 activity. Responses to BAY K8644 recovered
concurrently with the evoked activity during reperfusion (Fig
5). In
two experiments the evoked activity partly recovered after its total
failure and then deteriorated again during ischemia. In each
instance, BAY K8644 responses simultaneously recovered and
deteriorated with the evoked potential, indicating a close association
between the two activities. Longer applications (>10 seconds) were
required to overcome the local Rt drop caused by pressure
application and display the Rt increase induced by BAY
K8644. Since recovery took 3 to 5 minutes after long applications, they
were not suitable for repeated testing. Therefore, monitoring BAY K8644
action was confined to DC potential changes.
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Intracellular Recordings
CA1 neurons were impaled to assess
the direction of RMP
alterations during ischemia because both currents studied are
voltage dependent and can be inactivated by
hyperpolarization or excessive
depolarization.23 24 25 26 27
Most of these small neurons were
readily depolarized by electrode vibrations due to brain pulsation and
exhibited RMPs lower than actual (-38±2 mV, n=30, Fig
6), as reported previously.28 To avoid an
experimental bias tending to overestimate the mean membrane potential
difference between the control and ischemic neurons, we
evaluated all penetrations indicating a good electrode sealing even
though they had a low membrane potential. On induction of
ischemia, neurons further depolarized within a few minutes
(-26±3 mV, n=13, P<.001 by Student's
t
test, Fig 6). We were able to obtain stable recordings from two
neurons for more than 40 minutes and ligated the carotid arteries while
the electrode was still in the cell. RMPs of these cells were -52
and -50 mV and remained steady for 5 minutes before
ischemia was induced. After ligation of carotids, they were
depolarized by 16 mV in 2 and 5 minutes, respectively, and later by
another 10 mV with a slower time course29 30 (Fig
6). RMPs
of these neurons recovered to -42 and -40 mV after
recirculation. Despite limitations in determining the actual RMP, the
recorded RMP changes did not support the possibility that the
inactivation of NMDA- or BAY K 8644-induced currents was due to
hyperpolarization or excessive depolarization.
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Total blockade of NMDA-induced DC shifts and cellular swelling (extracellular resistance increase) by MK-801 strongly suggest that these changes are generated by cation and accompanying water influx through an NMDA receptor ion channel.20 21 22 The changes observed during ischemia in these parameters have therefore been regarded as a measure of altered NMDA receptor activity, although this is an indirect approach and these parameters might be influenced by other factors not related to channel activity. For example, ischemic neuronal swelling might obscure NMDA-induced neuronal swelling if neurons were already maximally swollen. However, we observed parallel changes in NMDA-induced DC shifts and resistance increases not only during mild ischemia when there was no significant cellular swelling but also with deepening of ischemia (compare Fig 3A
and 3B), suggesting
that altered
NMDA receptor activity was a major determinant of the observed changes.
One other factor that might influence channel activities is the
shrinkage of extracellular space during ischemia, which may
lead to an increase in local drug concentration. However, resistance
measurements showed that extracellular space was not shrunken when NMDA
effects were potentiated; conversely, it was shrunken when the drug
effects were depressed.
The dual effect of in vivo ischemia on NMDA effects is
consistent with in vitro findings in hippocampal slices
reporting that anoxia can depress or facilitate NMDA currents,
depending on experimental
conditions.31 32 33 These data also
agree with our previous report showing that the NMDA receptor
antagonist MK-801 restores partly deteriorated but not
severely depressed hippocampal evoked activity during
ischemia18 and suggest that one of the reasons for
inefficiency of NMDA antagonists during profound
ischemia may be the inactivation of NMDA currents in severe
energy failure. It is likely that, while increased extracellular
concentrations of excitatory amino acids and depolarization of neurons
provide a favorable milieu for NMDA receptor
activation,34 35 36 37 38
extracellular acidosis, increased
Zn2+, 
-aminobutyric acid and
adenosine levels, depletion of intracellular energy stores, and
rise in intracellular Ca2+ concentration may limit NMDA
receptor activation during
ischemia.10 39 40 41 42 43
The
recent demonstration that a particular redox form of nitric oxide,
nitrosonium ion (NO+), can inhibit NMDA receptor activity
through interaction with thiol groups44 also suggests that
the increase in nitric oxide level in ischemia45
constitutes another, yet less characterized mechanism for the
limitation of NMDA receptor activation. Loss of the response to
exogenously administered NMDA is unlikely to be due to saturation of
NMDA receptors by massive release of glutamate during ischemia
because inhibition of the NMDA responses was also observed before
ischemia-induced DC shifts developed. It has been shown
that substantial rises in extracellular glutamate are
consistently accompanied by large DC shifts.46
Moreover, microdialysis studies report a slower rise in extracellular
glutamate compared with the rapid decay of NMDA responses in our model.
Also, there is currently no evidence to support the unlikely
possibility that ischemia alters the sensitivity of NMDA or BAY
K8644 to their binding sites.
Our data also indicate that NMDA receptors are functional in ischemia that is not severe enough to cause transmission failure. This finding suggests that NMDA receptor-mediated neurotoxicity must be largely triggered before ischemia deepens and is therefore more likely to prevail in mildly ischemic areas.1 10 47 Studies showing that the NMDA receptor-mediated neurotoxicity is more significant in focal rather than global ischemia and in the penumbra rather than the core ischemic region support this idea.7 8 9 10 Reperfusion also appears to restore favorable conditions for NMDA receptor-mediated neurotoxicity.48
BAY K8644-induced DC shifts are likely to be caused by massive Ca2+ influx through DHP-sensitive Ca2+ channels activated by this powerful agonist. The fact that three Na+ ions are carried into the neurons for extrusion of every Ca2+ ion by Na+-Ca2+ exchanger is very likely to contribute to the development of extracellular negativity. Depolarization induced by cation influx may further facilitate opening of Ca2+ channels and hence may trigger a regenerative cycle. Glial uptake of increased extracellular K+ coming out through Ca2+-activated K+ channels and glutamate release induced by Ca2+ influx may also contribute to DC shifts. Although the ionic basis of BAY K8644-induced extracellular potential shift is not identified, its inhibition by nimodipine suggests that the primary event causing the potential shift is Ca2+ influx through DHP-sensitive Ca2+ channels.
The effect of ischemia on BAY K8644 responses was similar to its effect on NMDA responses. BAY K8644-induced extracellular potential shifts were increased during mild ischemia and depressed with deepening of ischemia. Although potentiation of these DC shifts did not reach statistical significance, possibly because of small sample size, we believe that this effect might be caused by facilitation of voltage-dependent Ca2+ channel activity by ischemic depolarization. On the other hand, inhibition of these responses could be attributed to increased intracellular Ca2+ or failure of channel phosphorylation.42 43 Inhibition of Ca2+ currents has also been demonstrated in hypoglycemia and anoxia in hippocampal slices.49 50 51 These observations were further elaborated by voltage clamping of hippocampal neurons or by recording presynaptic calcium influxes.52 53
In conclusion, these data suggest that NMDA and DHP-sensitive Ca2+ currents are inactivated during ischemia that is severe enough to cause transmission failure. During less intense ischemia and reperfusion, both channels are functional and can be overactivated to cause neurotoxicity.
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Selected Abbreviations and Acronyms |
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Received April 25, 1995; revision received September 12, 1995; accepted October 12, 1995.
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