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Biomedical subjects

J McCulloch

Publications and source records attributed to J McCulloch.

At least 181 records · Page 10Linked to original sources
PubMed1987

Capsaicin and blood-brain barrier permeability.

The influence of perivascular sensory afferent nerve fibres upon the permeability of the blood-brain barrier was examined in halothane-anaesthetised rats. Blood-brain barrier permeability was assessed by the rate of transfer of the small neutral amino acid, [14C]alpha-aminoisobutyric acid, from blood to brain and by gross extravasation of Evans blue albumin. In every brain area examined, the acute administration of capsaicin (0.15-5 mumol/kg, i.v.) failed to alter significantly the passage into the brain of the small neutral amino acid tracer or to effect dye extravasation. Capsaicin, at concentrations which cause the release of vasoactive neuropeptides from nerve endings and increase vascular permeability in peripheral tissues, does not increase the permeability of the blood-brain barrier.

Aminoisobutyric Acids↗
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

Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects.

The innervation of cerebral blood vessels by nerve fibers containing calcitonin gene-related peptide (CGRP) and the vasomotor effects of this peptide are described for a number of different mammalian species. CGRP-immunoreactive nerve fibers were present in the adventitia of cerebral arteries in all species examined (guinea pig, cat, rabbit, rat, and mouse). Numerous perikarya containing CGRP immunoreactivity are demonstrable in the trigeminal ganglion of all species. In the cerebral perivascular nerve fibers and in trigeminal perikarya, CGRP is often colocalized with substance P and neurokinin A. Marked interspecies differences exist both in the density of CGRP-immunoreactive nerve fibers and in the cerebrovascular levels measured with radioimmunoassay. The highest concentrations were observed in cerebral vessels from guinea pigs, the lowest concentration in rabbit vessels, and intermediate levels in the feline and human cerebral vasculature. CGRP is a potent dilator of cerebral arteries in all species examined (human pial, feline middle cerebral, rabbit, guinea pig and rat basilar arteries). The concentration of CGRP eliciting half-maximal responses ranged from 0.4 nM (human pial artery) to 3 nM (rat and rabbit basilar arteries). Pretreatment of cerebral arteries with low concentrations of either substance P (0.1 nM) or neurokinin A (3 nM) attenuated slightly the CGRP-induced relaxations of guinea pig basilar arteries. Calcitonin was found to be a very weak dilator of cerebral arteries from human and guinea pig. Thus, cardiovascular nerve fibers containing CGRP appear to be present in all mammalian species (although to varying degrees) and CGRP is invariably a potent dilator of the cerebral arteries for all species.

Animals↗
PubMed1987

Nerve fibers containing neuropeptide Y in the cerebrovascular bed: immunocytochemistry, radioimmunoassay, and vasomotor effects.

Perivascular nerve fibers containing neuropeptide Y (NPY)-like immunoreactivity were identified around cerebral blood vessels of human, cat, guinea pig, rat, and mouse. The major cerebral arteries were invested by dense plexuses; veins, small arteries, and arterioles were accompanied by few fibers. Removal of the superior cervical ganglion resulted in a reduction of NPY-like material in pial vessels and dura mater. Pretreatment with 6-hydroxydopamine or reserpine reduced the number of visible NPY fibers and the concentration of NPY in rat cerebral vessels. Sequential immunostaining with antibodies toward dopamine-beta-hydroxylase (DBH) (an enzyme involved in the synthesis of noradrenaline) and NPY revealed an identical localization of DBH and NPY in nerve cell bodies in the superior cervical ganglion and in perivascular fibers of pial blood vessels, suggesting their coexistence. Administration of NPY in vitro resulted in concentration-dependent contractions that were not modified by a sympathectomy. The contractions induced by noradrenaline, 5-hydroxytryptamine, and prostaglandin F2 alpha and the dilator responses to calcitonin gene-related peptide were not modified by NPY in rat cerebral arteries. However, the constrictor response to NPY was reduced by 70% in the presence of the calcium entry blocker nifedipine, and abolished following incubation in a calcium-free buffer. These data suggest an interaction of NPY at a postsynaptic site, which for induction of contraction may open calcium channels in the sarcolemma of cerebral arteries.

Animals↗
PubMed1987

Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia.

A method for the volumetric assessment of early cerebral infarction, together with its statistical and biological validation, is described. In halothane anaesthetised rats the stem of the right middle cerebral artery was occluded and 3 hours later (with full monitoring of respiratory and cardiovascular status) the animals were killed by perfusion fixation. In normotensive normocapnic animals the volume of infarction was 52 +/- 4 mm3 in the cerebral cortex and 21 +/- 1 mm3 in the corpus striatum. The reproducibility of the volumetric assessment was found to be excellent (coefficient of correlation 0.995 on 18 replicate measurements). The minimum number of stereotactic levels which must be assessed to yield accurate volumetric measurements of infarction is 8. The method is sensitive at detecting alterations in the amount of infarction. For example, it can readily detect the increase in amount of structural damage in cerebral cortex following a transient episode of hypotension. This approach allows an objective assessment of drug therapy and management strategies in the treatment of cerebral infarction.

Animals↗
PubMed1986

Protoporphyrinogen oxidase in porphyria variegata. A report of the findings in 7 families.

Protoporphyrinogen oxidase (PPO) activity was determined in 7 families with porphyria variegata (PV). Enzyme activity was reduced by 50% in 8 propositi and in 8 out of 16 prepubertal children. These results are in keeping with the concept that PV is inherited as an autosomal dominant disease. Enzyme activity was also reduced in the fathers of 2 of the propositi, who were suspected on family history of carrying the PV trait, but who had no clinical manifestations. Determination of PPO activity provides a reliable means of identifying PV and of identifying offspring who could, at puberty, become PV patients.

Adult↗
PubMed1986

Regional cerebral perfusion during hypertension depends on the hypertensive agent.

Cerebral blood flow (CBF) was measured in 40 regions of the rat central nervous system by the [14C]iodoantipyrine autoradiographic technique during a moderate elevation in mean arterial blood pressure (to ca. 150 mmHg), induced by i.v. infusion of either dopamine (DA) or noradrenaline (NA). Hypertension induced by DA resulted in significant increases (median = 44%) in local CBF in 38 of the 40 brain regions investigated. In contrast, during NA infusion, CBF was elevated only slightly (median = 15%) in a few (8 of 40) brain regions (P less than 0.05). The cerebrovascular response to hypertension appears to be dependent upon the catecholamine which is employed to elicit the elevation in arterial blood pressure.

Animals↗
PubMed1986

The effect of diazepam upon local cerebral glucose use in the conscious rat.

The effects of diazepam (0.1-1.0 mg/kg i.v.) upon local cerebral glucose utilization, were analysed in 61 anatomically discrete areas of the conscious rat brain using [14C]-2-deoxyglucose quantitative autoradiography. The administration of diazepam resulted in significant reductions in the rate of glucose use in every region investigated. The regional pattern of alterations in glucose utilization was rather homogeneous, with the majority of brain regions analysed showing reductions of between 20 and 40% in response to 0.3 mg/kg diazepam. Only two regions of the central nervous system differed significantly from the widespread, homogeneous reductions. In the mammillary body, the rate of glucose utilization was more sensitive to depression than elsewhere in the brain (55% reductions following 0.3 mg/kg diazepam), whilst in the lateral amygdala, the rate of glucose use was less sensitive (8% reductions following 0.3 mg/kg diazepam). The effects of diazepam were compared to those elicited by i.v. injection of the gamma-aminobutyric acid (GABA) agonists, muscimol and tetrahydroisoxazolopyridinol (THIP), as reported previously by the authors. Although muscimol and THIP, like diazepam, reduced glucose use in every region of the brain, visual inspection of the autoradiograms suggested that whilst the patterns of regional responsiveness to the two GABA agonists were almost identical, they were different to the pattern of response evoked by diazepam. A rigorous system of analysis was devised making use of the dose-response profiles in each of the 61 brain areas to construct a regional hierarchy of responsiveness to the three drugs and allowing comparison of their effects on the brain as a whole. This critical form of data evaluation revealed that there was a more regionally homogeneous response to diazepam than to either muscimol or THIP, and whilst the regional hierarchy of responses to the GABA agonists was very similar, both differed from diazepam. It would appear that whilst benzodiazepines may interact with the GABA receptor, their effects upon the integrated functional activity of the brain as a whole differs markedly from that evoked by putative GABA receptor agonists.

Animals↗
PubMed1986

Nimodipine and the haemodynamic and histopathological consequences of middle cerebral artery occlusion in the rat.

The effect of the administration of nimodipine (1 microgram kg-1 min-1), initiated 5 min after occlusion of a middle cerebral artery (MCA), upon cerebral haemodynamics ([14C]iodoantipyrine autoradiography) and neuropathological outcome (volume of histologically ischaemic tissue) was investigated in anaesthetized rats. Measurements were made of the level of local CBF (LCBF) in a total of 37 neuroanatomically defined areas, either ipsilateral or contralateral to the occluded vessel, and the autoradiograms were examined using a new approach to quantitative densitometry that employed a frequency distribution analysis of the CBF in sections of the brain at different coronal planes. Both methods of analysis showed that nimodipine, administered after the ischemic event, did not modify the pattern of CBF distribution after MCA occlusion. The extent of ischaemic brain damage was determined by histological examination. 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 neuropathological 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 nimodipine was administered before occlusion of the artery.

Animals↗
PubMed1986

Calcitonin gene-related peptide: functional role in cerebrovascular regulation.

Distribution studies disclosed that all major cerebral arteries and cortical arterioles of the cat were invested with fine varicose nerve fibers that contained calcitonin gene-related peptide (CGRP)-like immunoreactivity; the trigeminal ganglia likewise contained CGRP immunoreactivity. Sequential immunostaining with antibodies to CGRP and to substance P (SP) revealed identical distributions of these two peptides in trigeminal ganglia and cerebrovascular nerve fibers, suggesting that CGRP and SP are colocalized in these nerves. CGRP completely disappeared from ipsilateral blood vessels after unilateral section of the trigeminal nerve. Exogenous CGRP was a potent relaxant of feline middle cerebral arteries in vitro (maximum relaxation, 10.5 +/- 1.5 mN; concentration eliciting half-maximal response, 9.6 +/- 1.3 nM). Perivascular microapplication of CGRP to individual cortical arterioles of chloralose-anesthetized cats provoked dose-dependent dilatations (maximum increase in diameter, 38 +/- 5%; concentration eliciting half-maximal response, approximately equal to 3 nM). CGRP was significantly more potent than SP as a cerebrovascular dilator, both in vitro and in situ. Chronic division of the ipsilateral trigeminal nerve in cats did not modify the magnitude of arteriolar responses to perivascular microapplication of either vasoconstrictor or vasodilator agents, but the duration of vasoconstrictor responses to norepinephrine (0.1 mM) or alkaline solutions (pH 7.6) was significantly increased. The cerebrovascular trigeminal neuronal system, in which CGRP is the most potent vasoactive constituent, may participate in a reflex or local response to excessive cerebral vasoconstriction that restores normal vascular diameter.

Animals↗
PubMed1986

Catecholamines and the relationship between cerebral blood flow and glucose use.

The effects of hypertension induced by norepinephrine and dopamine infusion on the relationship between local cerebral blood flow (CBF) and local glucose use (GU) were examined in rats with the use of quantitative autoradiographic techniques. After rats recovered from anesthesia, dopamine or norepinephrine was infused at a rate that ensured moderate hypertension [mean arterial blood pressure (MABP) approximately 150 mmHg]. During dopamine infusion (approximately 200 micrograms X kg-1 X min-1), overall CBF-to-GU ratio throughout the brain was elevated (P less than 0.0001) when compared with saline controls. In contrast, during norepinephrine infusion (approximately 10 micrograms X kg-1 X min-1), the overall CBF-to-GU relationship was not altered significantly. The differential effect of the catecholamines was a consequence of the marked increases in local CBF and moderate decreases in GU observed during dopamine infusion, whereas during norepinephrine administration CBF and GU were not significantly altered in most brain regions. Blood-brain barrier (BBB) permeability was increased during moderate hypertension induced by dopamine and not when induced by norepinephrine. During extreme hypertension (MABP greater than 165 mmHg), heterogeneous increases in CBF and BBB permeability occurred (e.g., in the cerebellum and thalamus). Thus the cerebrovascular response to catecholamine infusion was critically dependent on the agent administered, the level of hypertension achieved, and the brain region examined.

Animals↗
PubMed1985

Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P.

The presence of a population of nerve fibers containing immunoreactive calcitonin gene-related peptide (CGRP) has been demonstrated around cerebral arteries of the cat with immunocytochemistry and radioimmunoassay. CGRP immunoreactivity in the feline cerebral vasculature, as characterized by high-performance liquid chromatography, is similar to authentic rat CGRP. Numerous perikarya containing CGRP are present in the trigeminal ganglia, and surgical lesions of the trigeminal ganglia significantly reduce the levels of CGRP in the cerebral vasculature, suggesting that this cranial nerve is the principal origin of these cerebrovascular nerve fibers. As demonstrated by sequential immunocytochemistry, CGRP coexists with substance P both in the trigeminal ganglion and nerve fibers around cerebral blood vessels. The presence of CGRP in the cerebrovascular trigeminal innervation provides further versatility and complexity for this sensory afferent system putatively involved in the transmission of intracranial pain.

Animals↗
PubMed1985

Effect of pretreatment with the calcium antagonist nimodipine on local cerebral blood flow and histopathology after middle cerebral artery occlusion.

We used the [14C]iodoantipyrine autoradiography technique to study the effect of pretreatment with the calcium antagonist nimodipine on local cerebral blood flow (lCBF) in rats that underwent middle cerebral artery (MCA) occlusion. In untreated control animals there were profound localized reductions in 1CBF 30 minutes after MCA occlusion. These were most pronounced in neocortical areas and in the caudate nucleus ipsilateral to the MCA occlusion. In animals pretreated with nimodipine (1 microgram X kg-1 X min-1 for 30 minutes before and 30 minutes after MCA occlusion), the ipsilateral decrease in 1CBF in cortical regions was significantly less than that in control animals. The drug did not appear to alter 1CBF in the ipsilateral caudate nucleus. Neuropathological quantification of the ischemic damage present 3 hours after occlusion showed that nimodipine pretreatment reduced the volume and extent of cellular damage in the periphery but not in the core of the lesion.

Acid-Base Equilibrium↗
PubMed1985

Pure cortical ischemia versus striatal ischemia. Circulatory, metabolic, and neuropathologic consequences.

Selective ischemic damage was produced either involving only the cortex or together with the striatum by occlusion of the middle cerebral artery proximal or distal to the lenticulostriate artery in the rat. The consequences in local cerebral blood flow, local cerebral glucose utilization, and neuropathology were investigated in the acute stage of ischemia. Caudate damage produced by proximal occlusion resulted in such secondary alterations as enhanced blood flow and metabolism in areas remote from the main lesion, such as in the globus pallidus and substantia nigra ipsilateral to occlusion. After distal occlusion, however, there were two patterns distinctly different from each other in the appearance of the autoradiograms. One was ipsilateral and the other was contralateral enhancement of blood flow and metabolism involving the striato-pallido-nigral axis without any striatal damage. We therefore suggest that these secondary alterations in circulation and metabolism contribute to a varied neurological dysfunction after focal cerebral ischemia. Furthermore, our currently introduced model of selective ischemic lesioning is important in studying the roles of cortical and striatal influences in ischemic pathophysiology.

Animals↗
PubMed1985

Distribution and vasomotor effects of peptide HI (PHI) in feline cerebral blood vessels in vitro and in situ.

Peptide HI (PHI)-immunoreactive nerve fibres were numerous around cerebral blood vessels of the cat. The number and distribution resemble that previously found for vasoactive intestinal polypeptide (VIP), a peptide with which PHI co-exists in pial arteries, at least in some segments. PHI and VIP elicit dilatation in a concentration-dependent manner in isolated middle cerebral arteries; the maximum effects were similar but VIP was considerably more potent. Neither effect was blocked by atropine, cimetidine or propranolol, confirming an action at a non-adrenergic, non-cholinergic site. In chloralose-anaesthetized cats PHI and VIP elicited concentration-dependent dilatations; the magnitude of responses was similar, however, considerably more PHI was necessary to elicit the same response as that of VIP. The results suggest that though both peptides are co-localized and may act at the same receptor, VIP is a more likely candidate for eliciting dilatation during physiological conditions.

Animals↗
PubMed1985

Effect of the calcium antagonist nimodipine on local cerebral blood flow and metabolic coupling.

The effects of a continuous infusion of the calcium antagonist nimodipine (1 microgram kg-1 min-1) on local CBF (LCBF) and local cerebral glucose utilisation (LCGU) were studied, using the quantitative autoradiographic [14C]iodoantipyrine and [14C]2-deoxyglucose techniques in 34 anatomically discrete regions of the brain in lightly restrained, conscious rats. The infusion of nimodipine at this concentration produced only a small (8%) reduction in the MABP. The administration of nimodipine did not alter the rate of glucose utilisation in any of the regions examined. By contrast, in 24 regions, CBF was increased significantly by 39-84% from control levels (for example, cerebral cortices, hippocampus, hypothalamus, and most thalamic nuclei). In vehicle-treated animals, there was an excellent correlation (p less than 0.01) between the local levels of CBF and glucose utilisation, with the ratio of flow to glucose use being approximately 1.5 ml mumol-1 in each brain region. During nimodipine treatment, there was a similarly excellent correlation (p less than 0.01) between LCBF and LCGU, but the median ratio between local flow and glucose use increased to 2.5 ml mumol-1.

Animals↗