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Biomedical subjects

J Ludbrook

Publications and source records attributed to J Ludbrook.

At least 73 records · Page 4Linked to original sources
PubMed1989

Role of central opiate receptor subtypes in the circulatory responses of awake rabbits to graded caval occlusions.

1. In unanaesthetized rabbits, haemorrhage was simulated by inflating a cuff placed round the inferior vena cava so that cardiac output fell at a constant rate of approximately 8% of its resting value per minute. The circulatory responses were measured after injections into the fourth ventricle of saline vehicle, selective opioid antagonists, selective opioid agonists, and agonist-antagonist mixtures. Three sets of experiments were done to determine if a specific subtype of opiate receptor within the central nervous system is responsible for the circulatory decompensation that occurs during simulated haemorrhage. 2. In six rabbits the effects of ascending doses of the antagonists naloxone (mu-selective), Mr 2266 (kappa- and mu-selective), ICI 174864 (delta-selective) and nor-binaltorphimine (kappa-selective) were tested. In three rabbits the effects of the antagonist naloxone, the agonists HTyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAGO, mu-selective), U 50488H (kappa-selective), and [D-Pen2,D-Pen5]-enkephalin (DPDPE, delta-selective), and combinations of these agonists with naloxone were tested. In four rabbits the dose-related effects of DAGO on respiratory, as well as circulatory, functions were examined. 3. After injecting saline vehicle, the circulatory response to simulated haemorrhage had two phases. During the first phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only approximately 10 mmHg. A second, decompensatory, phase began when cardiac output had fallen to approximately 50% of its resting level. At this point, there was an abrupt rise in systemic vascular conductance and a fall in mean arterial pressure to less than or equal to 40 mmHg. 4. The lower range of doses of naloxone (3-30 nmol), Mr 2266 (10-100 nmol), ICI 174864 (10-30 nmol), and all doses of nor-binaltorphimine (1-100 nmol), were without effect on the circulatory response to stimulated haemorrhage. Higher doses of naloxone (30-100 nmol), Mr 2266 (100-300 nmol) and ICI 174864 (30-100 nmol) abolished the decompensatory phase. The relative order of antagonist potency was ICI 174864 greater than or equal to naloxone greater than Mr 2266 greater than or equal to nor-binaltorphimine. 5. In the second set of experiments, the critical dose of naloxone necessary to prevent circulatory decompensation during simulated haemorrhage was 30-150 nmol. The delta-agonist DPDPE (50 nmol) did not affect the haemodynamic response to simulated haemorrhage, but it did block the effect of naloxone on the response.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Haemodynamic responses to acute blood loss: new roles for the heart, brain and endogenous opioids.

Information has come forward recently from several sources which provides new insights into the mechanisms that underlie the haemodynamic responses to acute blood loss. In unanaesthetised animals and human volunteers there are two distinct phases to these responses. At first, the engagement of baroreflexes results in a progressive rise in sympathetic vasoconstrictor drive and peripheral resistance, and the maintenance of arterial blood pressure at a near-normal level. When about one-third of blood volume has been lost, reflex sympathetic drive is switched off, and peripheral resistance and blood pressure fall abruptly to low levels despite a burst of vasopressin release. Research in conscious animals has now shown that the onset of this decompensatory phase is triggered by a signal from the heart, which activates an endogenous opioid mechanism in the brain. Activation of this mechanism can be prevented by administering a selective delta-receptor antagonist, or selective mu-receptor agonists (including alfentanil). It has not yet been established that this endogenous opioid mechanism is responsible for the decompensatory phase of acute blood loss in man, nor that it can be prevented or reversed by selective opioid agonists or antagonists.

Acute Disease↗
PubMed1988

Simulation of acute haemorrhage in unanaesthetized rabbits.

1. We have shown that it is feasible to match the linear rate of fall of cardiac output that occurs during haemorrhage at 2.7 ml/kg per min in unanaesthetized rabbits by constricting the thoracic inferior vena cava so as to decrease venous return. 2. The changes in systemic vascular resistance, arterial pressure and heart rate that occurred during haemorrhage were mimicked by simulated haemorrhage. They were reproducible when simulated haemorrhage was performed three times at 90 min intervals, and when it was repeated four times over 12 days. 3. Simulated haemorrhage caused rises in plasma renin activity (PRA) and plasma arginine vasopressin concentration (AVP) that were similar to those reported after haemorrhage. The response of PRA was unaffected by repeated simulated haemorrhage, but the response of AVP was less on the third occasion. 4. When the shed blood was re-infused after haemorrhage, cardiac output tended to remain low and systemic vascular resistance high. After simulated haemorrhage, all haemodynamic variables returned to normal within 2 min of releasing the caval cuff. 5. Haematocrit fell during haemorrhage, and remained low for at least 5 days after replacement of the shed blood. Haematocrit was unaffected by simulated haemorrhage. 6. Venous pressure below the inflatable cuff rose by 6 mmHg in the course of simulated haemorrhage. 7. We conclude that the central haemodynamic effects of haemorrhage can be closely and repeatedly simulated by inflating a cuff on the inferior vena cava. This provides a useful technique for repeatedly studying the effects of acute reduction of central blood volume in conscious animals.

Acute Disease↗
PubMed1988

Effect of naloxone on haemodynamic responses to acute blood loss in unanaesthetized rabbits.

1. We have tested the hypothesis that the pressor action of (-) naloxone HC1 after haemorrhage is due to antagonism of endogenous opiate mechanisms that are activated by haemorrhage, rather than to some more direct vasoconstrictor action of the drug. 2. Six conscious rabbits were treated intravenously with either naloxone (4 mg kg-1, then 0.1 mg kg-1 min-1) or equivalent volumes of saline. In unbled rabbits the naloxone regimen had no effect except to cause a transient bradycardia. After each treatment the rabbits were bled at a rate of 2.45 ml kg-1 min-1 until blood pressure fell to 40 mmHg or 28 ml kg-1 of blood had been withdrawn (17-24 ml kg-1 after saline, 21-28 ml kg-1 after naloxone). 3. Throughout both episodes of bleeding there was a progressive fall of cardiac output and rise of heart rate, at rates that were constant and independent of the prior treatment. 4. After saline treatment, bleeding at first resulted in a steep and progressive fall of systemic vascular conductance and a small fall in blood pressure. However, when blood loss exceeded 12.7 ml kg-1 (approximately 28% of blood volume) there was an abrupt rise in systemic vascular conductance and an abrupt fall in blood pressure. 5. After naloxone treatment, during the entire period of bleeding systemic vascular conductance fell steeply and blood pressure fell slowly. 6. The different effects of saline and naloxone on the haemodynamic responses to acute blood loss were not explicable by differences in haematocrit or net blood volume. 7. We conclude that endogenous opiate mechanisms are responsible for the abrupt vasodilation that occurs when more than 28% of blood volume is withdrawn rapidly from conscious rabbits. We suggest that these mechanisms reside in the central nervous system.

Acute Disease↗
PubMed1988

Baroreflex participation in redistribution of cardiac output at onset of exercise.

The distribution of cardiac output and systemic vascular conductance was measured in five rabbits. Cardiac output was measured by ascending aortic flowmetry and was partitioned according to the distribution of 15-micron radiolabeled microspheres injected into the left atrium. The rabbits were studied under four conditions: at rest and after 20 s of treadmill exercise, both before and approximately 5 min after acute barodenervation of the conscious animal. During exercise in the baroinnervated state, approximately 40% of the increased blood flow to skeletal and cardiac muscle was contributed by diversion from the splanchnic organs, kidneys, systemic arteriovenous anastomoses, and skin. This diversion of blood flow during exercise was absent after arterial barodenervation. We conclude that at the onset of exercise in rabbits the mismatch between cardiac output and the metabolic demands of skeletal and cardiac muscle is accommodated by vasoconstriction in other vascular beds. We suggest that the vasoconstriction in the splanchnic organs and skin may be caused by transient suppression of the reflex effects of arterial baroreceptor input at the onset of exercise.

Animals↗
PubMed1987

Selective manipulation of neurohumoral control of the cardiac pacemaker by drugs given intrapericardially.

A technique of intrapericardial administration of beta-adrenoceptor and muscarinic cholinergic receptor antagonist drugs has been tested in conscious rabbits. Intrapericardial propranolol or atenolol (50 micrograms/kg) had the same effect on isoprenaline heart rate dose-response curves and on the sympathetic component of the arterial baroreceptor-heart rate reflex as did conventional, 5-fold greater, intravenous doses of the drugs. The action of intrapericardial propranolol was attributable to its (-)isomer. Intrapericardial propranolol (50 micrograms/kg) had little effect on ventricular contractility. Plasma levels of propranolol and atenolol after intrapericardial administration were, respectively, 7- and 40-fold less than after the usual intravenous doses. Intrapericardial hyoscine methyl bromide (10 micrograms/kg) abolished baroreflex vagal effects on heart rate as effectively as did the conventional, 5-fold greater, intravenous dose. The duration of receptor blockade by both classes of drugs when given intrapericardially was at least 2 hr. We conclude that the rapid diffusion of beta-adrenoceptor and muscarinic cholinergic receptor blocking drugs from the pericardial sac to receptors on the sinoatrial cardiac pacemaker, and their prolonged actions, provides a useful technique for preventing the actions of the sympathetic and vagus nerves, and of circulating catecholamines, on the chronotropic functions of the heart.

Adrenergic beta-Antagonists↗
PubMed1987

Analysis of mechanisms responsible for the bradycardic action of naloxone after haemorrhage in the conscious rabbit.

We have analyzed the efferent mechanisms responsible for the bradycardia that occurs when naloxone (6 mg/kg) is given i.v. to conscious rabbits after acute blood loss of 17-20 ml/kg. Atenolol and hyoscine methyl bromide were given intrapericardially (i.p.c.), singly and in combination, to allow factorial analysis of the contributions of sympathoadrenal beta-adrenergic and vagal cholinergic mechanisms. In addition, the effects of ganglion blockade with mecamylamine on the heart rate response to naloxone, and of i.p.c. naloxone on the cardiac pacemaker, were tested. The treatments had little effect on the pressor response to naloxone. Central nervous mechanisms were responsible for most of the bradycardia of approximately 160 beats/min evoked by naloxone in sham-treated, bled, rabbits. Increased vagal drive accounted for one-half the response, withdrawal of sympathoadrenal drive for 20%, and there was no significant interaction. These effects appeared to be due to evocation of a baroreceptor-heart rate reflex by the concomitant rise in blood pressure. Non-cholinergic, non-adrenergic mechanisms were responsible for a fall in heart rate of approximately 35 beats/min, part of which was due to a direct action of naloxone on the cardiac pacemaker.

Animals↗
PubMed1987

A diamond jubilee.

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Academies and Institutes↗
PubMed1987

Vasodilator responses to acute blood loss.

There is new evidence from experiments in conscious animals that when acute blood loss exceeds about 30% of blood volume, reflex vasoconstriction is abruptly replaced by widespread vasodilatation, and there is a precipitous fall in arterial blood pressure. This vasodilatation is associated with a decline in sympathetic vasoconstrictor drive. It is likely that the signal which causes the switch from vasoconstriction to vasodilatation reaches the brain via afferent nerves from the heart. There is also circumstantial evidence that endogenous opiate mechanisms are involved in the translation of the cardiac afferent signal into failure of reflex sympathetic vasoconstrictor drive. These mechanisms may explain the 'vaso-vagal' reaction that can occur in man during or following acute, severe, blood loss.

Animals↗
PubMed1987

Sympathoadrenal mechanisms in cardiovascular responses to naloxone after hemorrhage.

Five rabbits were allotted to each of six treatments on a matched-individual basis. Treatments were none, sham, total adrenalectomy with adrenocorticoid replacement, intravenous guanethidine (15 mg X kg-1 X day-1), adrenalectomy + guanethidine, and adrenal medullectomy. The conscious rabbits were bled 20 ml/kg over 5 min. Naloxone (6 mg/kg) was injected intravenously. The responses of arterial pressure and of plasma epinephrine (E) and norepinephrine (NE) concentrations were measured. Factorial analysis was used to calculate the effects of sympathetic noradrenergic nerves (SYM) and the adrenal medulla (ADR) on the responses. In combination, SYM + ADR fully accounted for the pressor response observed in normal and sham-treated rabbits. SYM and ADR each made independent and approximately equal contributions to the response, but the SYM X ADR interaction was strongly antagonistic. The responses of plasma E and NE were fully accounted for by the adrenal glands and sympathetic nerves, respectively. The pressor responses after total adrenalectomy and adrenal medullectomy were similar. Thus hemorrhage-stimulated adrenal corticosteroid release was not essential to naloxone's action, and adrenal enkephalins were not responsible for naloxone's action on sympathetic pathways.

Adrenal Medulla↗
PubMed1986

Effects of acute versus chronic deletion of arterial baroreceptor input on the cardiovascular responses to exercise in the rabbit.

These experiments were designed to confirm that at the onset of treadmill exercise in rabbits the tonic reflex depressor effects of input to the central nervous system from arterial baroreceptors is abolished, thus contributing to the rise of systemic arterial pressure (SAP) and heart rate (HR). An inflatable cuff was placed around one common carotid artery after the remaining arterial baroreceptors had been surgically denervated. Transient inflation of the cuff caused reflex rises of SAP and HR, which were much reduced during the first minute of exercise. Deflation of the cuff caused a brisk fall of HR, which was completely abolished by exercise. A snare was placed around one carotid sinus nerve after the remaining arterial baroreceptors had been surgically denervated. Where the snare was tightened all arterial baroreceptor reflexes were immediately and permanently abolished. This allowed the reflex effects of baroreceptor input to be calculated by difference. The magnitude of these calculated effects, at rest and during exercise, diminished according to how long after barodenervation the observations were made. We conclude from the above experiments that the resting tonic reflex depression of SAP and HR caused by baroreceptor input is much reduced, rather than completely abolished, at the onset of exercise. We also conclude, from the effects of partial surgical barodenervation, and of unloading the carotid baroreceptors prior to exercise by inflating the carotid cuff, that resting input from the arterial baroreceptors must be near zero before the cardiovascular response to exercise is grossly altered.

Animals↗
PubMed1986

Factors influencing the effects of intravenous naloxone on arterial pressure and heart rate after haemorrhage in conscious rabbits.

The circulatory responses to different intravenous doses of naloxone were studied in conscious rabbits before and after haemorrhage, under different conditions including prior ganglion blockade. Unless there had been blood loss, naloxone elicited no pressor response, even in high dose. After bleeding so that arterial pressure fell to 40 mmHg, the dose-response relationship for naloxone had two components. Over a low-dose range (threshold 0.3 mg/kg) naloxone had a modest pressor effect but did not affect heart rate. Over a much higher dose range (threshold 0.6 mg/kg) naloxone caused a marked rise in arterial pressure and a profound bradycardia. The highest dose of naloxone examined (25 mg/kg) caused a rise in arterial pressure of 70 mmHg and a reduction in heart rate of 160 beats/min. The pressor and bradycardic effects of naloxone were the same whether post-haemorrhagic hypotension lasted 5, 10, 20 or 30 min. The responses to naloxone in low or high dose depended much more closely on the volume of blood removed than on the level to which arterial pressure fell. Even after non-hypotensive haemorrhage a high dose of naloxone had marked pressor and bradycardic effects. Ganglion blockade prior to haemorrhage abolished the pressor response to a low, but not to a high, dose of naloxone. It was concluded that prolonged and severe hypotension are not necessary to 'prime' the cardiovascular system to respond to naloxone after haemorrhage. In a high dose its pressor effects appear to be mediated post-ganglionically, but in a low dose it may act within the central nervous system.

Animals↗
PubMed1986

AIDS and surgery.

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Acquired Immunodeficiency Syndrome↗