Effect of Nimodipine on Cerebral Metabolism during Ischemia and Recirculation in the Mongolian Gerbil

Heffez, Dan S.; Passonneau, Janet V.

doi:10.1038/jcbfm.1985.79

Cited by 56 publications

(14 citation statements)

References 24 publications

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“…, 1985). Effects on postischemic energy metabolism could be demon strated with several compounds of this class of drugs (P roctor et aI., 1984;Heffez and Passonneau, 1985;Weber and Krieglstein, 1985;Bielenberg et aI., 1986;Krieglstein and Weber, 1986). Most of the effects hitherto observed have been demonstrated using the isolated perfused rat brain preparation.…”

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confidence: 98%

Effects of Cerebroprotective Agents on Cerebral Blood Flow and on Postischemic Energy Metabolism in the Rat Brain

Bielenberg

Beck

Sauer

et al. 1987

J Cereb Blood Flow Metab

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Summary: Male Wi star rats were subjected to forebrain ischemia of lO min duration by clamping both common carotid arteries and simultaneously lowering systemic blood pressure to 40 mm Hg by exsanguination. Re covery was achieved by removing the arterial clamps and reinfusing the blood. Cortical levels of high-energy phos phates and glycolytic substrates were determined enzy matically. Naftidrofuryl (10 or 20 mg/kg i.p.) or ketamine (5 mg/kg i.v.) were applied 30 min prior to the induction of ischemia. S(-)-Emopamil (4 mg/kg) or nimodipine (50 fLg/kg) were administered by intravenous infusion over 30 min. Nimodipine and emopamil increased the blood glu cose level and lowered preischemic blood pressure. Under control conditions, a tendency toward a higher cortical glucose level was observed in treated brains. Brain energy stores were exhausted after ischemia in control and treated animals to the same degree. Lactate levels, however, were higher in emopamil-treated an imals. This effect was attributed to the elevated pre ischemic glucose levels. During the early recovery pe riod, the restoration of high-energy phosphates was ac-A variety of the so-called cerebroprotective agents have been shown to ameliorate brain energy metabolism under hypoxic or ischemic conditions (Dirks et aI., 1984; Karcher et aI., 1984; Proctor et aI., 1984; Rachman et aI., 1984; Heffez and Passon neau, 1985;Krieglstein and Weber, 1986). The ef fects include, among others, increases in the level 480celerated by both calcium entry blockers. Nimodipine and emopamil increased the levels of glucose and glu cose-6-phosphate in the early postischemic period. Nafti drofuryl (10 mg/kg) increased the level of creatine-phos phate and ATP after 2 min of recovery. Naftidrofuryl (20 mg/kg) exerted no effect on cerebral energy metabolism, but considerably reduced postischemic blood pressure (possibly thereby masking its ameliorative action). Keta mine accelerated the postischemic restoration of high-en ergy phosphates. In the conscious rat, local cerebral blood flow (LCBF) was determined with the 14C-iodoan tipyrine technique following emopamil (20 mg/kg s.c.) or naftidrofuryl (10 mg/kg i.v.) application. Both com pounds increased LCBF values in the majority of grey matter structures. It was concluded that the cerebropro tective agents investigated share an accelerating effect on the postischemic restoration of high-energy phosphates in cerebral cortex. Key Words: Cerebral blood flow Cerebroprotective agents-Energy metabolism-Isch emia-Rat brain.of creatine-phosphate, ATP, glucose, and glucose-6-phosphate, as well as reduced ADP, AMP, and lactate levels. The interest mainly centers on the high-energy phosphates ATP and creatine-phos phate, as these substrates are essential for the maintenance of cellular function. A faster postisch emic restoration of these substrates, therefore, should improve the functional recovery of brain tissue. In the present study, compounds from dif ferent classes of drugs were investigated to eval uate whether or not they sh...

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confidence: 98%

Effects of Cerebroprotective Agents on Cerebral Blood Flow and on Postischemic Energy Metabolism in the Rat Brain

Bielenberg

Beck

Sauer

et al. 1987

J Cereb Blood Flow Metab

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“…1 Hemodynamic and metabolic studies revealed that neither blood flow nor energy metabolism is critically reduced during maturation, 27 indicating that the phenomenon of selective vulnerability cannot be explained by an energy crisis induced by postischemic recirculation disturbances. Instead, specific molecular mechanisms have been made responsible for the phenomenon.…”

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Effect of 5-minute ischemia on regional pH and energy state of the gerbil brain: relation to selective vulnerability of the hippocampus.

Munekata¹,

Hossmann²

1987

Stroke

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Adult male gerbils were submitted to 5-minute cerebral ischemia by bilateral carotid artery occlusion. At the end of ischemia and at various recirculation times ranging from 15 to 120 minutes, brains were frozen in situ and the regional distribution of ATP, glucose, and tissue pH was studied on coronal cryostat sections by bioluminescent and fluoroscopic techniques. During ischemia ATP was completely depleted, glucose decreased to< 10% of control, and regional tissue pH decreased from 7.04-7.09 to about 6.0. After the beginning of recirculation tissue pH and the regional content of metabolites exhibited a triphasic course. After 15 minutes pH returned to or even above normal, and ATP-and glucose-induced bioluminescence normalized. However, there was a secondary deterioration of both tissue acidosis and the metabolic state after 30 minutes. After longer recirculation times changes again improved and returned to normal within 2 hours. These changes were similar in all brain regions with the exception of the CA1 sector of the hippocampus, where the transient normalization of tissue pH was absent after 15 minutes of recirculation. This finding is in line with the previously observed microcirculatory insufficiency of this area and demonstrates that the CA1 sector of the hippocampus suffers more pronounced postischemic acidosis than other less vulnerable regions of the brain. (Stroke 1987;18:412-417)

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“…The effect of nimodipine on cellular energy metabolism following cerebral ischemia remains uncertain: Some investigators have reported that nimodipine retards the depletion of high-energy phosphates following cerebral ischemia, while others found nimodipine to have no effect on cerebral energy metabolism during ischemia (Bielenberg et al, 1987;Heffez and Passonneau, 1985;Kucharczyketal., 1989;Mabeetal., 1986;Protor et al, 1984;Sauter and Rudin, 1987). Nimodipine could potentially alter cerebral energy metabolism by improving cerebral perfusion to the ischémie region or by directly affecting ischémie cellular metabolism.…”

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confidence: 99%

The Effect of Nimodipine on High-Energy Phosphates and Intracellular pH During Cerebral Ischemia

Lemons¹,

Chehrazi²,

Kauten³

et al. 1993

Journal of Neurotrauma

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Experimental and clinical studies suggest that the calcium channel blocker nimodipine may reduce cerebral ischemic injury. Using rapid acquisition phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy, we examined the effect of nimodipine on cerebral energy metabolism during severe ischemia in gerbils. High-energy phosphates and intracellular pH were characterized at baseline and at 2-min intervals following bilateral common carotid artery (CCA) ligation. Serial forebrain spectroscopy was continued until phosphocreatine (PCr) and adenosine triphosphate (ATP) resonances disappeared. Controls (n = 10) were compared to gerbils receiving intraperitoneal nimodipine 30 min prior to carotid ligation, at the following doses: 0.5 mg/kg (n = 8), 1.0 mg/kg (n = 10), 2.0 mg/kg (n = 8), or 4.0 mg/kg (n = 4). In the control group, PCr and ATP peaks were undetectable after a mean of 5.4 +/- 0.47 min following CCA ligation. Compared with controls, the mean time for depletion of high-energy phosphates following carotid ligation was prolonged at nimodipine doses of 0.5 mg/kg and 1.0 mg/kg, but the differences did not reach statistical significance. In the 2.0 mg/kg group, however, ATP was preserved until 9.8 +/- 1.0 min following the onset of ischemia, significantly longer than the control group (p = 0.005, Mann-Whitney test). Nimodipine had no effect on the time course or severity of intracellular acidosis. In this model of severe ischemia, relatively high doses of nimodipine slowed the depletion of high-energy phosphates without altering intracellular acidosis. This suggests that nimodipine may provide cerebral protection by directly altering ischemic cellular metabolism.

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Effect of Nimodipine on Cerebral Metabolism during Ischemia and Recirculation in the Mongolian Gerbil

Cited by 56 publications

References 24 publications

Effects of Cerebroprotective Agents on Cerebral Blood Flow and on Postischemic Energy Metabolism in the Rat Brain

Effects of Cerebroprotective Agents on Cerebral Blood Flow and on Postischemic Energy Metabolism in the Rat Brain

Effect of 5-minute ischemia on regional pH and energy state of the gerbil brain: relation to selective vulnerability of the hippocampus.

The Effect of Nimodipine on High-Energy Phosphates and Intracellular pH During Cerebral Ischemia

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