The effects of the calcium entry blocker emopamil on physiological variables, local cerebral blood flow (LCBF) and on hippocampal cell damage were evaluated after 10 min of forebrain ischemia in the rat. LCBF was determined with the 14C-iodoantipyrine technique after 2, 10, and 60 min of postischemic recirculation. Histological evaluation was performed 7 days after ischemia in cortical and hippocampal tissue by determination of the percentage of necrotic neurons. Preischemic application of emopamil [4 mg/kg racemate or 2 mg/kg (S)-emopamil; i.v.] caused increased in LCBF in cortical areas but did not alter blood flow in the hippocampus at 2 min of recirculation. After 10 and 30 min of flow resumption no differences in LCBF between drug-treated and control animals were observed. In the histological series (S)-emopamil was applied at doses of 2, 4 or 6 mg/kg before the induction of ischemia. After 7 days of postischemic recovery, neuronal damage was significantly reduced by the calcium antagonist in hippocampal CA1 sector at all doses tested, the most prominent effects being observed with the lowest dose. At this dose cell loss in the CA3 sector was also reduced. In cortical tissue the number of necrotic cells remained unchanged by emopamil treatment. It is concluded that the calcium antagonist emopamil can reduce ischemia-induced neuronal cell damage. The compound improves circulation in cortical tissue only during early recovery but not at later phases of reflow, i.e. the period of delayed hypoperfusion. These increases in blood flow are not of crucial importance for ultimate neuronal death in this area.(ABSTRACT TRUNCATED AT 250 WORDS)

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Cerebral ischemia: pharmacological bases of drug therapy.

The cascade of reactions caused by ischemia in brain tissue is complex and not completely understood, but intensive investigation has led to convincing hypotheses. A disturbed calcium homeostasis and oxygen radicals seem to play a major role in postischemic neuronal damage. In accordance to these hypotheses drugs with different mechanisms of action have been developed. The aim of this paper is to give an overview over pathobiochemical mechanisms in cerebral ischemia and possibilities of pharmacological intervention.

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Brain damage caused by ischemia: pathophysiological and pharmacological aspects.

The distribution of brain cell injury after ischemic challenge is remarkable because only discrete brain areas are damaged, whereas other structures exhibit a very high resistance (selective neuronal death). The calcium hypothesis, one of the hypotheses that has been formulated to explain this selective vulnerability, postulates that an increase in excitatory amino acid release and the large calcium influx during ischemia leads to insufficient energy production and to stimulation of lipases, proteases, and endonucleases. This paper reviews the experimental data concerning the relationship between cerebral blood flow, glucose consumption and hippocampal morphological damage. The neuroprotective effects of some drugs against ischemic damage have also been discussed.

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[Action of domperidone on the lower esophageal sphincter. A double-blind cross-over study].

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[Measurement of free intracellular Ca2+ concentration in cultivated hippocampal neurons].

The cascade of pathobiochemical reactions caused by cerebral ischemia is complex and not completely understood. One important factor seems to be the disturbed calcium homeostasis. Measurement of cytosolic-free Ca2+ concentration [Ca2+]i is possible with the Ca(2+)-sensitive dye fura-2. Using this technique it can be investigated if, and how, neuroprotective drugs influence the cellular calcium homeostasis. In hippocampal neurons K+ or glutamate, added to the buffer solution, evoked elevations of [Ca2+]i in a concentration-dependent manner. We demonstrated that the calcium antagonist nimodipine or the non-competitive NMDA receptor antagonist dizocilpine added to the buffer solution could inhibit concentration-dependently the elevation of [Ca2+]i. The measurement of [Ca2+]i can be used for studies on the mechanism of action as well as for screening purposes of neuroprotective drugs.

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