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Biomedical subjects

J Ludbrook

Publications and source records attributed to J Ludbrook.

At least 55 records · Page 3Linked to original sources
PubMed1991

Use of nicotine, bradykinin and veratridine to elicit cardiovascular chemoreflexes in unanaesthetized rabbits.

1. We have characterized in unanaesthetized rabbits the reflex effects of injecting nicotine into the pericardial sac or left atrium on heart rate, arterial pressure, systemic vascular resistance and the amplitude and frequency of respiration. These effects were compared with those of atrial administration of nicotine and veratridine, and intrapericardial administration of veratridine and bradykinin. 2. Injection of nicotine (6.25-400 micrograms) into the pericardial sac caused dose-dependent falls of heart rate and arterial pressure, and a brief period of hypopnoea. The fall in arterial pressure was mainly due to a fall in systemic vascular resistance. The threshold dose was 25 micrograms. Near maximal falls in heart rate (108 beats/min) and arterial pressure (47 mmHg) occurred at a dose of 200-400 micrograms. The latency between injection and the onset of bradycardia was 3.0 s. 3. The effects of intrapericardial nicotine on arterial pressure and respiration were antagonized in a dose-dependent fashion by intrapericardial mecamylamine (1-100 micrograms/kg) but were unaffected by intrapericardial hyoscine methylbromide (10 micrograms/kg) or vecuronium (1-10 micrograms/kg). The haemodynamic and respiratory effects were abolished by intrapericardial procaine. The haemodynamic effects were increased, though not significantly, by sino-aortic baroreceptor denervation. In decerebrate, artificially ventilated rabbits, bilateral cervical vagotomy converted the hypotensive and bradycardic response into a slowly developing tachycardia without change in arterial pressure. 4. Left atrial injection of nicotine (6.25-100 micrograms) caused bradycardia, a rise in arterial pressure, and prolonged hyperpnoea preceded by transient hypopnoea. After sino-aortic barodenervation it caused profound falls in heart rate and arterial pressure and transient hypopnoea, which were abolished by intrapericardial procaine. 5. Intrapericardial injection of veratridine (50-100 micrograms) had no consistent effect under control conditions. After sino-aortic barodenervation it caused falls in heart rate and arterial pressure which were abolished by intrapericardial procaine. Left atrial injection of veratridine caused highly variable haemodynamic effects. 6. Intrapericardial bradykinin (2.5-25 micrograms) caused rises in both arterial pressure and heart rate. These were abolished by intrapericardial procaine. 7. We conclude that when nicotine is injected into the pericardial sac of conscious rabbits the reflex haemodynamic and respiratory effects are due to the selective activation of neuronal-type nicotinic cholinoceptors on vagal afferents that originate in the epicardium. The reflex effects of left atrial nicotine are probably due to the excitation of a combination of carotid chemoreceptors and cardiac receptors. 8. The effects of nicotine, veratridine and bradykinin that we observed in conscious rabbits were profoundly different from those reported in anaesthetized rabbits.

Animals↗
PubMed1991

On making multiple comparisons in clinical and experimental pharmacology and physiology.

1. It is a central thesis of this review that in clinical and experimental pharmacology and physiology the goal of statistical analysis should be to minimize the risk of making any false-positive inferences from the results of an experiment (experimentwise Type I error). 2. It is common in clinical and experimental pharmacology and physiology for the effects of several treatments to be tested within a single experiment. Specific intercomparisons of these several effects, made in a pairwise or more complex fashion, inflates the risk of making false-positive inferences unless special statistical procedures are used. 3. A number of multiple comparison procedures is described and their ability to control experimentwise Type I error is evaluated critically. 4. When only a few (less than 5) of all possible pairwise or more complex comparisons are made between treatment groups, the Dunn-Sidák procedure provides maximum protection against excessive experimentwise Type I error and is very convenient to use. 5. When a control group is compared with all other treatment groups in a pairwise fashion, especially when the number of groups is large, the Dunnett procedure is more powerful than the Dunn-Sidák. 6. If investigators insist on making all possible pairwise comparisons among treatment groups, the Tukey-Kramer procedure provides maximum protection against false-positive inferences but inflates the Type II error rate. If it is especially important to avoid Type II error then the more complicated, stepwise procedures of the Ryan-Peritz-Welsch variety should be considered.

Analysis of Variance↗
PubMed1991

Chemosensitive cardiopulmonary afferents and the haemodynamic response to simulated haemorrhage in conscious rabbits.

1. We set out to test whether the signal from the heart that initiates the decompensatory phase of acute central hypovolaemia in conscious rabbits is conveyed by chemosensitive afferents. 2. Haemorrhage was simulated by inflating an inferior vena caval cuff so that cardiac output fell at a constant rate of 8% of its baseline level per min. After sham or vehicle treatments the haemodynamic response had two phases. In the first, sympathoexcitatory, phase systemic vascular conductance fell in proportion to cardiac output so that mean arterial pressure fell by only 13 mmHg. When cardiac output had fallen by approximately 50% a second, sympathoinhibitory, phase supervened. There was an abrupt rise of systemic vascular conductance and an abrupt fall of mean arterial pressure, to approximately 40 mmHg. 3. The sympathoinhibitory phase was prevented by injection of the delta-opioid antagonist ICI 174864 (100-300 nmol) or the mu-opioid agonist H-Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAMGO) (100-300 pmol) into the fourth cerebral ventricle. 4. 5-HT3 receptors on myocardial or pulmonary afferents were excited by injection of ascending doses of phenylbiguanide (6.25-400 micrograms) into the left or right atrium respectively. Neuronal-type nicotinic cholinoceptors in the epicardium were excited by injecting ascending doses of nicotine bitartrate (6.25-400 micrograms) into the pericardial sac. Each of these treatment regimens caused a reproducible, dose-dependent, fall in mean arterial pressure. Intravenous injection of the 5-HT3 antagonist MDL 72222 (1.0 mg kg-1) markedly attenuated the responses to phenylbiguanide. Intrapericardial injection of the neuronal-type nicotinic cholinoceptor antagonist mecamylamine HCl (0.1 mgkg- ') abolished the effects of intrapericardial nicotine. Neither of these treatments affected the haemodynamic response to simulated haemorrhage. 5. Injection into the fourth ventricle of ICI 174864 (100-300nmol) or DAMGO (100-300pmol) had no effects on the dose-response relationships for phenylbiguanide or nicotine. 6. We conclude that the cardiac afferents responsible for initiating the sympathoinhibitory phase of simulated haemorrhage in conscious rabbits do not correspond to the populations of phenylbiguanidesensitive cardiopulmonary afferents, nor to the population of nicotine-sensitive epicardial afferents. We also conclude that the reflex haemodynamic responses to atrial phenylbiguanide and intrapericardial nicotine do not depend on an endogenous delta-opioid receptor mechanism in the brainstem, and are not affected by exposure of the brainstem to exogeneous DAMGO.

Afferent Pathways↗
PubMed1991

Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals.

In conscious mammals including humans, the neurohumoral and hemodynamic responses to progressive acute hypovolemia have two distinct phases. There is an initial arterial baroreceptor-mediated phase in which the fall in cardiac output is nearly matched by a sympathetically mediated increase in peripheral resistance so that arterial pressure is maintained near normal levels. In most species, adrenal catecholamines and vasopressin contribute little to this phase. Increased renin release appears to augment the sympathetically mediated vasoconstriction. When blood volume has fallen by a critical amount (approximately 30%), a second phase develops abruptly. This phase is characterized by withdrawal of sympathetic vasoconstrictor drive, relative or absolute bradycardia, an increase in release of adrenal catecholamines and vasopressin, and a profound fall in arterial pressure. In rabbits and rats the signal that initiates this phase appears to travel in cardiopulmonary afferents. In dogs and humans its origin is unknown. Central opioidergic and serotonergic mechanisms may be involved.

Acute Disease↗
PubMed1990

Cardiovascular responses to graded treadmill exercise during the development of doxorubicin induced heart failure in rabbits.

STUDY OBJECTIVE: The aim was to examine the haemodynamic and humoral responses to graded treadmill exercise, serially during the development of congestive heart failure. DESIGN: Doxorubicin (1 mg.kg-1) was given to rabbits twice weekly intravenously over 8 weeks to induce a low output congestive cardiomyopathy. Treadmill exercise at 8 and 16 m.min-1 was performed at weeks 0, 2, 4, 6, 7, and 8. During each exercise study, continuous recordings were made of cardiac output, mean arterial pressure, and heart rate, and central venous blood was sampled at rest and during the last 10 s of exercise for plasma noradrenaline and plasma renin activity. EXPERIMENTAL MATERIAL: Six cross-bred English rabbits, mean weight 2.6 kg, received doxorubicin treatment; three control rabbits received vehicle injection. MEASUREMENTS AND MAIN RESULTS: Over the first 2 weeks, resting haemodynamic variables and responses to exercise were normal in all rabbits. Thereafter, doxorubicin treated rabbits had progressive falls in resting cardiac index and mean arterial pressure, and rises in resting heart rate and systemic vascular resistance. The normal increases in cardiac index and mean arterial pressure with exercise were progressively attenuated, despite an increase in resting and exercising heart rate. The resting levels of plasma noradrenaline and plasma renin rose after the fourth week of doxorubicin treatment. Throughout the experiment, exercise consistently raised plasma noradrenaline and renin, but the exercising levels of both hormones increased as heart failure progressed. Four of the six doxorubicin treated rabbits became exhausted in the final run and there was an intense rise in systemic vascular resistance. CONCLUSIONS: In this rabbit model of chronic heart failure, sympathetic vasoconstrictor drive is greater than normal at rest, and is greatly exaggerated during exercise. It is suggested that this abnormal response to exercise results from a combination of failure of arterial pressure to reach the elevated set point of the arterial baroreflex, increased afferent input from exercising muscles due to their underperfusion, and increase in central command due to muscle fatigue.

Animals↗
PubMed1990

Effects of halothane, ketamine, propofol and alfentanil anaesthesia on circulatory control in rabbits.

1. We have made a within-rabbit comparison of the effects of four general anaesthetic regimens on the haemodynamic response to acute reduction in central blood volume and on baroreflex control of heart rate. 2. Acute haemorrhage was simulated by gradually inflating a cuff on the inferior vena cava in order to cause cardiac output to fall at a constant rate of 8.5%/min while the responses of systemic vascular resistance, arterial pressure and heart rate were measured. The full range of the baroreceptor-heart rate reflex was elicited by inflating aortic and vena caval cuffs. These indices of circulatory control were repeatedly measured within five protocols, to which each rabbit was exposed in randomized order. 3. In each protocol the rabbit was first studied unanaesthetized. Then a small dose of thiopentone sodium was given (16 mg/kg). In the four main protocols the rabbit was then intubated and ventilated, first with 100% oxygen and then with 50% nitrous oxide, during administration of one of four anaesthetic agents. These were halothane (2.0 and 2.5%), ketamine (2.5 mg/kg per min), propofol (0.83 and 1.25 mg/kg per min) and alfentanil (2.5 and 3.33 micrograms/kg per min). In a sham protocol the effects of 100% oxygen, then those of 50 and 75% nitrous oxide, were studied while the rabbit remained conscious. 4. In unanaesthetized rabbits, in the presence or absence of nitrous oxide, the normal biphasic haemodynamic response to simulated haemorrhage occurred. The first, vasoconstrictor, phase was attenuated by halothane, ketamine and propofol, so that arterial pressure fell more steeply than normal. Not only was the vasoconstrictor phase unaffected by alfentanil but it was extended, so that arterial pressure remained at a normal level even when cardiac output had fallen by 59%. This effect of alfentanil appeared to be mediated centrally, since it could be reproduced by injecting small doses (1.5-7.5 micrograms) into the fourth ventricle. All four anaesthetic agents and nitrous oxide attenuated the baroreceptor control of heart rate. The effect was least with nitrous oxide and alfentanil, greatest with halothane.

Alfentanil↗
PubMed1990

Characteristics of cardiovascular reflexes originating from 5-HT3 receptors in the heart and lungs of unanaesthetized rabbits.

1. When phenylbiguanide (1-PBG) (6.25-400 micrograms) was injected into the left atrium, right atrium or pulmonary artery of unanesthetized rabbits it caused dose-dependent falls of heart rate and arterial pressure, and short-lived hypopnoea or apnoea. The threshold dose was 50-100 micrograms. Maximal falls of heart rate (86-108 beats/min) and arterial pressure (33-35 mmHg) occurred at a dose of 200 micrograms. The latency between injection and onset of the bradycardia was 2.2-2.6 s and did not depend on the route. Cardiac output fell transiently with heart rate, but at the time of the maximal fall of arterial pressure it had returned to normal. All effects were abolished by intrapericardial procaine. The haemodynamic effects were exaggerated by sino-aortic barodenervation. Intrapericardial 1-PBG (200-400 micrograms) was without effect. Injection of 1-PBG (greater than 50-100 micrograms) into the aortic arch caused a variable increase in heart rate and arterial pressure. 2. When both cervical vagus nerves were crushed the depressor effects of atrial 1-PBG were reduced by only 76-84%. 3. The dose-response curves for left atrial and pulmonary artery injection of 1-PBG were shifted successively to the right by intravenous infusion of the 5-HT3 antagonist MDL72222 (0.1 and 1.0 mg/kg). 4. We conclude that in unanesthetized rabbits left atrial 1-PBG selectively excites myocardial afferents, whereas right atrial or pulmonary artery 1-PBG excites afferents that originate close to the pulmonary vasculature. In each case 1-PBG acts through pharmacologically specific 5-HT3 receptors. The afferents run mainly, but not exclusively, in the vagus nerves. The reflex fall of arterial pressure is accounted for almost entirely by a decrease in peripheral resistance.

Animals↗
PubMed1990

Cardiovascular reflexes from cardiac sensory receptors.

The mammalian heart, especially its left ventricle, is densely innervated by sensory nerves. One set of these travels to the brainstem in the vagus nerves; the other to the spinal cord in sympathetic nerves. Excitation of vagal cardiac afferents, especially unmyelinated afferents from the left ventricle, cause a reflex bradycardia and fall in blood pressure and, under some conditions, a massive release of AVP. The sympathetic afferents convey the sensation of cardiac pain, but innocuous stimuli may cause a reflex tachycardia and rise in blood pressure. Both sympathetic and vagal cardiac afferents can be excited by mechanical distension of the heart (mechanoreceptors), and by a variety of foreign and endogenous chemical substances (chemosensitive receptors). It is not yet clear whether the effective natural stimulus to these receptors is mechanical, or through the chemical products of myocardial metabolism. Neither is it clear whether information from the heart exerts a minute-to-minute regulatory effect on the circulation, or whether it has a purely defensive role in the face of extreme disturbances of cardiac function. Cardiogenic reflexes are also thought to be the cause of haemodynamic and humoral disturbances that occur in clinical conditions such as myocardial ischaemia or infarction, left ventricular outflow obstruction, and acute reduction in central blood volume as well as during coronary angiography.

Afferent Pathways↗
PubMed1990

Effects of mu-opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits.

1. Cardiac output, arterial pressure, heart rate, systemic vascular conductance, respiratory rate and arterial blood PO2 and PCO2 were measured in unanaesthetized rabbits. Haemorrhage was simulated by inflating a cuff placed around the inferior vena cava so that cardiac output fell at a constant rate of about 8% of its resting value per min. 2. The effects of drug treatments on resting haemodynamic and respiratory variables, and on the haemodynamic response to simulated haemorrhage, were tested. The treatments were; 4th ventricular (-)-naloxone HCl (10-100 nmol), 4th ventricular H-Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAMGO; 30-300 pmol), and i.v. morphine sulphate (0.5-5.0 mumol kg-1). The interactions of graded 4th ventricular doses of naloxone (3-100 nmol) with the actions of DAMGO (100-300 pmol) on these responses were also assessed. 3. After sham treatments, the circulatory response to simulated haemorrhage had two phases. During the first compensatory phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only about 7 mmHg. A second decompensatory phase supervened when cardiac output had fallen by about 50%. At this point systemic vascular conductance rose abruptly and arterial pressure fell to less than or equal to 40 mmHg. 4. Low 4th ventricular doses of naloxone (10-30 nmol) and DAMGO (30-100 pmol) had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of naloxone (30-100 nmol) and DAMGO (100-300 pmol) prevented the decompensatory phase. These high doses of naloxone and DAMGO lowered resting heart rate without affecting the other haemodynamic or respiratory variables. 5. Low doses of i.v. morphine (0.5-1.Spumolkg-1) also had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of morphine (1.5-5.Opmol kg 1) abolished the decompensatory phase. These high doses caused respiratory depression without affecting the resting haemodynamic variables. 6. The prevention of circulatory decompensation by high doses of DAMGO was reversed by 3-10nmol of naloxone in 3 out of 4 rabbits and by 10-30 nmol of naloxone in all 4 rabbits. The decompensatory phase was, however, prevented by the combined high doses of DAMGO (100-300pmol) and naloxone (30-100 nmol). 7. These findings provide strong evidence that activation of mu-opioid receptors in the central nervous system abolishes circulatory decompensation during acute reduction of central blood volume in conscious rabbits. This effect does not appear to be due to activation of arterial chemoreceptors or to a non-specific increase in sympathetic vasoconstrictor drive, since respiratory depression and hypertension were not observed after 4th ventricular doses of DAMGO which abolished circulatory decompensation. Our results also provide indirect confirmation of our previous finding that naloxone acts to prevent circulatory decompensation by an antagonist action at central delta-receptors.

Animals↗
PubMed1989

Faint heart.

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Animals↗
PubMed1989

Intracisternal naloxone and cardiac nerve blockade prevent vasodilatation during simulated haemorrhage in awake rabbits.

1. Acute haemorrhage was simulated in five unanaesthetized rabbits, by inflating a cuff on the inferior vena cava so that cardiac output fell by 8.3% of its resting level per minute. Simulated haemorrhage was performed after sham treatment, after graded doses of intravenous and intracisternal naloxone, and after cardiac nerve blockade with intrapericardial procaine. 2. After sham treatment, the haemodynamic response to simulated haemorrhage was biphasic. During the first phase, systemic vascular conductance fell steadily, heart rate rose steadily, and arterial pressure fell only slightly. A second decompensatory phase began abruptly when cardiac output had fallen to approximately 55% of its resting level. Vascular conductance rose steeply, heart rate fell slowly, and arterial pressure fell precipitately. 3. Treatment with naloxone (intravenous, 0.04-0.4 mg kg-1; intracisternal, 0.2-2 micrograms kg-1) did not affect either phase of the haemodynamic response to simulated haemorrhage. 4. After treatment with larger doses of naloxone (intravenous, 4-8 mg kg-1; intracisternal, 4-69 micrograms kg-1), the first phase was unaffected, but the second phase no longer occurred. Throughout simulated haemorrhage, systemic vascular conductance fell steadily, heart rate rose, and arterial pressure was well maintained. The dose of intracisternal naloxone which prevented the second phase was 90-900 times less than the corresponding intravenous dose. The second phase was also prevented by cardiac nerve blockade. 5. We conclude that an endogenous opiate mechanism is responsible for the haemodynamic decompensation that occurs when cardiac output falls to a critical level. The mechanism is located within the central nervous system. It is triggered by a signal from the heart.

Acute Disease↗