The major pharmacological findings with nimodipine reviewed in this chapter are summarized in TABLE 3. On the basis of these findings, the following conclusions appear to be justified: 1. Nimodipine is a 1,4-dihydropyridine with Ca2+ channel antagonist properties. It is more lipophilic than nifedipine and its distribution volume in the brain of rats is higher than that of nifedipine. 2. Nimodipine dilates cerebral vessels at considerably lower concentrations than required for dilatation of peripheral blood vessels. It can, therefore, improve cerebral blood flow at doses that do not reduce systemic arterial pressure. 3. Nimodipine inhibits 45Ca uptake into vascular smooth muscle and neuronal cells. 4. Nimodipine antagonized postischemic cerebral hypoperfusion in cats and prolonged life of stroke-prone spontaneously hypertensive (SH) rats at doses that have little if any effect on arterial blood pressure. 5. Nimodipine reduced neurological deficits in dogs and monkeys with global cerebral ischemia. In focal ischemia (MCA occlusion) nimodipine reduced infarct size and neurological deficits and normalized intracellular brain pH. 6. In addition to its cerebral vasodilator effect, nimodipine appears to have a direct neuronal action. The suggested evidence for the neuronal site of action of nimodipine includes: a. Presence of nimodipine binding sites in brain. b. Blockade by nimodipine of Ca2+ channels in single nerve cells and in endocrine cells under conditions of sustained depolarization. c. Interactions with centrally acting drugs. d. Effects on release of various neurotransmitters from neuronal tissue or endocrine cells. e. Demonstration of anticonvulsant action of nimodipine. f. Blockade of behavioral effects of Ca2+ channel agonists by calcium channel antagonists.

Summary:The regional content of biochemical sub strates of energy-producing metabolism was assessed in cat brains following prolonged cerebral ischemia. Isch emia was produced by intrathoracic occlusion of the in nominate, the left subclavian, and both mammarian ar teries, and addi�onal lowering of the systolic blood pres sure to 80 mm Hg. After 60 min of global ischemia and 3 h of recirculation, the regional distribution of glucose, ATP, and NADH was evaluated on intact brain sections by bioluminescence and fluorescence techniques. Addi tionally, the content of different substrates related to en ergy and redox state was assessed in small tissue sam ples. Recirculation following global ischemia led to three different patterns of biochemical substrates: in 6 of 14 animals, regional distribution of glucose, ATP, and NADH was similar to that of control animals. These animals ex hibited recovery of evoked potentials and reappearance of low-voltage EEG activity. In five animals, ATP wasThe mechanisms responsible for occurrence or absence of functional recovery of the nervous system after prolonged ischemia are still poorly un derstood. It is evident that breakdown of energy producing metabolism during ischemia is not a lim iting factor for recovery of functional activity during recirculation, because a substantial restoration of energy-rich compounds has been observed after 60 min of complete ischemia of the total brain (Klei hues et aI., 1975). Instead, other biochemical or bio physical disturbances such as changes in the cal cium activity (Harris et aI. , 1981), increased lipo lytic activity as indicated by formation of free fatty acids (Bazan, 1970), disturbances of protein biosyn thesis (Kleihues and Hossmann, 1971), or formation of free radicals leading to lipid peroxidation (Flamm 321decreased in small circumscribed regions belonging to border zones of cerebral vessels. In these regions, glu cose was high and NADH-fluorescence was low, indi cating that glucose deficiency was not the limiting factor for ATP depletion. In this group, evoked potentials re covered, but the EEG did not. In three animals, glucose and ATP were low throughout the whole brain, and e1ec trophysiological recovery was absent. The pattern and localization of biochemical lesions and the correlation with hemodynamic and electrophysiological parameters sug gest that disturbances of energy-producing metabolism are caused by regional ischemic episodes during the re circulation period and can be prevented by the immediate and homogeneous blood reperfusion of the brain after cerebrocirculatory arrest.

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Glycerol, the end product of phospholipid degradation, was measured in cat brains under pathophysiological conditions known to cause activation of lipolysis, namely, bicuculline-induced seizures, permanent focal cerebral ischemia (2 hr of middle cerebral artery occlusion), and global cerebral ischemia (15 min of complete cerebral ischemia with or without 2 hr of recirculation). In addition, ATP and lactate were measured in order to correlate the activation of lipid degradation with disturbances in the energy-producing metabolism. A highly significant increase in the tissue glycerol content was observed after 1 hr of bicuculline-induced seizures (from 0.29 +/- 0.07 mumol/g in control animals to 1.30 +/- 0.06 mumol/g in seizure animals; P less than 0.001) or after 15 min of complete cerebral ischemia (from 0.29 +/- 0.07 to 1.17 +/- 0.14 mumol/g; P less than 0.01). Furthermore, a close correlation was found between the increase in glycerol and the increase in lactate or decrease in ATP after permanent focal ischemia. In contrast, following recirculation after complete cerebral ischemia, restoration of the energy pool did not lead to a reduction of the glycerol formed during ischemia. It is concluded that glycerol is a useful indicator of lipid degradation under pathological conditions. Since glycerol formed during vascular occlusion is trapped in brain cells, presumably owing to low glycerol kinase activity, it can be used as a stable postischemic indicator of ischemia-induced lipid degradation.

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