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Biomedical subjects

J Chalmers

Publications and source records attributed to J Chalmers.

At least 73 records · Page 4Linked to original sources
PubMed1997

Central control mechanisms in hypertension.

There is substantial evidence for an activation of the sympathetic nervous system in man as well as in genetic models of hypertension, such as the spontaneously hypertensive rat (SHR), but we are only beginning to understand the central mechanisms that generate changes in sympathetic activity and elevate blood pressure (BP). Significant recent advances have been made in defining the neural pathways involved in BP regulation and in identifying the neurotransmitters these neurones utilise. In this overview, we describe the neural pathways within the medulla oblongata and spinal cord that participate in BP control and examine the role of amino acid neurotransmitters within these pathways. We demonstrate how alterations in these pathways explain the sympathetic activation observed in the SHR and contribute to hypertension in this model. Lastly, we examine the application of modern molecular biological approaches to further our understanding of the neural regulation of the circulation. In these studies, we used the administration of antisense oligonucleotides to interrupt gene expression.

Animals↗
PubMed1997

Role of AMPA/kainate receptors in transmission of the sympathetic baroreflex in rat CVLM.

We examined the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors within the caudal ventrolateral medulla (CVLM) in mediating the sympathetic baroreceptor reflex in anesthetized and paralyzed rats. Bilateral microinjection into CVLM of either DL-2-amino-5-phosphonovaleric acid [APV; a selective N-methyl-D-aspartic acid (NMDA) receptor antagonist, 20 mM, 100 nl] or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a selective AMPA/kainate receptor antagonist, 2 mM, 100 nl) alone failed to eliminate the aortic nerve stimulation-evoked hypotension and inhibition of splanchnic sympathetic nerve activity (SNA) or the cardiac-related rhythmicity of SNA. All components of the sympathetic-baroreceptor reflex were abolished when kynurenate (100 mM, 30 nl) or mixtures of APV and CNQX (10 and 1 mM, respectively, 100 or 30 nl) were injected into CVLM. Injection of APV or CNQX into CVLM reduced aortic nerve-evoked inhibitory responses of bulbospinal sympathoexcitatory neurons in rostral ventrolateral medulla (RVLM). The extent of this reduction was variable. Usually, significant inhibition was preserved. In seven RVLM neurons, intravenous injection of MK-801 (NMDA receptor antagonist, 2 mg/kg) failed to eliminate aortic nerve-evoked inhibitory responses. However, inhibitory responses were abolished when CNQX was injected into CVLM after intravenous MK-801. We conclude that both NMDA and AMPA/kainate receptors in CVLM transmit baroreceptor information.

2-Amino-5-phosphonovalerate↗
PubMed1997

Respiratory activity of the rat posterior cricoarytenoid muscle.

An anatomic and electrophysiological study of the rat posterior cricoarytenoid (PCA) muscle is described. The intramuscular nerve distribution of the PCA branch of the recurrent laryngeal nerve was demonstrated by a modified Sihler's stain. The nerve to the PCA was found to terminate in superior and inferior branches with a distribution that appeared to be confined to the PCA muscle. Electromyography (EMG) recordings of PCA muscle activity in anesthetized rats were obtained under stereotaxic control together with measurement of phrenic nerve discharge. A total of 151 recordings were made in 7 PCA muscles from 4 rats. Phasic inspiratory activity with a waveform similar to that of phrenic nerve discharge was found in 134 recordings, while a biphasic pattern with both inspiratory and post-inspiratory peaks was recorded from random sites within the PCA muscle on 17 occasions. The PCA EMG activity commenced 24.6 +/- 2.2 milliseconds (p < .0001) before phrenic nerve discharge. The results are in accord with findings of earlier studies that show that PCA muscle activity commences prior to inspiratory airflow and diaphragmatic muscle activity. The data suggest that PCA and diaphragm motoneurons share common or similar medullary pre-motoneurons. The earlier onset of PCA muscle activity may indicate a role for medullary pre-inspiratory neurons in initiating PCA activity.

Animals↗
PubMed1996

AMPA/kainate receptors mediate sympathetic chemoreceptor reflex in the rostral ventrolateral medulla.

Previous studies have reported that information from carotid chemoreceptors activates sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) exclusively via N-methyl-D-aspartic acid (NMDA) receptors. In this study, we examined the possible involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in the RVLM on sympathetic chemoreceptor reflex in pentobarbitone anaesthetised, vagotomised and artificially ventilated rats. Carotid chemoreceptor stimulation with brief N2 inhalation increased splanchnic sympathetic nerve activity and arterial pressure in animals that had received an intravenous injection of the non-competitive NMDA receptor blocker, MK-801 (2 mg/kg). RVLM sympathetic premotor neurons could also be activated by brief hypoxia in the presence of MK-801. However, microinjection of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a selective AMPA/kainate receptor antagonist, 2 mM, 100 nl) into the RVLM after intravenous MK-801 abolished the hypoxia evoked sympathoexcitatory response. These results demonstrate that AMPA/kainate receptors in the RVLM are involved in the chemoreceptor reflex pathway.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

Thyrotropin-releasing hormone immunoreactive boutons form close appositions with medullary expiratory neurons in the rat.

The aim of the present study was to assess the size of the input from TRH immunoreactive varicosities to medullary respiratory neurons in the Bötzinger complex and caudal ventral respiratory group. Neurobiotin was intracellularly injected into seven neurons in the Bötzinger complex, between 0.4 and 0.9 mm caudal to the facial nucleus. Five of the seven Bötzinger neurons had extensive local axonal projections, with bouton-like varicosities clustered predominantly between their somata and the nucleus ambiguus. Seven neurons in the caudal ventral respiratory group, located between 1.6 and 2.4 mm caudal to the facial nucleus, were also labelled. All but one caudal respiratory neurons had no, or very few, medullary collaterals. TRH immunoreactive fibres were seen in many medullary nuclei, including the ventral reticular formation. Bötzinger neurons were closely apposed by an average of 29 +/- 8 TRH immunoreactive boutons/neuron (mean +/- S.D., n = 7). In contrast, caudal ventral respiratory group neurons were apposed by only 5 +/- 3 TRH immunoreactive boutons/neuron (n = 7). Bötzinger neurons form many intramedullary and bulbospinal inhibitory connections with premotoneurons and motoneurons that are important in the timing, amplitude and shape, of respiratory activity. Our findings suggest a role for endogenous TRH-containing neurons in modulating the activity of inhibitory Bötzinger neurons and neurons in the caudal ventral respiratory group. The significance of the apparent difference in size of this input remains to be determined.

Animals↗
PubMed1996

The treatment of hypertension.

1. A 'retrospective' of the development of the drug treatment of hypertension is presented from the early days of ganglion blockers to the present time together with a review of the evidence of benefit from treatment. 2. Current issues and debates are summarised including shortfalls in the control of hypertension in populations, difficulties surrounding the measurement of blood pressure, disagreement on the levels of blood pressure to treat, the goal blood pressures to aim at, issues surrounding lifestyle measures such as the low salt diet and low intensity exercise, and treatment with diuretics and with calcium antagonists. 3. A 'perspective' is presented on some avenues for progress in the years ahead. These will include the identification of genetic markers to determine the hypertensive individuals with the greatest risk of death and of cardiovascular complications.

Antihypertensive Agents↗
PubMed1996

Treatment guidelines in hypertension: current limitations and future solutions.

AREAS OF AGREEMENT: Among the many guidelines and recommendations put forward by national and international authorities in recent years, there has been close agreement that the physician should assess each patient carefully over many months, should address the total profile of cardiovascular risk not just the raised blood pressure, and should treat patients right up to the age of 85 years with either classical essential hypertension or isolated systolic hypertension. The major guidelines described five groups of first-line antihypertensive drugs: diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists and alpha-blockers. AREAS OF UNCERTAINTY: In other areas, the various guidelines were either united in uncertainty, or divided on the best course of action. The availability of many new methods and approaches for the measurement of blood pressure has introduced greater uncertainty into the interpretation of the blood pressure level in the individual patient, with question marks still surrounding the interpretation of white-coat hypertension, of ambulatory blood pressure monitoring and of home blood pressure readings in relation to clinic blood pressure. There is lack of uniformity in recommendations for the threshold values at which raised blood pressure should be lowered and in the recommendations for the target blood pressure the physician should set in the individual patient. CHOICE OF DRUG TO INITIATE TREATMENT: Since the publication of the major guidelines in 1993 and 1994, the greatest uncertainty has surrounded the choice of drugs to initiate treatment. This reflects the fact that so far no major trials have been completed confirming that the newer agents such as ACE inhibitors, calcium antagonists or alpha-blockers reduce cardiovascular morbidity and mortality in hypertensive patients. While awaiting the results of the many prospective randomized trials that are in progress with these newer agents, a number of case-control studies have raised concerns that non-potassium-sparing diuretics may increase the incidence of sudden cardiac death and that calcium antagonists might increase the occurrence of coronary heart disease in hypertensive subjects. CURRENT ACTION: These issues highlight the importance of initiating prospective, randomized, controlled trials early in the development of all new drugs. While awaiting the results of trials currently in progress, the physician should continue to use all five groups of antihypertensive drugs, tailoring the choice of drug to suit the individual patient, and should use low doses of antihypertensive drugs either alone, or in appropriate combinations.

Calcium Channel Blockers↗
PubMed1996

Blood pressure lowering in patients with cerebrovascular disease: results of the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) pilot phase.

1. Among patients with cerebrovascular disease, there is a direct and continuous association between blood pressure and the risk of stroke, but previous trials of blood pressure lowering in this patient group have been inconclusive. 2. PROGRESS (Perindopril Protection Against Recurrent Stroke Study) is a multicentre, randomized, placebo-controlled trial that aims to determine reliably the effect of angiotensin converting enzyme (ACE) inhibitor-based blood pressure lowering on stroke risk in patients with a history of cerebrovascular disease. If a 4 week run-in period on active perindopril is well tolerated, participants are randomized to either perindopril (4 mg) +/- indapamide (2.5 mg) or matching placebo(s). The primary study outcome is stroke and follow-up is for a minimum of 4 years. 3. For the pilot study nearly 5000 medical records were screened and 60 patients with recent cerebrovascular events were approached directly in hospital or at a clinic visit. Sixty-seven patients entered the run-in phase (52 from retrospective screening and 15 by prospective approach) and 60 patients proceeded to randomization. Treatment with perindopril was well tolerated; only three patients were withdrawn due to side effects and four were withdrawn for other reasons. The mean age of randomized patients was 68 years; 70% were male and 55% were 'non-hypertensive'. The mean entry blood pressure was 142/83 mmHg and following pre-randomization treatment this was reduced by 7/4 mmHg. 4. Most patients were identified by retrospective review of medical records, but this was less efficient than prospective methods. Blood pressure lowering was well tolerated by both hypertensive and non-hypertensive patients with cerebrovascular disease. The small numbers of patients and the non-randomized nature of the data reported limit the conclusions that can be drawn, but the results confirm the feasibility of the main study.

Antihypertensive Agents↗
PubMed1996

Role of excitatory amino acid receptors in cardiorespiratory coupling in ventrolateral medulla.

The role of (+/-)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)-kainate and N-methyl-D-aspartate (NMDA) receptors in the rostral ventrolateral medulla (RVLM) and caudal ventrolateral medulla (CVLM) on the central respiratory drive (CRD)-related activity of splanchnic sympathetic nerve activity (SNA) was examined in rats. SNA increased during inspiration (I peak) and postinspiration (PI peak). Bilateral microinjections of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; AMPA-kainate antagonist) or DL-2-amino-5-phosphonovaleric acid (APV; NMDA antagonist) into RVLM abolished the PI, but not the I, peak. Blockade of all excitatory amino acid receptors in RVLM with kynurenate, or mixtures of APV and CNQX, also failed to eliminate the I peak. Somatosympathetic responses were abolished by CNQX injection into RVLM, but were unaffected by APV. CNQX, but not APV, injection into CVLM increased the PI peak of SNA. Our findings suggest the following. 1) Both NMDA and AMPA-kainate receptors in RVLM are involved in the coupling between the sympathetic nervous system and CRD, which generates the PI peak seen in SNA. 2) The I peak of SNA is independent of excitatory amino acid transmission within RVLM. 3) There are different relative amounts of NMDA and AMPA-kainate receptors at synapses where respiratory and somatic inputs converge onto RVLM neurons. 4) Glutamatergic inputs to CVLM neurons modulate the coupling between SNA and CRD in RVLM.

2-Amino-5-phosphonovalerate↗
PubMed1996

Altered c-fos in rostral medulla and spinal cord of spontaneously hypertensive rats.

Neurons immunoreactive for Fos, the protein product of the immediate early gene c-fos, have been compared in the rostral ventral medulla and spinal cord of conscious normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) after baroreceptor unloading. Hypotension induced by a 60-minute intravenous infusion of sodium nitroprusside reduced baroreceptor activity; controls received intravenous saline. In WKY, 474 +/- 56 (n=6) Fos-positive neurons were identified in the rostral ventral medulla after nitroprusside infusion, a fivefold increase from controls; 50% of the tyrosine hydroxylase-containing neurons in the rostral ventral medulla were activated by this hypotension. Sympathetic preganglionic neurons, mainly sympathoadrenal neurons, were Fos positive after nitroprusside, but Fos-positive sympathetic preganglionic neurons were not observed in control WKY. In SHR, Fos immunoreactivity in the rostral ventral medulla was elevated in the control group compared with the WKY controls (236 +/- 31 and 93 +/- 15, respectively, n=6 for both). Nitroprusside hypotension did not further increase Fos immunoreactivity in the rostral ventral medulla, although the number of Fos-positive spinal sympathetic neurons increased. Our results have identified different neuronal activities between WKY and SHR in sites that are critical to sympathetic outflow. In WKY, nitroprusside effects are consistent with an activation of rostral ventral medulla neurons, including bulbospinal neurons, that are normally inhibited by baroreceptor activity. In SHR, basal nerve activity is increased, so even at rest, rostral ventral medulla neurons and sympathetic preganglionic neurons, mainly sympathoadrenal neurons, are Fos immunoreactive. These activated neurons are likely to contribute to the elevated blood pressure in this rat strain.

Animals↗
PubMed1996

How have patients reacted to the implications of the DCCT?

OBJECTIVES: To assess the reactions of people with insulin-treated diabetes (ITD) to the results of the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: A leaflet documenting the purpose and results of the DCCT was circulated to all 771 patients ages 15-60 years with ITD attending our clinic. Patients were invited to complete and return a questionnaire on their responses. RESULTS: Of 550 respondents, 330 felt encouraged to improve glycemic control. Female respondents (P = 0.003) and younger age-groups (15-25 years, P = 0.001) were most likely to want to improve control. Patients with long duration of diabetes (> 20 years, P = 0.00001), hypoglycemia unawareness (P = 0.0001), or previous severe hypoglycemia (P = 0.001) were less likely to want to improve their control. Fear of hypoglycemia concerned all age-groups, whereas female respondents were most likely to be worried about the potential for weight gain (P = 0.00006). CONCLUSIONS: Knowledge of the results of the DCCT encourages significant numbers of patients to want to improve glycemic control. Fear of hypoglycemia and, in women, weight gain may prove significant impediments to the clinical implementation of the results of the DCCT.

Adolescent↗
PubMed1996

Delayed diagnosis of juvenile primary hyperparathyroidism.

Primary hyperparathyroidism (PHP) is most common in adults in the fifth and sixth decades of life, but is seen infrequently in adolescence and is extremely rare in children under the age of 14 years. We report the case of a young female whom we suspect had PHP from the age of 6 years. This condition remained undiagnosed for the next 11 years in spite of repeated hospital admissions. The hypercalcaemia which was initially labelled as 'idiopathic' was eventually found to be secondary to a parathyroid adenoma, which was treated successfully by surgery. The case illustrates two important advances: (1) in parathyroid hormone measurement with a new sensitive immuno-radiometric assay, and (2) in the development of radionuclide scanning for localization of parathyroid adenoma(s). No case of hypercalcaemia should be labelled as 'idiopathic' or left unexplained without a detailed exploration of the neck to exclude PHP arising from a parathyroid adenoma.

Adenoma↗