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E T MacKenzie

Publications and source records attributed to E T MacKenzie.

At least 91 records · Page 5Linked to original sources
PubMed1987

Effects of the GABA receptor agonist, progabide, upon local cerebral glucose utilization.

The effects of a specific GABA receptor agonist, progabide, have been examined on local cerebral glucose utilization through the use of the autoradiographic [14C]2-deoxyglucose technique in conscious rats. The intraperitoneal administration of progabide (80-320 mg.kg-1) resulted in a heterogeneous pattern of significantly reduced glucose utilization throughout the 50 discrete regions of the brain that were studied. Insignificant decreases in local cerebral glucose use were noted following the low dose of progabide (80 mg.kg-1). Following progabide (160 mg.kg-1), reductions of approximately 20% in glucose utilization were observed in most of the extrapyramidal system (substantia nigra, pars compacta and reticulata; globus pallidus; caudate nucleus), some thalamic nuclei (lateral geniculate body, anterior and ventrolateral thalamic nuclei), a number of areas related to the limbic system (cingulate cortex; amygdala; hypothalamus; lateral habenula; nucleus accumbens; dorsal hippocampus as well as the CA3 field) and the raphé nuclei. In contrast, layer IV of the neocortex, the cerebellum and cerebellar nuclei, displayed only minimal (10-15%) reductions in glucose utilization. At the highest dose (320 mg.kg-1) examined, progabide effected widespread though heterogeneously distributed decreases in glucose use. The overall pattern of decreased glucose use seen with progabide was different from that noted with previously studied GABA-mimetic drugs, such as muscimol, except for those changes observed in the extrapyramidal and sensory-motor areas for which similar dose-response relationships occurred. A significant correlation was observed between progabide-induced decreases in glucose utilization and in serotonin synthesis in a number of brain areas. The pattern of progabide-induced changes in integrated functional activity is compatible with its neurochemical spectrum and could indicate the loci at which its anticonvulsant, antidepressant and extrapyramidal activities are initiated.

Animals↗
PubMed1987

Neuronal versus endothelial origin of vasoactive acetylcholine in pial vessels.

Functional pial vessels denuded in situ of the endothelial cell layer exhibit a markedly decreased choline uptake capacity (-53%) but integrally preserved choline acetyltransferase (ChAT) activity and acetylcholine (ACh) release mechanisms. These studies demonstrate that endothelial cells possess a specific choline uptake system. However, the unimpaired ChAT activity in denuded pial vessels implies that the endothelial pool of choline is not significantly metabolized into ACh. In spite of possible differences in the mechanisms that govern release processes in endothelial and neuronal elements, taken together the findings of the present study suggest that the ACh released following depolarization of pial blood vessels originates predominantly from cholinergic perivascular nerve terminals.

Acetylcholine↗
PubMed1987

The concept of coupling blood flow to brain function: revision required?

A tight coupling exists between brain function and cerebral perfusion in most situations. The Roy and Sherrington hypothesis has been widely accepted to account for the phenomenon: increased neuronal metabolic activity will give rise to the accumulation of vasoactive catabolites, which decrease vascular resistance and thereby increase blood flow until normal homeostasis is reestablished. However, the hypothesis does not account for the disproportionate increase in flow that occurs in a number of circumstances. There are additional difficulties in reconciling more recent experimental data with the Roy and Sherrington hypothesis. In this review we direct attention toward the rich perivascular nerve supply to all parts of the cerebral circulation as possibly being an alternative control system allowing for rapid parallel changes in flow and neuronal activity.

Animals↗
PubMed1987

Cortical hypometabolism and its recovery following nucleus basalis lesions in baboons: a PET study.

The cerebral metabolic rate for glucose was measured serially with positron emission tomography and [18F]fluorodeoxyglucose in five baboons with stereotactic electrocoagulation of the left nucleus basalis of Meynert (NbM). Four days after lesion, a significant metabolic depression was present in the ipsilateral cerebral cortex, most marked in the frontotemporal region, and which recovered progressively within 6-13 weeks. These data demonstrate that adaptive mechanisms efficiently compensate for the cortical metabolic effects of NbM-lesion-induced cholinergic deafferentation. Moreover, unilateral NbM lesions also induced a transient reduction in contralateral cortical metabolic rate, the mechanisms of which are discussed. Explanation of these effects of cholinergic deafferentation in the primate could further our understanding of the metabolic deficits observed in dementia of the Alzheimer's type.

Animals↗
PubMed1987

NADH fluorescence in vivo: changes in cerebral oxidative metabolism and perfusion induced by pentobarbital, indomethacin, and salicylate.

The effects of two prostaglandin synthesis inhibitors on brain oxidative metabolism and cerebral blood volume were studied by the nicotinamide adenine dinucleotide (reduced) (NADH) fluorescence technique in rats. Indomethacin (5, 10, and 15 mg/kg) and sodium salicylate (50, 100, and 300 mg/kg) were administered intravenously to groups of rats anesthetized with either nitrous oxide or pentobarbital (40 mg/kg, i.p.). The effects of pentobarbital alone were also examined: pentobarbital induced a progressive reduction in blood volume 4 min following intraperitoneal administration. A reduced NADH fluorescence (oxidation) was noted approximately 9 min after pentobarbital treatment. In N2O-anesthetized rats, the effects of salicylate were dose-dependent. Low doses (50 and 100 mg/kg) decreased both blood volume and NADH fluorescence; in contrast, salicylate at 300 mg/kg increased blood volume and NADH fluorescence. Following pentobarbital, the effects of salicylate (50 and 100 mg/kg) were reversed: increases in both blood volume and NADH fluorescence were seen. In the absence of pentobarbital, it would appear that salicylate induces a cerebral vasoconstriction, an effect that may be obscured by a central stimulation provoked by this drug. Under N2O anesthesia, indomethacin, in a dose-related manner, induced a decrease in blood volume that was accompanied by a dose-related increase in NADH fluorescence (reduction). The changes induced by the highest dose of indomethacin (15 mg/kg) were essentially abolished by pentobarbital. These results support those studies in which indomethacin-induced cerebral vasoconstriction could be abolished by barbiturates. Furthermore, our experiments demonstrate, following indomethacin infusion, a decrease in brain oxidative metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Concentrations of putative neurovascular transmitters in major cerebral arteries and small pial vessels of various species.

The levels of noradrenaline, neuropeptide Y, 5-hydroxytryptamine, and substance P were measured and compared between the large arteries of the circle of Willis and the small cerebral vessels of the pia mater in the rat, rabbit, cat, and monkey. In all species, noradrenaline and neuropeptide Y concentrations were greater in the larger arteries than in small pial vessels. Noradrenaline concentrations were dramatically reduced following cervical sympathectomy, with the extent of diminution differing greatly in the various species; the effects of cervical ganglionectomy on neuropeptide Y concentrations were less pronounced. 5-Hydroxytryptamine concentrations in rats, cats, and rabbits were significantly greater in the small pial vessels, although measurable concentrations existed in the circle of Willis. In cats and monkeys, substance P was found in major arteries, but was not detectable at the level of the small pial vessels. The differences in the regional distribution of the various neurotransmitter candidates in the cerebrovascular bed may reflect their physiological significance.

Animals↗
PubMed1987

Serotonergic neuron stimulation modulates thalamocortical glucose use in the conscious rat.

We have studied the effects, in the conscious rat, of electrical stimulation of the dorsal or median raphe nuclei on integrated functional activity, as assessed by the quantitative 2-deoxyglucose autoradiographic technique. Stimulation of serotonergic neurons elicits metabolic changes in cortical and thalamic regions that are not limited to those structures known to receive the densest serotonergic innervation. The thalamic nuclei that are activated by raphe stimulation include those that subserve the processing of somesthetic, accessory visual, and limbic information. Raphe stimulation increased cortical glucose use in a laminar and columnar pattern, but only in a highly circumscribed region that corresponds to the somatotopic representation of the rat's face and head. These findings indicate that ascending serotonergic neurons play an important modulatory role in the regulation of thalamocortical glucose use, observations that may be of value in the understanding of the etiology and expression of classic migraine.

Animals↗
PubMed1987

Cerebral circulatory and metabolic effects of perivascular neurotransmitters.

In this article we review the most recent literature that concerns the various neurotransmitters that are known to innervate the cerebral circulation. The best characterized of these systems (the adrenergic and serotonergic pathways) are discussed extensively, but other putative neurovascular pathways (cholinergic and peptidergic nerves) was covered. The review will be divided into five major sections: the origin and nature of the perivascular nerve fibers in the cerebrovascular bed (this section encompasses both morphological and biochemical investigations); the response of isolated cerebral vessels to neurotransmitters and transmural nerve stimulation (covering the uptake and release of transmitters by brain vessels as well as the pre- and postsynaptic effects of these agents on cerebrovascular smooth muscle); the effects of neurotransmitter and other vasoactive agents on cerebral perfusion and metabolism in vivo. This section includes the effects of perivascular nerve stimulation or ablation on cerebral blood flow as well as on capillary (i.e., blood-brain barrier) properties. The regional metabolic effects of neurotransmitters are compared to their known effects on neuronal function; the involvement of various neurotransmitters in a number of cerebrovascular diseases (in particular, migraine, cerebral vasospasm following subarachnoid hemorrhage and cerebral ischemia, or stroke); and we attempt to synthesize the ever-increasing literature on the origin and function of the multiple innervation of two other noncerebral, intracranial tissues: the choroid plexus and the dura mater.

Animals↗
PubMed1986

Functional mapping of the effects of lesions of the habenular nuclei and their afferents in the rat.

Through the use of the quantitative autoradiographic 2-[14C]deoxyglucose technique, we have investigated the functional significance of the habenular nuclei by the measurement of local cerebral glucose utilization (LCGU) in discrete brain areas of conscious rats following 3 kinds of lesioning. Bilateral electrolytic lesions of the habenular nuclei decreased LCGU in a limited number of well-defined brain areas (the interpeduncular nucleus, median and dorsal raphe, mammillary body and dorsal tegmental nucleus) at 7 and 14 days after lesions. These changes were also observed 180 days following lesioning except that of the dorsal tegmental nucleus. At 14 days after bilateral ibotenic acid-induced lesions of the lateral habenula, LCGU was significantly decreased in the median and dorsal raphe, mammillary body and interpeduncular nucleus. In further studies, bilateral electrolytic lesions of the stria medullaris (which conveys the major afferents to the habenula) decreased glucose use in the interpeduncular nucleus less than that observed after bilateral electrolytic lesions of the habenular nuclei. A highly significant positive correlation was observed between LCGU and choline acetyltransferase activity in the interpeduncular nucleus after all types of lesion. These results further support the view that the medial and the lateral habenula exert a major influence upon functional activity in the interpeduncular nucleus and the mesencephalic raphe nuclei, respectively.

Animals↗
PubMed1986

Temporal effects of habenular lesions on glucose utilization in the anterior raphé nuclei of the rat.

The effects of bilateral electrolytic lesions of both lateral and medial habenular nuclei on local cerebral glucose utilization have been examined in conscious rats by the use of the quantitative 2-deoxy[14C]glucose autoradiographic technique. Habenular lesions markedly reduced the use of glucose in the median raphé and, to a lesser extent, in the dorsal raphé nuclei (which receive major afferents from the lateral habenula) at 7, 14 and 180 days after the lesion. Habenular lesions failed to alter the use of glucose in the entopeduncular nucleus, lateral hypothalamic area and the nucleus of the diagonal band of Broca which project to the habenula. These data add further support to the view that the habenula exerts a major facilitatory influence upon functional activity in the anterior raphé nuclei.

Animals↗
PubMed1985

Neurochemical studies on the existence, origin and characteristics of the serotonergic innervation of small pial vessels.

Substantial concentrations of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), comparable to those found in brain tissue, were measured in the small pial vessels of the rat, rabbit and cat. Both rat and rabbit pial vessels exhibited a high affinity uptake process with kinetic parameters similar to those identified for the cerebral cortex. Labelled 5-HT, taken up by isolated rabbit pial vessels was released, in a calcium-dependent manner, by potassium-induced depolarization. Various pharmacological manipulations were carried out in the rat. Systemic administration of the 5-HT precursor, 5-hydroxytryptophan and the monoamine oxidase inhibitor, pargyline, significantly increased the concentration of 5-HT in the pial vessels; in contrast, two depleting agents (p-chloroamphetamine and reserpine) and the tryptophan hydroxylase inhibitor, p-chlorophenylalanine, all decreased the perivascular 5-HT levels. A serotonergic antagonist (methysergide) and a 5-HT receptor agonist (MK 212) respectively increased and decreased the concentrations of 5-HIAA in the pial vessels. These pharmacologically induced changes observed in pial vessels were not dissimilar from those noted for cortical tissue. Electrolytic lesions of the nuclei raphes medianus and/or dorsalis markedly decreased the levels of 5-HT and 5-HIAA in these small cerebral arterioles. Electrical stimulation of these nuclei decreased 5-HT although 5-HIAA concentrations tended to increase. A number of conclusions may be drawn from these studies. Thus, there is a serotonergic innervation of the cerebral circulation in several laboratory species which unequivocally originates in the raphé nuclei. Furthermore, these perivascular fibres possess synthetic, storage, release, inactivation and autoregulatory processes for 5-HT which, when further elucidated, may offer some rationale for the treatment of those cerebrovascular diseases in which this neurotransmitter and vasoactive agent is believed to be of pathological importance.

Animals↗
PubMed1985

Functional bases for a central serotonergic involvement in classic migraine: a speculative view.

The rôle of serotonin (5-HT) in the cerebrovascular bed is the subject of the following review. Cerebral blood vessels are supplied with 5-HT-containing fibres which originate in the raphé nuclei in the brainstem. The activation of this system may result in a constriction of large arteries and a dilatation of arterioles. Intra-arterial administration of 5-HT causes reduction in cerebral blood flow and metabolism provided it bypasses the blood-brain barrier. The findings, marked changes in plasma levels of 5-HT and in cerebral blood flow during a classic migraine attack, are suggestive of an involvement of the 5-HT system.

Animals↗
PubMed1985

Cerebrovascular responses to haemorrhagic hypotension in anaesthetized cats. Effects of alpha-adrenoceptor antagonists.

Haemorrhagic hypotension induces the phenomenon of cerebrovascular autoregulation and, concomitantly, involves an activation of the sympathetic nervous system. As brain vessels in cats have an atypical adrenoceptor distribution we studied the effects of an alpha-adrenoceptor antagonist on the autoregulatory response to haemorrhage. Cortical blood flow was studied by the H2 technique in chloralose-anaesthetized cats subjected to a period of graded haemorrhage over 3 h. Three groups of cats were studied: control, i.e. those receiving saline (n = 10); yohimbine-treated (200 micrograms . kg-1 . h-1, n = 7); and prazosin-treated (50 micrograms . kg-1 . h-1, n = 6). In the control group, cortical blood flow remained relatively constant when mean arterial pressure was decreased from 102 +/- 1 mmHg (mean +/- SE) to approximately 50 +/- 1 mmHg; thereafter, blood flow decreased with decreasing perfusion pressure. In the arterial pressure range 64-55 mmHg, cortical blood flow was significantly higher in the yohimbine group (109 +/- 12 ml . 100 g-1 . min-1) compared to the control group (69 +/- 6 ml . min-1) and remained higher in the yohimbine-treated cats at more extreme levels of hypotension. Blood flow did not fall significantly in the yohimbine-treated cats until mean arterial pressures of 31 +/- 1 mmHg were attained. In the prazosin-treated cats, flow began to decrease at arterial pressures even greater than those observed in the control group. Thus, there is a sympathetic vasoconstriction of brain arteries that is primarily mediated by alpha 2-adrenoceptors in the feline cerebrovascular bed.

Anesthesia, General↗
PubMed1984

Indoleaminergic mechanisms in brain vessels; localization, concentration, uptake and in vitro responses of 5-hydroxytryptamine.

Immunocytochemical studies have revealed the presence of 5-HT-containing nerve fibres in all parts of the cerebrovascular bed (arteries, arterioles and veins) of mouse, rat, guinea-pig, rabbit and cat. Biochemical measurements (using HPLC) revealed substantial concentrations of 5-HT and 5-HIAA in the pial vessels of the rat, rabbit, cat and man, the amounts corresponding well with the density of the perivascular nerve supply. The uptake of 3H-5-HT was studied in arteries removed from the circle of Willis in rats. Maximum uptake was reached after 15 min of incubation at 37 degrees C and plateaued at 30 min. The reaction was temperature-dependent and found to be absent if performed at 0 degrees C. Pharmacological experiments on isolated middle cerebral and basilar arteries showed that vessels from rat and dog were contracted by approximately 90% upon administration of 5-HT, whereas vessels from guinea-pig, rabbit, cat and man were contracted by 40 to 60% relative to 124 mM K+. The EC50 values in the different species varied by between 1.5 X 10(-7) M (rat) and 3 X 10(-9) M (dog). The 5-HT-induced contractions were blocked by the 5-HT antagonists, methysergide, methergoline and ketanserin. Transmural nerve stimulation (TNS) of the rabbit basilar artery revealed a tetrodotoxin sensitive constriction whereas TNS of cat and dog middle cerebral arteries caused a tetrodotoxin-sensitive relaxation. The relaxation was not significantly attenuated until high doses of methergoline (3 X 10(-6) M) or ketanserin (3 X 10(-5) M) had been given.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Ischaemic brain damage induced by rapid lowering of arterial pressure in hypertension.

Mean arterial pressure (MAP) and cerebral blood flow were monitored in six normotensive [MAP = 99 +/- 3 mmHg (s.e.m.)] and seven baboons with renovascular hypertension (MAP = 140 +/- 5 mmHg). Arterial pressure was decreased sufficiently rapidly and for a sufficient time, as determined by the electroencephalogram (EEG), to result in ischaemic brain damage. Using a combination of a bolus injection of trimetaphan, head-up tilt and acute withdrawal of blood, an isoelectric EEG was achieved at a higher MAP in the hypertensive (32 +/- 2 mmHg) than in the normotensive (19 +/- 1 mmHg: P less than 0.001) animals. Cerebral blood flow decreased to an equivalent degree in both groups. Ischaemic brain damage accentuated in the arterial boundary zones was seen in five normotensive and six hypertensive animals. This is further evidence that the resistance vessels in chronic hypertension may limit the degree of hypotension (therapeutic or accidental) that can be tolerated by the hypertensive patient.

Animals↗