Biomedical subjects

I M Macrae

Publications and source records attributed to I M Macrae.

50 records · Page 3Linked to original sources

PubMed1991

Endothelin-1-induced hypertension: a consequence of medullary ischemia?

The central hemodynamic effects of the peptide endothelin-1 (ET-1) have been investigated in the conscious, normotensive rat. Intracisternal administration of ET-1 (0.01-0.03 nmol) gave rise to an increase in mean arterial pressure with minimal effects on heart rate and was accompanied in some cases by barrel rolling activity. Intracisternal administration of 0.03 nmol ET-1 gave rise to a significant elevation in plasma noradrenaline and adrenaline levels. This elevation in plasma catecholamines was present only in those animals that also exhibited marked behavioral changes. Autoradiographic measurement of cerebral blood flow carried out during the maximum response to 0.03 nmol of intracisternal ET-1 revealed a widespread and profound ischemia throughout the caudal brainstem. Cerebral ischemia is known to activate compensatory circulatory reflexes in the medulla oblongata that result in increased sympathetic and vagal outflow. This is the most likely cause of intracisternal ET-1-induced hypertension. ET-1 is unique in its ability to override the brain's autoregulatory mechanisms and induce ischemia of pathological magnitude.

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PubMed1990

Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat.

Endothelin-1 (1 nmol) was applied to the exposed left middle cerebral artery (MCA) in anaesthetised adult male Sprague-Dawley rats. Local cerebral blood flow (1CBF), using [14C]iodoantipyrine and quantitative autoradiography, was measured in 27 anatomically defined structures, 10 min after topical application of endothelin-1. In those areas supplied by the MCA, 1CBF was markedly reduced beyond the threshold for ischaemic damage (e.g. dorsolateral caudate nucleus reduced from 131 +/- 3 to 29 +/- 25 ml.100 g-1.min-1, sensorimotor cortex from 109 +/- 5 to 31 +/- 21 ml.100 g-1.min-1). Distant areas were not affected.

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PubMed1990

Specific alterations in cardiovascular function and in glucose utilisation within lower brainstem nuclei following intracisternal neuropeptide Y in the conscious rat.

In the conscious normotensive rat, intracisternal neuropeptide Y (NPY) (1.25 nmol i.c.) gave rise to alterations in peripheral haemodynamic variables and glucose use within discrete areas of the CNS as measured by [14C]2-deoxyglucose autoradiography. The haemodynamic response to i.c. NPY comprised a transient hypertension followed by a prolonged hypotension and bradycardia. These cardiovascular responses to NPY were accompanied by a significant reduction in function related glucose use in the area postrema (-29% from vehicle-injected controls), nucleus tractus solitarius (caudal portion -24%, rostral portion -19%), Kolliker-Fuse nucleus (-14%), inferior colliculus (-18%) and subfornical organ (-19%). It is proposed that the area postrema, nucleus tractus solitarius and Kolliker-Fuse nucleus in the brainstem are involved functionally in the haemodynamic response to i.c. NPY.

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PubMed1990

Effect of neuropeptide Y on alpha 2-adrenoceptor-mediated cardiovascular responses in the pithed rat.

1. The effects of neuropeptide Y (NPY) on the cardiovascular responses induced by stimulation of pre and postjunctional alpha 2-adrenoceptors were studied in the pithed normotensive rat. 2. The increase in diastolic blood pressure induced by cumulative injection of xylazine (1-1000 micrograms kg-1, i.v.) were potentiated by NPY (5 micrograms kg-1) but not affected by a lower dose (0.75 micrograms kg-1) of this peptide. 3. Xylazine (1-100 micrograms kg-1) inhibited in a dose-dependent manner the tachycardia induced by continuous electrical stimulation (0.2 Hz, 2 ms, 60 V) of the spinal cord (C7-Thl). 4. NPY (5 micrograms kg-1 but not 0.75 micrograms kg-1) enhanced the inhibitory effect of xylazine on the tachycardia induced by electrical stimulation without having any direct effect on heart rate. 5. These results suggest that there may be a positive interaction between NPY receptors, postjunctional alpha 2-adrenoceptors and between NPY receptors and postjunctional alpha 2-adrenoceptors in the cardiovascular system of the rat.

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PubMed1989

The cardiovascular actions of clonidine and neuropeptide-Y in the ventrolateral medulla of the rat.

1. The cardiovascular responses to neuropeptide-Y (NPY) (25 and 50 pmol) and clonidine (10 and 20 nmol) were examined following microinjection into the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Mean arterial pressure (MAP) and heart rate (HR) were measured in anaesthetized rats, pre- and post-injection. 2. The alpha 2-adrenoceptor agonist clonidine (10 and 20 nmol) reduced MAP and HR significantly when microinjected into the CVLM and RVLM. 3. NPY (25 and 50 pmol) microinjected into the CVLM decreased MAP and HR. However, in the RVLM neither dose had a significant cardiovascular effect. 4. The possibility of a functional interaction between the adrenergic system and NPY was examined by co-administration of clonidine and NPY in doses that gave submaximal blood pressure responses. In the CVLM this produced hypotension and bradycardia which was similar in magnitude to the sum of their individual responses, indicating that in this area their actions appear to be independent. 5. In the RVLM, where NPY has no significant cardiovascular effects, co-administration with clonidine, did not alter the response to clonidine. 6. It appears that in the areas investigated, there is no functional interaction between NPY and clonidine.

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PubMed1988

Cardiovascular significance of neuropeptide Y in the caudal ventrolateral medulla of the rat.

The cardiovascular effects of intracisternal and intraparenchymal injection of neuropeptide Y (NPY) into the caudal ventrolateral medulla (CVLM) were investigated in anaesthetized normotensive rats. Intracisternal administration of 1.25 nmol NPY gave rise to a significant fall in blood pressure and heart rate, maximal 1 h postinjection. More localized microinjections of NPY into the CVLM similarly produced dose-dependent falls in blood pressure and heart rate. The bradycardia was significantly reduced or abolished by cardiac vagal blockade induced by: (1) pretreatment with the peripheral muscarinic antagonist methylatropine; or (2) ipsilateral vagotomy. These procedures also gave rise to a small reduction in the hypotensive response to NPY but the remaining component of the response was still significantly different from control, saline responses which were without significant haemodynamic effects. The results of this study provide further evidence for a central role for NPY in cardiovascular control. In the CVLM NPY responses appear to involve at least two different mechanisms: the fall in heart rate results from activation of cardiac vagal neurons in the nucleus ambiguus. The hypotensive response is more complex. The fall in blood pressure may be due in part to an activation of A1 noradrenergic neurons resulting in reduced sympathetic outflow but a small component of the response is a result of the profound slowing of the heart.

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PubMed1987

Vasomotor effects of atrial natriuretic peptides on feline pial arterioles.

Vasomotor responses to atrial natriuretic peptide (ANP), atriopeptin I and atriopeptin II were examined on individual pial vessels on the cortical surface of chloralose-anaesthetized cats. The peptides were administered by subarachnoid perivascular microapplication in an open skull preparation. Changes in vessel calibre were quantified and compared to those of the vehicle, artificial cerebrospinal fluid, which was without significant vasomotor effect. All 3 atrial peptides significantly increased pial arteriolar calibre. ANP, the most potent, gave rise to a maximum increase in arterial calibre of 33 +/- 4% (mean +/- S.E.M., n = 7, P less than 0.05) at 10(-6) M. The concentration of ANP effecting half the maximum response was approximately 7 nmol. Atriopeptin I and II were equipotent with a maximum increase in calibre at 10(-6) M of 21 +/- 4% (n = 10) and 23 +/- 2% (n =6), respectively. The concentration of these peptides effecting half the maximum response was, similar to ANP, in the nanomolar range. Samples of pial arterioles along with middle cerebral and basilar arteries were processed for immunohistochemistry using a polyclonal antibody raised against human ANP. No specific ANP-immunoreactivity was found associated with these vessels. However, dense granular ANP-immunoreactive deposits were clearly demonstrated in sections of feline atria. We conclude that all 3 peptides studied are vasoactive in the cerebral circulation, ANP being the most potent. Since there is no evidence for perivascular ANP nerves around these vessels, the physiological significance of these findings must await identification of the source of ANP.

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PubMed1986

Distribution of subgroups of noradrenaline neurons in the coeliac ganglion of the guinea-pig.

The distributions within the coeliac ganglion of different chemically coded subgroups of noradrenaline neurons, and the relationships between these neurons and nerve fibres projecting to the ganglion from the intestine, have been assessed quantitatively by use of an immunohistochemical double-staining method. Noradrenaline (NA) neurons made up 99% of all cell bodies. Of these, 21% were also reactive for somatostatin (NA/SOM neurons), 53% were also reactive for NPY (NA/NPY neurons), and 26% were not reactive for either peptide. NA neurons without reactivity for any of the peptides whose localization was tested have been designated NA/-. A small percentage, about 1%, of neurons were reactive for both NPY and SOM. The three major types of NA neurons were arranged in clumps or ribbons throughout the ganglia, with a tendency for NA/SOM neurons to be medial and NA/NPY neurons to be lateral in the ganglia. A small group of neurons (less than 1%) encoded with dynorphin, NPY and vasoactive intestinal peptide (VIP) was encountered. VIP-immunoreactive nerve terminals, projecting to the ganglion from cell bodies in the intestine, ended around NA/SOM and NA/- neurons but not around NA/NPY neurons. Thus, the VIP axons from the intestine end selectively around neurons that modify intestinal function (NA/SOM and NA/- neurons) but not around neurons, the terminals of which supply blood vessels (NA/NPY neurons).

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PubMed1985

New approaches to the study of bulbospinal (B3) serotonergic neurons in the control of blood pressure.

The technique of in vivo brain dialysis, recently described by Ungerstedt et al. (1982) provides an opportunity for the direct collection, identification and measurement of neurotransmitters released by activation of a particular pathway. Whereas Ungerstedt et al. used the method for the study of dopamine release by nigrostriatal neurons, it is applied here for the first time to the study of serotonin released by descending spinal neurons regulating sympathetic activity and in turn blood pressure. The first set of experiments performed were designed to test the hypothesis, arising out of previous experiments in the authors' laboratory, that bulbospinal serotonin neurons can exert a pressor effect through release of serotonin in the intermedio-lateral cell column. Micro-injections of kainic acid were made into the area of the lateral B3 serotonin cell group in the medulla. This elicited an increase in the release of serotonin in the spinal cord, measured using in vivo dialysis, accompanied by an increase in blood pressure. Pretreatment with 5.7-dihydroxytryptamine (5.7DHT) 2 weeks earlier completely prevented the increase in serotonin release and in blood pressure evoked by micro-injection of kainic acid into the B3 serotonin cells. These experiments used the technique of brain dialysis to support the hypothesis that bulbospinal serotonin nerves can exert a pressor action. In a second set of experiments L-glutamate was injected into the region of the lateral B3 serotonin cells near to the ventral surface of the medulla, and also into the midline B3 serotonin cells in the raphe, in order to activate neuronal cell bodies without stimulating fibres of passage.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1984

Release of noradrenaline and dopamine by nerve stimulation in the guinea-pig and rat vas deferens.

Spontaneous and nerve stimulated release of noradrenaline and dopamine from rat and guinea-pig vas deferens have been measured electrochemically after separation by high performance liquid chromatography (h.p.l.c.). In the absence of nerve stimulation both noradrenaline (NA) and dopamine were released into the bathing fluid in the rat but in the guinea-pig only noradrenaline could be detected. Drugs which block neuronal and extraneuronal uptake of catecholamines had little effect on spontaneous overflow but both tetraethylammonium and phenoxybenzamine increased overflow. Transmural nerve stimulation (5-10 Hz) increased catecholamine overflow in both species and dopamine release was now measurable from the guinea-pig vas. In the rat, the proportion of dopamine to NA was unchanged from that released spontaneously. The release of both amines was little affected by drugs that block neuronal and extraneuronal uptake and a monoamine oxidase inhibitor, but was inhibited by tetrodotoxin 0.2 microgram ml-1. In the guinea-pig tetraethylammonium 10 mM doubled overflow and phenoxybenzamine 10(-5)M increased it by five times but the dopamine percentage remained constant and equal to the control. Following nerve stimulation the amount of dopamine released expressed as a percentage of total catecholamine release was 6% for the rat and 1.3% for the guinea-pig. These values were considerably higher than the comparable figures for dopamine: NA content of the two tissues (2% and 0.5% respectively). Repeated periods of stimulation depleted these tissue stores and the depletion of dopamine was significantly greater than that of NA. 6 Our interpretation of these results is that both dopamine and NA are released from a common store during normal noradrenergic transmission. While all or most of the axonal dopamine is contained in this releasable pool, most of the axonal NA lies in a second, less readily released pool.

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PubMed1983

The contractile response to and the release of noradrenaline by transmural nerve stimulation in the guinea-pig vas deferens and a comparison with the response to noradrenaline.

The release of noradrenaline from the guinea-pig vas deferens by transmural stimulation was measured electrochemically after separation by h.p.l.c. Variations in release with different durations of stimulation were then compared with the mechanical response during stimulation. During long periods of 270 s of stimulation at 10 Hz the average release of noradrenaline in the final 250 s remained at about 50% of that released during the first 20 s yet the mechanical response throughout the later time declined to near zero. Superfusion with constant concentrations of noradrenaline produced mechanical responses similar to those from transmural nerve stimulation, an initial rapid contraction declining to a low level of maintained activity. During the later period, when the response to infused noradrenaline was low, the twitch response to transmural stimulation was potentiated. Phentolamine 10(-6)M reduced the potentiation of the twitch response to transmural stimulation by noradrenaline and propranolol 10(-6)M enhanced the potentiation. These results suggest that the decline in the adrenergic component of the response to prolonged transmural nerve stimulation is not the result of a decline in noradrenaline release but mainly due to desensitization to the contractile effect of noradrenaline. Since the similar desensitization produced by infused noradrenaline does not reduce the twitch response to transmural nerve stimulation it is unlikely that the transmitter responsible for that component is noradrenaline.

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PubMedDate not supplied

Effects of neuropeptide Y on forskolin, alpha 2- and beta-adrenoceptor-regulated cAMP levels in the rat brain slice.

Neuropeptide Y (10(-6) M) significantly attenuated forskolin-stimulated cAMP levels in slices of the medulla oblongata from WKY rats. No effect of NPY was observed on basal levels of cAMP in this region. Pretreatment with pertussis toxin (2 micrograms and 5 micrograms) IC prevented the reduction of forskolin-stimulated cAMP levels elicited by NPY in the medulla oblongata, suggesting that NPY is acting through an inhibitory guanine nucleotide binding protein to reduce cAMP accumulation. Moxonidine, an alpha 2-adrenoceptor agonist, was observed to reduce forskolin-stimulated cAMP levels in medullary slices. This inhibitory response was attenuated in the presence of NPY (10(-6) M). The beta-adrenoceptor agonist isoprenaline also elevated cAMP levels in the medulla oblongata; however, NPY did not alter this response. It is therefore proposed that the previously reported hemodynamic actions of NPY in the medulla oblongata, an area of cardiovascular significance, may be mediated via a reduction in cAMP levels. Moreover, an interaction between NPY and alpha 2-adrenoceptors, but not beta-adrenoceptors, on cAMP production in the medulla slice preparation was evident.

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PubMedDate not supplied

Midline B3 serotonin nerves in rat medulla are involved in hypotensive effect of methyldopa.

Previous experiments in this laboratory have shown that microinjection of methyldopa onto the ventrolateral cells of the B3 serotonin neurons in the medulla elicits a hypotensive response mediated by a projection descending into the spinal cord. The present experiments were designed to investigate the role of the midline cells of the B3 serotonin neurons in the medulla, coinciding with the raphe magnus. In spontaneously hypertensive, stroke-prone rats, microinjection of methyldopa into the area of the midline B3 serotonin cell group in the ventral medulla caused a potent hypotension of 30-40 mm Hg, which was maximal 2-3 h after administration and was abolished by the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) injected intracerebroventricularly. However, intraspinal injection of 5,7-DHT to produce a more selective lesion of only descending serotonin projections in the spinal cord did not affect this hypotension. Further, 5,7-DHT lesion of serotonin nerves travelling in the median forebrain bundle, one of the main ascending pathways from the B3 serotonin cells, did not affect the fall in blood pressure associated with a midline B3 serotonin methyldopa injection. It is concluded therefore that, unlike the ventrolateral B3 cells which mediate a methyldopa-induced hypotension via descending projections, the midline serotonin B3 cells in the medulla contribute to the hypotensive action of methyldopa, either by way of an ascending projection which does not pass through the median forebrain bundle, or through a projection restricted to the caudal brainstem.

5,7-Dihydroxytryptamine↗

PubMedDate not supplied

Endothelin, cerebral ischaemia and infarction.

Endothelin-1 (ET-1) is a 21 aminoacid peptide with potent vasoconstrictor properties. It is synthesised and released by endothelial cells in both the peripheral and cerebral vasculature and is also localised within neurones in discrete brain areas where it may contribute to the central regulation of blood pressure. We have shown that intracisternal ET-1 in conscious rats induces a marked pressor response that is associated with an intense widespread reduction in cerebral blood flow. Subsequent studies with local application of ET-1 to the middle cerebral artery (MCA) revealed a dose dependent reversible vasoconstriction of the artery that resulted in profound reductions in local cerebral blood flow and the development of cerebral infarction. Thus abluminal application of ET-1 to the MCA offers a simple model of reversible focal cerebral ischaemia in the rat that complements the existing models of permanent MCA occlusion. The ET-1 model will help to provide new insights into the mechanisms of cerebral ischaemia and reperfusion injury, and to evaluate the usefulness of novel strategies of neuroprotection.

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