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J Chalmers

Publications and source records attributed to J Chalmers.

At least 91 records · Page 5Linked to original sources
PubMed1996

[Role of diuretics in the treatment of hypertension: from large controlled trials to international guidelines].

Diuretics were used in most of the major trials that demonstrated that lowering the blood pressure reduced cardiovascular morbidity and mortality. Nevertheless in the second half of the eighties, there were misgivings about the widespread use of thiazide diuretics, driven in part by the relative failure of the large trials to reduce myocardial infarction-to the extent predicted by large scale epidemiological studies. There was much attention on metabolic side effects of thiazide diuretics including dyslipidaemia, glucose intolerance, hypokalaemia, hyperuricaemia, and then microalbuminuria particularly in diabetic subjects. These issues were current when JNC (IV) (1988) and the WHO-ISH guidelines (1989) were being written. Three major clinical trials SHEP, STOP and MRC published in the early nineties established that thiazide diuretics alone, or in combination with beta blockers, did reduce cardiovascular morbidity and mortality in elderly subjects with hypertension. All guidelines published since 1993 include diuretics among the first line drugs. Possibly the most important factor in the restoration of diuretics has been the use of progressively lower doses that minimise the metabolic side effects. Diuretics are effective as monotherapy in the treatment of mild essential hypertension and of isolated systolic hypertension in elderly subjects. They are very useful in combination with beta blockers or with ACE inhibitors. They should be avoided in patients with gout and should not be used as first line drugs in patients with diabetes. They should only be used with caution in young obese subjects with dyslipidaemia and increased risk of coronary artery disease, facing many decades of treatment for hypertension. However there is no doubt that diuretics are effective, cheap and have a central role in the control of hypertension in all communities around the world.

Adult↗
PubMed1995

Synapses on axons of sympathetic preganglionic neurons in rat and rabbit thoracic spinal cord.

Axosomatic and axodendritic synapses occur on sympathetic preganglionic neurons, but it is not yet known whether their axons receive synaptic input, which could be particularly effective at regulating sympathetic outflow. Here, we examined retrogradely labelled sympathetic preganglionic axons to see if they received synapses. Cholera toxin B subunit (CTB) or CTB conjugated to horseradish peroxidase (CTB-HRP) was used to label neurons projecting to the rat or rabbit superior cervical ganglion, the rat adrenal medulla, or the rabbit stellate ganglion. At the light microscopic level, small groups of CTB-immunoreactive axons travelled through the ventral horn near its lateral boundary, with occasional axons taking a more medial course. The axons passed through the ventrolateral funiculus to exit at the ventral roots. In parasagittal section, a few axons branched within the ventral horn, sending processes rostrally and caudally for short distances before they turned ventrally to exit the spinal cord. At the ultrastructural level, CTB-immunoreactive rat and rabbit sympathetic preganglionic axons were almost exclusively unmyelinated. In contrast, labelling with CTB-HRP revealed both myelinated and unmyelinated axons in the ventral horn, the ventrolateral white matter, and the ventral roots. CTB-HRP also allowed the detection of the initial segment of a sympathetic preganglionic axon. Synapses, with vesicles clustered presynaptically and membrane specializations postsynaptically, were found on some unmyelinated CTB-immunoreactive axons. Occasional axons received several synapses. Synapses were most common on CTB-containing axons just ventral to the intermediolateral cell column. One synapse was found on an axon within 2 microns of its origin from a proximal dendrite. Rare synapses were found several hundred micrometers ventral to the intermediolateral cell column. One branching axon had synapses just below the branch point on both the main axon and the axonal branch. These findings indicate an extensive synaptic input to the axons of at least some sympathetic preganglionic neurons. These axoaxonic synapses could have a profound effect on sympathetic activity.

Animals↗
PubMed1995

Serotonin inputs to rabbit sympathetic preganglionic neurons projecting to the superior cervical ganglion or adrenal medulla.

The input from serotonin-containing nerve fibres to rabbit sympathetic preganglionic neurons projecting to either the superior cervical ganglion or the adrenal medulla was investigated by combining retrograde tracing with the B subunit of cholera toxin and immunocytochemistry for serotonin. There were pronounced rostrocaudal variations in the density of serotonin fibres in the rabbit intermediolateral cell column from T1 to L4; maximum numbers of fibres were found in T3-6 and L3-4 and minimum numbers in T1 and T10-12. By light microscopy, retrogradely labelled sympathetic preganglionic neurons projecting to the superior cervical ganglion or the adrenal medulla received variable densities of close appositions from serotonin-immunoreactive fibres. Some neurons from each population received many close appositions, whereas others received moderate numbers or few appositions. Appositions occurred on the cell bodies, dendrites, and occasionally axons of sympathetic preganglionic neurons. Rare neurons in both groups of retrogradely labelled cells received no appositions from serotonin-containing nerve fibres. At the ultrastructural level, synapses were found between serotonin-positive boutons and sympathetic preganglionic neurons projecting either to the superior cervical ganglion or to the adrenal medulla. These results indicate that, through direct synaptic contacts, serotonin-immunoreactive, presumably bulbospinal, nerve fibres affect the activity of the vast majority of sympathetic preganglionic neurons that send axons either to the superior cervical ganglion or to the adrenal medulla. This serotonin input may be sympathoexcitatory and could mediate increases in sympathetic nerve activity and in the release of catecholamines from the adrenal medulla.

Adrenal Medulla↗
PubMed1995

Aminoacetone metabolism by semicarbazide-sensitive amine oxidase in rat aorta.

High speed (105,000 g/60 min) membrane fractions from rat aorta homogenates metabolized the aliphatic amine aminoacetone (AA) to methylglyoxal (MG) with a Km of 19 +/- 3 microM, and Vmax of 510 +/- 169 nmol MG/hr/mg protein. This deaminating activity appears to be due to a semicarbazide-sensitive amine oxidase (SSAO), which is associated with smooth muscle cells in blood vessels of the rat and other species. AA was a competitive inhibitor (Ki of 28 +/- 6 microM) of the metabolism of benzylamine, a synthetic amine often used as an assay substrate for SSAO. AA is produced endogenously from mitochondrial metabolism of threonine and glycine, and thus could be a physiological substrate for SSAO, whereas the production of MG by SSAO could have cytotoxic implications for cellular function.

Acetone↗
PubMed1995

Abnormal insulin treatment behaviour: a major cause of ketoacidosis in the young adult.

Diabetic ketoacidosis occurs more frequently in the young adult population than in any other age group. In a 3-year retrospective casenote review of all patients admitted with ketoacidosis to this hospital, we have defined the clinical characteristics of ketoacidosis in this age group. Young adults (< 25 years) had worse preceding glycaemic control (median HbA1 14.6 vs 10.1%, p = 0.0001) and more frequent episodes of ketoacidosis in the previous 5 years (3 vs 0, p = 0.0001) than older adults (> 25 years); on admission they had lower blood urea concentrations (p = 0.0001) and had a lower incidence of systolic hypotension (6% vs 32%, p = 0.007). There were fewer complications of ketoacidosis in the young adults, and the duration of hospital stay was less than that in the older age group (4 vs 8 days, p = 0.0003). Young adults were less likely to have a proven underlying infective or other organic precipitant for ketoacidosis, but were investigated and treated in a similar way to older adults. Insulin error or manipulation was identified in 42% of young adults; abnormal insulin treatment behaviour is likely to be the major cause of ketoacidosis in this age group.

Adolescent↗
PubMed1995

Central inspiration increases barosensitivity of neurons in rat rostral ventrolateral medulla.

Barosensitive neurons in the rostral ventrolateral medulla (RVLM) often have a respiratory-related modulation of their activity. However, the extent of the interaction between baroreceptor and respiratory inputs is controversial. The main aim of the present study was to determine the effect of central respiratory drive (CRD) on the barosensitivity of RVLM neurons. Extracellular recordings were obtained from 68 barosensitive neurons in the RVLM of anesthetized, paralyzed, and bilaterally vagotomized Sprague-Dawley rats. Examination of phrenic-triggered histograms revealed five activity patterns among barosensitive neurons: inspiratory depression (type I, n = 20), early inspiratory activation (type II, n = 14), postinspiratory activation (type III, n = 18), expiratory depression (type IV, n = 5) and no modulation (type V, n = 11). In most neurons (types I and III and 56% of type II) inhibition produced by aortic nerve stimulation was greater in inspiration than in expiration. Cardiac-related modulation, as an index of natural phasic baroreceptor activation, was also greater in inspiration than expiration in type III neurons. The results demonstrate that CRD modulates the baroreflex at the level of the RVLM.

Animals↗
PubMed1995

Antisense to thyrotropin releasing hormone receptor reduces arterial blood pressure in spontaneously hypertensive rats.

We report in the present study the effect of intrathecal treatment with antisense oligonucleotides complementary to thyrotropin releasing hormone (TRH) receptor mRNA on the pressor response to intrathecal administration of TRH and on resting arterial blood pressure in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). In 16-week-old male WKY rats, 18-base phosphodiester antisense or mismatch oligonucleotides to TRH receptor mRNA (100 micrograms per day) were injected intrathecally for 3 days. Twenty-four hours after the last injection, the magnitude of the pressor response to intrathecal TRH (10 micrograms) was significantly smaller in the antisense-treated group (n = 7) compared with mismatch-treated controls (n = 7) (change in mean arterial pressure, +20.3 +/- 3.0 versus +32.6 +/- 2.5 mm Hg, P < .01). No differences were observed in the pressor responses to injection of N-methyl-D-aspartic acid. Resting arterial blood pressure was unaffected by antisense treatment in WKY rats. In separate experiments, 16-week-old male SHR were treated with antisense (n = 7) or mismatch (n = 6) oligonucleotides for 3 days. Mean resting arterial blood pressure was significantly reduced by treatment with antisense oligonucleotides (from 157 +/- 4.8 to 119 +/- 8.8 mm Hg, P < .01), but no significant changes were observed in mismatch-treated animals. Our results suggest that the expression of TRH receptors in spinal sympathetic preganglionic neurons can be selectively reduced by intrathecal treatment with antisense oligonucleotides and that TRH projections to sympathetic preganglionic neurons play an important role in the elevation of arterial blood pressure in SHR.

Animals↗
PubMed1995

Hypertension in the elderly: benefits of treatment.

It has long been known that hypertension increases the risk of cardiovascular morbidity and mortality and that this risk increases with age. It has taken much longer to establish that lowering the blood pressure in elderly subjects will reduce this risk. Early studies published in 1985-86 indicated that treating classical essential hypertension in elderly subjects who were mainly less than 75 years of age, or even below 70 years, did reduce cardiovascular morbidity and mortality. More recent studies have extended the evidence and established that major benefits can be harvested by treating mild and moderate hypertension in subjects between 70 and 85 years who have classical hypertension with raised diastolic and systolic blood pressure. Recent evidence has also established that the treatment of isolated systolic hypertension in elderly patients up to the age of 80 and above, will reduce morbidity and mortality. In all of these recent studies, the major gain of lowering the pressure has been a reduction in the incidence of fatal and non-fatal stroke, but there is also some evidence of reduction in risk associated with coronary artery disease. Overall the evidence of benefit is sufficiently strong to advise the practising doctor to lower the blood pressure in elderly patients up to the age of 85 with raised diastolic or systolic blood pressure.

Aging↗
PubMed1994

A set of ninety-seven overlapping yeast artificial chromosome clones spanning the human Y chromosome euchromatin.

Contiguous arrays of yeast artificial chromosomes (YACs) extending from proximal heterochromatic Yq into the pseudoautosomal portion of the Y chromosome and separated by a small interval at the centromere have been constructed. A total of 97 YACs have been aligned along the Y chromosome by STS content analysis using 222 sequence tagged sites (STSs) that detect 263 loci. Forty-five of the STSs used are novel. Their inclusion provides a significant improvement over previously available maps on the density of STS coverage along the Y chromosome, reducing the average spacing to 120 kb assuming a length of 30 Mb for the euchromatin. The average size of 61 YACs determined by pulsed-field gel electrophoresis analysis was at least 0.9 Mb. Minor differences noted between the ordering of STSs on this map compared with those previously reported may be attributed to inherent polymorphism between the Y chromosomes used to construct the YAC libraries.

Base Sequence↗
PubMed1994

Intracellular recording from sympathetic preganglionic neurons in cat lumbar spinal cord.

Sympathetic preganglionic neurons (SPN) are responsible for the control of many autonomic targets including the heart and blood vessels. Previous intracellular studies have examined the morphology of SPN in the thoracic spinal cord, but there are no intracellular studies of SPN in the lumbar spinal cord. In this study we identified lumbar SPN using intracellular recording and dye-filling so that we could study their entire soma-dendritic tree, as well as their axons. At the same time, axonal conduction velocity was measured, and any evidence of an input in phase with phrenic nerve discharge was noted. Intracellular recordings were made from SPN in the L3 (n = 125) and T3 (n = 17) segments of the cat spinal cord. Axonal conduction velocities ranged from 0.6-8.4 m/s. In 85 lumbar SPN, the recordings lasted long enough to assess respiratory-related modulation. A respiratory-related modulation of the membrane potential was seen in 7 of these 85 neurons. All 7 respiratory-related neurons had a conduction velocity of 2.0 m/s or less, while none of the SPN with conduction velocities of more than 2.0 m/s had a respiratory rhythmicity. Histological analysis of 50 biocytin-filled SPN, including 3 with a respiratory-related modulation of their membrane potential, revealed that they occurred mostly in the principal part of the intermediolateral cell column and tended to be elongated in the rostro-caudal direction. Dendrites ramified in the intermediolateral cell column, the dorsolateral white matter and the ventral and medial gray matter. Axons arose either from cell bodies or from primary dendrites and did not bifurcate or have varicose intraspinal collaterals. This is the first report of the morphology of intracellularly filled SPN in the lumbar spinal cord.

Animals↗
PubMed1994

Close appositions between tyrosine hydroxylase immunoreactive boutons and respiratory neurons in the rat ventrolateral medulla.

The extent of the adrenergic input to respiratory neurons in the ventrolateral medulla oblongata of rats was assessed by using a combination of intracellular recording, dye filling, and immunohistochemistry. Twenty-two neurons that displayed a pronounced respiration-related modulation of their membrane potential, and could not be antidromically activated by electrical stimulation of the superior laryngeal, vagus, or facial nerves, were labelled by intracellular injection of biocytin. Three types of respiration-related neurons were labelled: small neurons located in the Bötzinger complex between 0.5 and 1.0 mm caudal to the facial nucleus; medium-sized neurons located in the ventral respiratory group 1.0 to 2.0 mm caudal to the facial nucleus; and large motoneurons located within the nucleus ambiguus 0.5 to 2.0 mm caudal to the facial nucleus. Small Bötzinger neurons [length = 22 +/- 5 microns, width = 13 +/- 3 microns, area = 222 +/- 79 microns2; (mean +/- SD, n = 5)] had membrane potentials of -15 to -27 mV during the recording period. Four of five of these cells had profuse axonal terminations between 50 microns caudal and 450 microns rostral to their somata, suggesting that they may form part of local networks responsible for generating respiratory activity. Medium-sized ventral respiratory group neurons (length = 26 +/- 5 microns, width = 18 +/- 4 microns, area = 377 +/- 141 microns2; n = 5) were found in the vicinity of the nucleus ambiguus dorsal to the lateral reticular nucleus. Three of five of these neurons had an axon that crossed the midline and travelled caudally. One axon had a collateral with varicosities close to its soma. The somata of motoneurons (length = 29 +/- 6 microns, width = 21 +/- 4 microns, area = 485 +/- 142 microns2; n = 12) were located within the nucleus ambiguus, and had axons that could be traced to exist points from the medulla. Tyrosine hydroxylase immunoreactive cells and their terminal fibres within the medulla were localised by immunocytochemistry. Small Bötzinger neurons received the largest number of close appositions from tyrosine hydroxylase immunoreactive boutons (13 +/- 2 appositions/neuron; n = 5). Medium-sized ventral respiratory group neurons received fewer appositions (8 +/- 4 appositions/neuron; n = 5). Most motoneurons (n = 10) received few appositions from tyrosine hydroxylase immunoreactive boutons, while two received none. The average number was 3 +/- 3 appositions/neuron (n = 12).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Projections from inspiratory neurons of the ventral respiratory group to the subretrofacial nucleus of the cat.

Arterial blood pressure and the activity of many sympathetic nerves are known to be affected by changes in central respiratory activity. The central neurons responsible for this respiratory modulation are unknown. In the present study we have labelled inspiratory neurons (n = 24) in the rostral ventral respiratory group and Bötzinger complex in the medulla oblongata of the cat using intracellular injection of biocytin. The filled neurons were examined to see if they had axonal projections to the subretrofacial nucleus, an important brainstem nucleus in the tonic and reflex control of blood pressure. The subretrofacial nucleus was identified histologically as a cluster of neurons in the rostral ventrolateral medulla, some of which are tyrosine hydroxylase immunoreactive. Varicose axons arising from labelled inspiratory neurons were mostly found dorsal to this cluster, within the area corresponding to the Bötzinger complex. A small number of axon varicosities were seen in the subretrofacial nucleus. The results suggest that a part of the respiratory modulation of sympathetic nerve activity may be due to a direct synaptic input from inspiratory neurons of the ventral respiratory group to neurons of the subretrofacial nucleus.

Animals↗
PubMed1994

Central neurons and neurotransmitters in the control of blood pressure.

1. In this paper we review recent work from our laboratory on two major pathways important in the central control of blood pressure. 2. We report experiments on the sympatho-excitatory bulbospinal pathway from the rostral ventral medulla. Here we focus particularly on the role of excitatory amino acids. 3. We review studies on the short inhibitory or depressor pathway ascending from the caudal to the rostral ventral medulla, which is thought to use gamma-aminobutyric acid (GABA) as its neurotransmitter. We report on experiments with the immediate early gene, c-fos, demonstrating that its expression in the bulbospinal pressor neurons is increased by stimuli that activate these nerves, and that this expression can be blocked in vivo by treatment with an antisense oligonucleotide. We also show that basal and stimulated expression of the c-fos gene is important in the central control of blood pressure.

Animals↗
PubMed1994

Kynurenic acid, an endogenous glutamate antagonist, in SHR and WKY rats: possible role in central blood pressure regulation.

1. Kynurenine aminotransferase catalyzes the conversion of kynurenine to kynurenic acid, an endogenous antagonist of excitatory amino acid receptors. The kynurenic acid content and kynurenine aminotransferase activity was measured in micro-dissected regions of spontaneously hypertensive rats (SHR) and their normotensive controls (Wistar-Kyoto rats: WKY). 2. Of the brain regions examined the highest kynurenine aminotransferase activity was found in the medulla followed by the olfactory bulb and the cerebellum, with the spinal cord showing the lowest activity. 3. All samples from SHR showed greatly reduced kynurenine aminotransferase activity compared to WKY. These reductions were most pronounced in the medulla and spinal cord, approximately 45-55%, and lowest in the cerebellum and olfactory bulbs, approximately 25-30%. 4. The kynurenic acid content of the rostral and caudal medulla as well as the spinal cord was also significantly lower in SHR. 5. These results suggest that there may be a deficiency in the kynurenic acid content and kynurenine aminotransferase activity in the SHR. 6. Given the accumulating evidence of the importance of medullary glutamatergic pathways in the control of blood pressure, as well as the higher sensitivity of cardiovascular neurons of SHR to applied glutamate, it seems possible that endogenous kynurenic acid in the brain may play a role in the control of blood pressure and the pathogenesis of experimental hypertension in the SHR.

Animals↗
PubMed1994

c-fos antisense in rostral ventral medulla reduces arterial blood pressure.

The effect of blocking the expression of c-fos in the rostral ventral medulla (RVM) on the control of arterial blood pressure was determined. In six male Wistar-Kyoto rats (WKY), unilateral injection of an antisense oligonucleotide to c-fos mRNA suppressed the expression of Fos-like immunoreactivity in neurons in the RVM in response to inhibition of depressor neurons in the caudal ventrolateral medulla (CVLM). Under pentobarbital anesthesia the mean arterial pressure of rats injected with antisense oligonucleotide (n = 10) bilaterally into RVM was significantly reduced after 6 h compared with sense-treated controls (n = 9) (76.5 +/- 3.7 vs. 92.4 +/- 3.5 mmHg; P < 0.05). Furthermore, the pressor response to bilateral injection of muscimol into CVLM was significantly smaller in rats injected with antisense oligonucleotide 6 h earlier (n = 6) compared with sense-treated controls (n = 6) (changes in mean arterial pressure, +40.3 +/- 3.6 vs. +68.7 +/- 4.8 mmHg, P < 0.005). These studies demonstrate that expression of c-fos in the RVM can be blocked in vivo by treatment with an antisense oligonucleotide, and that basal and stimulated expression of the c-fos gene is important in the central control of arterial blood pressure.

Animals↗