Effect of the Calcium Antagonist Nimodipine on Local Cerebral Blood Flow and Metabolic Coupling

Mohamed, A. A.; Mendelow, AD; Teasdale, Graham M.; Harper, A. M.; McCulloch, James

doi:10.1038/jcbfm.1985.4

Cited by 78 publications

(19 citation statements)

References 35 publications

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“…Several possible mechanisms suggest that such drugs ameliorate ischemic cerebral damage by affecting cerebral vasoconstriction, 518 platelet aggregation, 19 and neuronal membrane and mitochondrial functions. 20 Recent investigations into brain ischemia in several animal species 2 -4 -21 - 22 and stroke patients 23 -24 have shown that calcium entry blockers may improve cerebral blood flow and metabolism. Improvements in neurologic and neuropathologic outcomes have also been observed in other studies.…”

Section: Discussionmentioning

confidence: 99%

Attenuated neuropathology by nilvadipine after middle cerebral artery occlusion in rats.

Kawamura

Shirasawa

Fukasawa

et al. 1991

Stroke

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We investigated the effects of nilvadipine, a calcium antagonist, on cerebral ischemia in rats. Under halothane anesthesia, 30 rats had a 3-0 nylon suture introduced through the ex'tracranial internal carotid artery to occlude the left middle cerebral artery. Nilvadipine was dissolved in polyethylene glycol 400. Immediately following occlusion, group 1 rats (n=10) were treated subcutaneously with vehicle and group 2 and 3 rats were treated with 1.0 (n=10) add 3.2 (n = 10) nig/kg nilvadipine, respectively. Pcrfusion fixation was performed 24 hours later, and the histopathologlc outcomes were quantified. In group 1 infarct volume was 28.2 ±11.4% of the total cerebral volume; in groups 2 and 3 infarct volumes were 25.5±11.6% (NS) and 13.9±9.2% (p<0.05 different from group 1), respectively. Nilvadipine decreased ischemic neuronal injury in a dose-dependent manner and may be of use in the treatment of cerebral ischemia. 1 Thus, the inhibition of Ca 2+ entry into cells has been proposed as a therapeutic measure for cerebral ischemia, 2 " 4 and recent evidence suggests that calcium entry blockers attenuate ischemic neuronal damage through two mechanisms: dilation of cerebral vessels and prevention of excessive Ca 2+ influx into cytoplasmic and mitochondria! compartments.2 -5 ' 6 Nilvadipine (FR 34235) is a new dihydropyridine calcium entry blocker structurally related to nifedipine 7 but 5-10 times more potent against KC1-induced vasoconstriction in dog coronary and basilar artery strips.8 Previous research has shown that nilvadipine has a potent vasodilator effect similar to that of nifedipine on norepinephrine-induced constriction in the basilar artery 9 and thoracic aorta 10 of rabbits. Moreover, nilvadipine was effective in reducing ischemia in a dog model of chronic coronary artery occlusion 1 ' and may be a therapeutic agent for cerebral ischemia. 12We investigated the effects of nilvadipine on focal cerebral ischemia. In an improved rat model of uniFrom the Departments of Surgical Neurology (S.K., N.Y.) and Pathology (M.S., H.F.), Research Institute for Brain and Blood Vessels-Akita, Akita Japan.Address for correspondence: Shingo Kawamura, MD, Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-Akita, 6-10, Senshu-kubota-machi, Akita 010, Japan.Received May 1, 1990; accepted September 20, 1990. lateral middle cerebral artery (MCA) occlusion, we used the intraluminal suture technique 13 -14 and assessed histopathologic outcomes. Materials and MethodsThirty adult male Sprague-Dawley rats weighing 250-340 g were housed at 22±2°C, 50+10% humidity, and a 12-hour light/dark cycle with free access to food and water. Halothane was used to induce (4% in a mixture of 75% N 2 O and 25% O 2 ) and maintain (1%) anesthesia; 0.25 mg i.p. atropine sulfate was used for premedication. Each rat was allowed to breathe spontaneously, and rectal temperature was maintained at 37 C C with a heating pad. The tail artery was cannulated for continuous monitoring of mean arterial blood pressure, as well as f...

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Section: Discussionmentioning

confidence: 99%

Attenuated neuropathology by nilvadipine after middle cerebral artery occlusion in rats.

Kawamura

Shirasawa

Fukasawa

et al. 1991

Stroke

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“…These data are derived from reanalysis of the CBF investigations of Mohamed et al (1985a). Only data from the hemisphere ipsilateral to MCA occlusion are shown.…”

Section: Effect Of Nimodipine On Lcbf After Mca Occlusionmentioning

confidence: 99%

Nimodipine and the Haemodynamic and Histopathological Consequences of Middle Cerebral Artery Occlusion in the Rat

Gotoh

Mohamed

McCulloch

et al. 1986

J Cereb Blood Flow Metab

146

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Summary:The effect of the administration of nimodipine (1 f-lg kg-I min-I), initiated 5 min after occlusion of a middle cerebral artery (MCA), upon cerebral haemody namics ([14Cjiodoantipyrine autoradiography) and neuro pathological outcome (volume of histologically ischaemic tissue) was investigated in anaesthetized rats. Measure ments were made of the level of local CBF (LCBF) in a total of 37 neuroanatomically defined areas, either ipsi lateral or contralateral to the occluded vessel, and the autoradiograms were examined using a new approach to quantitative densitometry that employed a frequency dis tribution analysis of the CBF in sections of the brain at different coronal planes. Both methods of analysis showed that nimodipine, administered after the isch aemic event, did not modify the pattern of CBF distri-The outcome of an ischaemic insult may be im proved by the prevention of CBF falling below a critical threshold or by increasing the tolerance of neuronal cells to the ischaemic insult. It is sug gested that both of these can be achieved by cal cium antagonists because calcium is crucially in volved both in vasomotor events in cerebral vessels and in the evolution of irreversible damage at the cellular level (Siesjo, 198 1). 321bution after MCA occlusion, The extent of ischaemic brain damage was determined by histological examina tion, There was no evidence that the extent of ischaemic damage, either in sections at eight different coronal planes or in overall volume, was significantly different in animals that received nimodipine from that observed in animals that received only the vehicle used to dissolve the drug, The lack of cerebral circulatory and neuropath ological alterations when nimodipine administration is initiated after occlusion of the MCA is contrasted with the higher levels of LCBF and the reductions in the volume of ischaemic tissue that were found when nimo dipine was administered before occlusion of the artery.

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“…The part of the increase in CBF produced by felodipine and nicardipine may be ex plained by the enhanced CMR02. However, the percent increases in CMR02 produced by felodipine and nicardipine were much smaller than those in CBF, indicating that the in crease in CBF produced by these drugs was mainly due to a direct vasodilating action on the cerebral blood vessels; if a substance in creases CBF through enhancement of the cerebral oxygen consumption, the percent increase in CBF would be equal to the percent increase in cerebral oxygen consumption (10,14).…”

Section: Discussionmentioning

confidence: 99%

“…This is in accordance with the results of experiments conducted by d'Avella et al (13) in unanesthetized rats with nimodipine, another dihydropyridine calcium antagonist. Although Haws et al (12) and Mohamed et al (14) reported that nimodipine did not in crease CMRO2 or cerebral glucose uptake, their experiments were conducted in an esthetized animals. As a possible explanation for the enhancement of the cerebral metabolic rates, the elevation of cyclic AMP level due to inhibition of phosphodiesterase (15, 16) could be invoked, for it was known that intracarotid administration of cyclic AMP or intracisternal dibutyryl cyclic AMP could increase CBF, CMR02 and cerebral glucose consumption and reduce CVR in the baboon (17).…”

Section: Discussionmentioning

confidence: 99%

Effects of calcium antagonists, felodipine and nicardipine, on cerebral circulation in dogs.

et al. 1990

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Abstract-The effects of a calcium antagonist of the dihydropyridine type, felodipine, on the cerebral circulation were studied in comparison with those of nicardipine in pancuronium-bromide immobilized unanesthetized dogs. Felodipine (0.3-10 iig/ kg. i.v.) and nicardipine (0.3-10 ,cig/kg, i.v.) produced a dose-related decrease in mean blood pressure with almost equal potencies.However, at a dose of 3 iig/kg, felodipine produced a more prominent increase in cerebral blood flow (CBF) than nicardipine.Decreases in cerebral vascular resistance were significantly greater in the felodipine group at doses of 0.3 and 3 /tg/kg, when compared with the nicardipine group.Cerebral oxygen consumption calculated by multiplying the arterio-venous difference of oxygen content by CBF was increased by these two drugs, but the changes were minimal. These data suggest that the increase in CBF produced by felodipine and nicardipine was primarily due to the direct dilatation of the cerebral blood vessels.

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Effect of the Calcium Antagonist Nimodipine on Local Cerebral Blood Flow and Metabolic Coupling

Cited by 78 publications

References 35 publications

Attenuated neuropathology by nilvadipine after middle cerebral artery occlusion in rats.

Attenuated neuropathology by nilvadipine after middle cerebral artery occlusion in rats.

Nimodipine and the Haemodynamic and Histopathological Consequences of Middle Cerebral Artery Occlusion in the Rat

Effects of calcium antagonists, felodipine and nicardipine, on cerebral circulation in dogs.

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