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Biomedical subjects

J Chalmers

Publications and source records attributed to J Chalmers.

At least 145 records · Page 8Linked to original sources
PubMed1990

Diltiazem and atenolol in essential hypertension: additivity of effects on blood pressure and cardiac conduction with combination therapy.

In 15 patients with mild to moderate essential hypertension, the effects of diltiazem (120 mg twice daily) were compared with those of atenolol (50 mg once daily), the two drugs in combination, and placebo in a randomized double-blind cross-over study with treatment phases of 4 weeks duration. Blood pressure was reduced in the active treatment phases (supine blood pressure: diltiazem, 172/92 mmHg; atenolol, 172/92 mmHg; diltiazem plus atenolol, 164/88 mmHg; pooled estimate of s.e.m. by analysis of variance = 3/1) compared with placebo (180/101 mmHg). Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination. The time interval from the beginning of the P wave to the beginning of the QRS complex (P-R interval) was longer during combination therapy (0.184s) compared with either diltiazem (0.175s) or atenolol (0.174s) alone, or placebo (0.164s); s.e.m. by analysis of variance = 0.003. No clinically significant conduction disturbances occurred. Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem. Thus, in subjects with uncomplicated essential hypertension, diltiazem and atenolol had equal antihypertensive efficacy when used alone, and fully additive effects in combination, on both blood pressure and cardiac conduction.

Atenolol↗
PubMed1990

Differences in the central hypotensive actions of alpha-methyldopa and clonidine in the spontaneously hypertensive rat: contribution of neurons arising from the B3 and the C1 areas of the rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) is the proposed site of origin of bulbospinal excitatory vasomotor neurons, and this brainstem area gives rise to chemically distinct populations of neurons, including serotonin-containing neurons of the B3 group and epinephrine-containing neurons of the C1 group, which independently serve sympathoexcitatory functions. In the present study, we sought to establish (a) whether distinct and chemically specific pathways originating in the C1 or B3 regions are involved in the antihypertensive effects of alpha-methyldopa (methyldopa) and clonidine and (b) if so, whether these effects are related to an activation of alpha-adrenoceptors in these areas. Microinjections of methyldopa (6 nmol) or clonidine (5 nmol) were made in the C1 or B3 area in intact spontaneously hypertensive rats (SHR), pretreated with 5,7-dihydroxytryptamine (5,7-DHT) or with phentolamine. The microinjection of clonidine into both the B3 and the C1 area caused a rapid decrease in arterial pressure, whereas microinjection of methyldopa lowered the arterial pressure only after injection into the B3 area. Pretreatment with intracerebroventricular (i.c.v.) 5,7-DHT attenuated the hypotension produced by microinjection of clonidine into the B3 area, suggesting that this effect is mediated by serotonin-containing neurons. Central pretreatment with phentolamine reduced the hypotensive effects produced by injection of clonidine into either area and of methyldopa into the B3 region, consistent with previous suggestions that these central effects are mediated through alpha-adrenoceptors. These results suggest that both serotonin-containing and epinephrine-containing neurons contribute to the central action of clonidine, whereas the effects of methyldopa injection in RVLM appear to be mediated by serotonin-containing but not by epinephrine-containing neurons.

5,7-Dihydroxytryptamine↗
PubMed1990

Effect of intrathecal amino acid receptor antagonists on basal blood pressure and pressor responses to brainstem stimulation in normotensive and hypertensive rats.

The importance of spinal cord amino acid receptors in the regulation of blood pressure was investigated in normotensive (Wistar Kyoto, WKY), spontaneously hypertensive (SHR), and stroke-prone spontaneously hypertensive (SPR) rats. Also investigated was the possible role of these spinal cord receptors in mediating pressor changes evoked by electrical stimulation of two separate areas of the rostral ventrolateral medulla (RVLM) containing different neuronal populations, either the adrenaline-containing C1 area or the serotonin-containing B3 area. Intrathecal administration of the amino acid receptor antagonist kynurenate (KYN), or the selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (2APV), reduced basal blood pressure in anesthetized SHR and SPR in a dose-dependent manner, but were ineffective or elicited only small decreases in WKY. In all three strains, electrical stimulation in RVLM, in either the C1 or B3 area, evoked frequency-dependent pressor responses. Administration of 2APV or KYN was effective in attenuating these pressor responses in all three strains of rats. The effects of stimulation in the RVLM-B3 area were virtually abolished by administration of 2APV followed by the serotonin receptor antagonist methysergide. The results suggest that spinal cord excitatory amino acid receptors are important in blood pressure regulation in rats. Amino acid receptors, perhaps of the NMDA subtype, appeared to mediate pressor responses to stimulation of the RVLM-C1 and RVLM-B3 regions in both normotensive and hypertensive animals. On the other hand, excitatory amino acid receptor antagonists reduced basal blood pressure only in the hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1990

A lack of potency for the delta-opioid antagonist naltrindole after microinjection into the rostral ventrolateral medulla of rabbits.

1. Naltrindole is a novel delta-opioid antagonist which is highly potent in vitro. We examined the effects on arterial pressure of naltrindole (0.3-300 pmol) after microinjection into the pressor area of the rostral ventrolateral medulla of chloralose-anaesthetized rabbits. 2. Naltrindole itself had no significant effects on arterial pressure, and only slightly attenuated the hypotensive effect of an exogenous agonist ( [D-Ala2, D-Leu5]-enkephalin). This is in contrast to previous demonstration of a marked pressor effect following another delta-antagonist, ICI 174,864. 3. Thus, naltrindole, tested in vivo against endogenous opioid effects, does not appear to be as potent as it is in vitro, and in this case was virtually ineffective.

Animals↗
PubMed1990

Cardiovascular effects of opioid antagonist naloxone in rostral ventrolateral medulla of rabbits.

We have examined the influence of endogenous opioids on the basal and reflex control of arterial blood pressure in the pressor region of the rostral ventrolateral medulla (RVLM) of chloralose-anesthetized rabbits. We tested basal effects both in intact animals and after hypotensive hemorrhage. Bilateral administration of the opiod antagonist naloxone (20 nmol, 100 nl) directly into the RVLM induced a gradual and prolonged increase in mean arterial pressure (MAP) (+17 +/- 2 mmHg). This was preceded by a brief and mild depressor effect (-9 +/- 3 mmHg), which was attributable to a transient reduction in excitability immediately after naloxone injection. When naloxone was administered into the RVLM after hemorrhage (20 ml/kg), it improved recovery of MAP relative to saline controls, again producing a gradual, prolonged pressor response (+29 +/- 5 mmHg). The effect of naloxone on a baroreflex in intact animals was only transient, with a brief, nonsignificant attenuation of the reflex depressor response to aortic nerve stimulation. We conclude that endogenous opioids exert a tonic inhibitory influence on RVLM pressor neurons and that this input remains active after hemorrhage. The RVLM may thus be one site for the beneficial effects of naloxone in preventing circulatory decompensation after hemorrhage. In contrast, opioid neurons are not an essential component of baroreflex-mediated sympathoinhibition in the RVLM.

Animals↗
PubMed1990

Mechanisms of impaired excretion of a fluid load after cardiac denervation in dogs.

The influence of cardiac innervation on the renal response to volume expansion was investigated. Systemic hemodynamic, plasma hormone, and renal clearance measurements were made before, during, and after intravenous administration of 1,000 ml 0.9% saline over 10 min to six control and six cardiac-denervated, chloralose-anesthetized mongrel dogs. Volume expansion resulted in a two- to threefold rise in plasma atrial natriuretic peptide (ANP) concentrations and a 50% rise in glomerular filtration rate (GFR) in both groups. Plasma renin activity (PRA) and plasma arginine vasopressin remained higher throughout in cardiac-denervated compared with control dogs. The marked increases in urine flow rate and sodium and free water clearances seen in the controls were attenuated or abolished after cardiac denervation. These differences were due to the influence of higher PRA and vasopressin in these animals compared with the controls, rather than differences in hemodynamic responses operating via GFR or in direct humoral responses via ANP secretion.

Animals↗
PubMed1990

Altered cardiovascular and neurohumoral responses to head-up tilt after heart-lung transplantation.

Heart-lung transplantation results in afferent and efferent denervation of the transplanted organs including interruption of the central connections from the low-pressure receptors in the atria and pulmonary veins. We investigated whether the cardiovascular and neurohumoral responses to the postural stimulus of head-up tilt were affected after transplantation. Responses in eight heart-lung transplant recipients were studied and compared with those in eight normal subjects matched for age and sex during passive head-up tilt at 45 degrees for 1 hour. The transplant group had a higher initial heart rate (99 +/- 2 versus 68 +/- 2 beats/min, p less than 0.001) and diastolic blood pressure (88 +/- 5 versus 76 +/- 2 mm Hg, p less than 0.05) than did the control group. The increases in heart rate and diastolic blood pressure during head-up tilt were similar in the two groups. Systolic blood pressure remained unchanged. The decrease in cardiac output (30% versus 18%, p less than 0.05) and the increase in systemic vascular resistance (52% versus 28%, p less than 0.05) were greater in the transplant group. Baseline levels of norepinephrine, epinephrine, vasopressin, and plasma renin activity were similar in the two groups. Atrial natriuretic peptide concentrations were higher in the transplant group (26 +/- 3.8 versus 9.7 +/- 1.6 pmol/l, p less than 0.001). During head-up tilt, plasma norepinephrine levels increased to a greater extent in the transplant group than in the control group (83% versus 53%, p less than 0.01), indicating an increased sympathetic response. In contrast, plasma renin activity increased significantly in the control group but not in the transplant group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Tonic opioid inhibition of the pressor region of the rostral ventrolateral medulla of rabbits is mediated by delta receptors.

From previous observations, we have suggested that an endogenous opioid input tonically inhibits the pressor neurons of the rostral ventrolateral medulla (RVLM) of rabbits. In the present studies, the specific opioid receptor subtype(s) which may be activated by such an endogenous innervation were examined using local administration of selective antagonists. The RVLM pressor region of chloralose-anesthetized and artificially ventilated rabbits was functionally identified by local administration of L-glutamate (5 nmol). Selective blockade of neither mu nor kappa receptors in the RVLM after bilateral injections of beta-funaltrexamine (300-900 pmol) or nor-binaltorphimine (1 nmol), respectively, had any effect on either mean arterial pressure or heart rate. Delta receptors were blocked with ICI 174,864 (30-300 pmol). After the highest dose, there was a significant pressor effect (+32 +/- 6 mm Hg, mean +/- S.E.), which was of immediate onset and rapid time course (approximately 15 min), and which was accompanied by a bradycardia. In contrast, vehicle injections or injection of an inactive analog (ICI 178,173) had no effects. These results, together with previous pharmacological and anatomical evidence, suggest that there exists an enkephalinergic input to the RVLM that tonically inhibits the presympathetic pressor neurons via activation of delta-opioid receptors.

Animals↗
PubMed1990

Analysis of time trends, individual subject responses and background variation in crossover factorial studies with antihypertensive drugs.

In studying patients with mild hypertension, we used a double-blind, randomly allocated crossover, 2 x 2 factorial design to obtain more precise estimates of the effectiveness of individual hypertensive drugs and of the interactions when used in combination. In the present study, we reanalysed data from our own previously completed crossover factorial studies in order to determine the optimal length of phases and to try to exploit patient heterogeneity by comparing blood pressure responses within each patient to the two different drugs in each study. An analysis of the 'weeks within phases' variation (analysis of variance) applied to all phases, to the placebo phases alone and to the active treatment phases alone, of the individual factorial studies and of pooled data from studies of similar design, only revealed differences in the first week of our 4-week phases. Accordingly, we suggest that 4 weeks is an optimal phase length, since only the values from the third and fourth weeks showed the full expression of a drug's antihypertensive effect, avoiding the problem of a carryover effect and the need for a more complex intervening washout placebo phase. Comparing the blood pressure reductions shown by individual patients in response to different antihypertensive drugs using arbitrary criteria of greater than or equal to 5, 10 and 15 mmHg for diastolic and greater than or equal to 5, 10 and 20 mmHg for systolic pressure, we were unable to distinguish between the two separate drugs in each factorial study, due to the magnitude of the background variation which had a coefficient of variation of 5-7%.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗
PubMed1990

Making resource management work.

Following Government pressure for more resource management, nurses at the Radcliffe Infirmary set up a pilot scheme putting the system into action. This, the first of a two-part series, describes how ward sisters assumed responsibility for budgeting their wards.

Health Resources↗
PubMed1989

Evidence for an excitatory amino acid pathway in the brainstem and for its involvement in cardiovascular control.

The source and possible role of excitatory amino acid projections to areas of the ventrolateral medulla (VLM) involved in cardiovascular control were studied. Following the injection of [3H]D-aspartate ([3H]D-Asp), a selective tracer for excitatory amino acid pathways, into vasopressor or vasodepressor areas of the VLM in rats, more than 90% of retrogradely labelled neurones were found in the nucleus of the solitary tract (NTS). Very few of the [3H]D-Asp-labelled cells were immunoreactive for tyrosine hydroxylase, none for phenylethanolamine-N-methyltransferase or gamma-aminobutyric acid. The density of labelled cells in the NTS was similar to that obtained with the non-selective tracers wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and WGA-colloidal gold, but these tracers also labelled other cell groups in the medulla. Furthermore, the decrease in blood pressure, caused by pharmacological activation of neurones in the NTS of rats, or by electrical stimulation of the aortic depressor nerve in rabbits could be blocked by the selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate injected into the caudal vasodepressor area of the VLM. This area corresponds to the termination of [3H]D-Asp transporting NTS neurones. These results provide evidence that a population of NTS neurones projecting to the VLM use excitatory amino acids as transmitters. Among other possible functions, this pathway may mediate tonic and reflex control of blood pressure via NMDA receptors in the VLM.

2-Amino-5-phosphonovalerate↗
PubMed1989

Correlation between fall in blood pressure and in vivo amine release after alpha-methylDOPA.

Blood pressure (BP), hypothalamic tissue concentrations and the in vivo overflow of endogenous and alpha-methylated catecholamines were measured in urethane anaesthetised rats after alpha-methylDOPA (mDOPA) administration (200 mg/kg i.p.). Four hours after mDOPA, BP fell to its lowest value, 60% of control, and slowly returned towards control levels by 24 h. This was closely correlated with the evoked overflow of alpha-methylnoradrenaline (mNA, r = 0.9) and noradrenaline (NA, r = 0.7) but not dopamine (DA) or alpha-methyldopamine (mDA). However, the tissue content of mNA rose much more gradually and was not maximal until after 12 h while mDA content followed the development of the hypotension. The results provide direct evidence for a false transmitter role for mNA in the brain, and suggest that the release of newly synthesised mNA is responsible for the hypotensive effect of mDOPA. Differences in the time course of overflow and storage of NA and mNA suggest the presence of separate transmitter storage and releasable pools.

Animals↗
PubMed1989

Effects of neuropeptide Y on the renal, mesenteric and hindlimb vascular beds of the conscious rabbit.

The effects of neuropeptide Y (NPY, 10 micrograms/kg bolus i.v.) on renal, mesenteric and hindlimb blood flow were determined in intact conscious rabbits with chronically implanted Doppler ultrasonic flow transducers. The role of sympathetic neuro-effectors was assessed using inhibition of peripheral alpha-adrenoceptors with phentolamine in each group, and in the renal flow group following chemical sympathectomy with 6-hydroxydopamine. In controls, NPY caused markedly non-uniform peak responses. Renal blood flow fell from 2.16 +/- 0.12 kHz to a minimum of 0.26 +/- 0.07 kHz following NPY administration (P less than 0.05). Mesenteric blood flow was reduced from 2.04 +/- 1.17 to 1.54 +/- 0.11 kHz (P less than 0.05). blood flow increased transiently from 2.33 +/- 0.15 to a peak of 3.33 +/- 0.19 kHz (P less than 0.05). Renal vascular resistance rose by 1189 +/- 309% and mesenteric resistance by 54 +/- 9% (P less than 0.05), while hindlimb resistance fell by 24 +/- 3% (P less than 0.05). Pretreatment with phentolamine accentuated the peak pressor response and the reduction in heart rate induced by NPY administration but had little effect on the local haemodynamic changes in each vascular bed. There was no change in the renal vascular response to NPY following sympathectomy. Indeed, the peak NPY-induced reduction in renal blood flow seen in control animals (87 +/- 4%) was unaffected by either alpha-adrenoceptor inhibition (90 +/- 5%) or by sympathectomy (86 +/- 5%). In conscious rabbits with intact cardiovascular reflexes, pharmacological doses of NPY cause profound renal vasoconstriction with smaller changes in mesenteric and hindlimb flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

An enkephalin-containing pathway from nucleus tractus solitarius to the pressor area of the rostral ventrolateral medulla of the rabbit.

A technique combining retrograde tracing of wheat germ-conjugated gold particles with immunocytochemical demonstration of enkephalin-containing neurons was used to study intramedullary enkephalin-containing pathways to the pressor area of the rostral ventrolateral medulla in rabbits. The rostral ventrolateral medulla represents a main source of bulbospinal sympathoexcitatory neurons, and is critical to the tonic and reflex control of blood pressure. Firstly, the distribution of enkephalin-positive neurons and terminal fibres in rabbit medulla were described, with special reference to a moderately dense terminal plexus in the rostral ventrolateral medulla. Then, retrograde tracing studies were conducted; the rostral ventrolateral medullary pressor region was first localized by injection of L-glutamate (25 nmol in 50 nl). Slow (30-min) injections of wheat germ-gold (1.00 microliter) were then made at the same coordinates, resulting in a restricted injection site corresponding to the C1 pressor area, verified by the presence of tyrosine hydroxylase- and neuropeptide Y-containing neurons. Transported gold was revealed by silver reduction, and enkephalin immunoreactive cells were revealed by immunocytochemistry. Enkephalin-positive gold-containing neurons were found primarily in the nucleus tractus solitarius, especially in the commissural and medial intermediate subnuclei. Cells in the nucleus tractus solitarius containing other transmitters (substance P. galanin, neuropeptide Y and catecholamines) did not show the same degree or pattern of double-labelling, suggesting that the transport was not due to non-specific silver reduction or spread from the pipette track. The potential importance of this endogenous intramedullary opiate system is discussed in terms of medullary control of the cardiovascular system. It is hypothesized that this opiate projection from the nucleus tractus solitarius to the rostral ventrolateral medulla could play an important modulatory function, influencing baroreceptor or other cardiopulmonary reflex pathways involved in the primary regulation of the cardiovascular system. Furthermore, this pathway could represent a central substrate underlying opiate effects on the cardiovascular system during such conditions as hemorrhagic shock, stress or opiate intoxication.

Animals↗
PubMed1989

Neuropeptide Y in the sympathetic control of blood pressure in hypertensive subjects.

Neuropeptide Y (NPY) coexists with noradrenaline in postganglionic sympathetic neurons and with noradrenaline and adrenaline in the central nervous system. The possibility that NPY is released into the circulation during activation of the sympathoadrenal system was investigated in ten moderately hypertensive volunteers using three different stimuli. In healthy moderately hypertensive volunteers cold pressor test, head up tilt and graded bicycle exercise resulted in increased blood pressure, heart rate and plasma catecholamine concentrations. While there was a trend for plasma NPY-like immunoreactivity (NPY-LI) to increase during cold pressor test and head up tilt, NPY-LI concentration only increased significantly during bicycle exercise, the stimulus of greatest duration. These results suggest that plasma NPY-LI can be released into the circulation on sympathoadrenal activation in moderately hypertensive subjects and demonstrate that the pattern of release is similar to that previously observed in normotensive subjects.

Adrenal Glands↗
PubMed1988

Release of substance P in the nucleus tractus solitarius measured by in vivo microdialysis: response to stimulation of the aortic depressor nerves in rabbit.

Substance P (SP) is found in high concentration in the nucleus tractus solitarius (NTS), and is a neurotransmitter candidate in primary baroreceptor afferents to the NTS. Release of SP in the medial NTS of halothane-anesthetized rabbits was measured by in vivo microdialysis. Bilateral electrical stimulation of the aortic depressor nerves (ADN) elicited a significant elevation in SP collected during the period following stimulation, while sham stimulation had no effect. Perfusion through the dialysis probe with a high-potassium (150 mM) solution caused a large increase in the level of SP collected, verifying the neural origin of this release. Possible explanations for the delay in increased release of SP include interaction with carotid afferents, diffusion time, or excitation of SP-containing inputs to the NTS originating elsewhere in the brain. This study demonstrates that SP release in the NTS is elevated by activation of baroreceptor afferents, supporting the hypothesis that SP plays a role in the central integration of cardiovascular control. Whether this release is from primary afferent terminals, or from another source, remains to be seen.

Animals↗
PubMed1988

Effects of intrathecal administration of methysergide, phentolamine, and pindolol on pressor responses to electrical stimulation of the rostral ventrolateral medulla.

Neurons projecting from the rostral ventrolateral medulla (RVLM) to the spinal cord are important in blood pressure control. The present experiments examined the role of spinal adrenoreceptors and serotonin receptors in mediating the pressor effects of electrical stimulation of the RVLM. Accordingly the effects on blood pressure of electrical stimulation of the RVLM were studied before and after intrathecal administration of adrenergic or serotonergic antagonists in normotensive and hypertensive rats. Electrical stimulation in the area of the RVLM-B3 serotonin-containing neurons in Wistar-Kyoto (WKY) rats increased blood pressure, and the pressor responses were reduced by intrathecal methysergide (30 and 100 micrograms). Similar findings were seen in spontaneously hypertensive rats (SHR). In WKY, electrical stimulation in the area of the RVLM-C1 epinephrine-containing neurons, increased mean arterial pressure (MAP), but the pressor responses were unaffected by intrathecal phentolamine (15 micrograms), pindolol (2 micrograms), or methysergide (30 and 100 micrograms), or saline. The results suggest that the pressor effects of stimulation of the RVLM-B3 area are mediated at least in part through activation of spinal serotonin receptors. The lack of effect of phentolamine and pindolol on the RVLM-C1 area pressor responses raises a question regarding the importance of spinal adrenergic receptors in mediating these effects.

Animals↗