Biomedical subjects

M A Hanson

Publications and source records attributed to M A Hanson.

At least 127 records · Page 7Linked to original sources

PubMed1991

Quantitative studies of the vasculature of the carotid body in fetal and newborn sheep.

Resetting of the hypoxic sensitivity of the carotid chemoreceptors from the fetal to the adult arterial PO2 range follows the rise in PO2 which occurs after birth. The mechanism of this resetting is unknown. To study whether it is accompanied by a change in the carotid body microvasculature, 2 pairs of carotid bodies from fetal sheep (145 days gestation) and 2 pairs from 7-8 days-old lambs were examined. The ratio of the area of small vessels (6-16 microns diameter) or of larger vessels (greater than 16 microns diameter) to the total area of individual lobules of the carotid body was measured, using a semi-automatic image analysis system. This quantified the number and total cross-sectional area of small vessels and of larger vessels in 20 sections of 5 microns thickness taken at random from 200-350 sections cut from each carotid body. When the carotid bodies of the fetus and neonate were compared, the neonates showed increases in the percentage of the lobule area occupied by both small and large vessels, but the difference was only significant in the case of the larger vessels. There was no difference in the ratio of the area occupied by smaller vessels to the extravascular area of the lobule. Our results do not support the idea that the post-natal resetting of chemoreceptor sensitivity from the fetal to the post-natal range is accompanied by a change in the perfusion of the carotid body chemoreceptor cells.

Animals↗

PubMed1990

Almitrine mimics hypoxia in fetal sheep with lateral pontine lesions.

Almitrine bimesylate is a potent and long-lasting respiratory stimulant in adult species. It acts by stimulating the peripheral chemoreceptors, where it has been shown to accumulate specifically, although its exact mechanism of action is uncertain. In the fetal lamb, however, it produces a profound inhibition of breathing even after denervation of the peripheral chemoreceptors. In this respect its action is similar to hypoxia. To investigate whether almitrine is hypoxia mimetic, we examined the effect of almitrine in nine fetal lambs of 120-130 days gestation. Five had lesions in the lateral pons that changed the fetal depressive response to hypoxia to one of stimulation. In the remaining four fetuses, the lesions did not bilaterally encompass the appropriate area of the pons; thus they still showed the normal fetal depressive response to hypoxia and so acted as controls. Almitrine (10 mg iv) caused a pronounced stimulation of breathing that lasted 406 +/- 26 min in all five fetuses with lesions that caused a stimulatory response to hypoxia. However, in the remaining four fetuses, in which the response to hypoxia was inhibitory, almitrine caused an inhibition of breathing that lasted 184 +/- 28 min. We conclude that the action of almitrine is like that of hypoxia and that, because it acts specifically on the chemoreceptors, it may prove to be a useful tool in the study of possible central chemoreceptor mechanisms.

Almitrine↗

PubMed1990

Role of the carotid chemoreceptors in the respiratory response of newborn lambs to alternate pairs of breaths of air and a hypoxic gas.

We measured the reflex respiratory response to a 2-breath alternation in fractional inspired oxygen in two groups of lambs. Test runs where F(I),O2 was made to alternate (between 0.21 and 0.14) were compared with control runs in which it was held at 0.21. Within 36 h of birth we cut the carotid sinus nerves bilaterally in one group of lambs (n = 5) whilst in a second group (n = 5) sham operations were carried out. The alternating responses in seven respiratory variables were compared between test and control runs in each group of lambs at postnatal days 5-6 and again at postnatal days 10-11. In sham-operated lambs at days 5-6 there was a significant response in most respiratory variables during test runs and by days 10-11 the response was increased, primarily as a consequence of an increase in the tidal volume component of the response, indicating a postnatal maturation of the responses. The time-scale of this maturation is appropriate to that of peripheral chemoreceptor resetting. There was no significant response to the test in the denervated lambs at 5-6 days but by days 10-11 a small response was measured in some variables. Our results therefore indicate that the reflex respiratory response to alternations in FI,O2 is primarily mediated by the carotid chemoreceptors. The development of a response mediated by the aortic chemoreceptors may account for the small alternating response in the denervated lambs at days 10-11.

Animals↗

PubMed1989

The pattern of breathing of fetal sheep in graded hypoxia.

We examined the effects on fetal breathing movements (FBM) and electrocortical activity (ECoG) of maintaining fetal arterial PO2 (PaO2) at 16.9 +/- 1.9 mmHg for 20 min in unanaesthetized, chronically instrumented fetal sheep in utero at 122-132 days gestation. In 82% of trials, a pattern of regular FBM occurred characterised by its large (35 +/- 7 mmHg) excursions in tracheal pressure and its low frequency (ca. 3 per min) compared to the irregular FBM occurring during normoxia (ca. 5 mmHg and ca. 90 per min, respectively) (PaO2 ca. 23 mmHg). The occurrence of FBM in mild hypoxia was independent of the ECoG state of the fetus and it also occurred in fetuses in which the carotid sinus nerves and cervical vagosympathetic trunks had been sectioned bilaterally. Reducing PaO2 to between 16 and 11 mmHg produced a cessation of FBM, as reported by other workers. The FBM in mild hypoxia were distinct from 'gasping', which occurs only when PaO2 was reduced to much lower levels. The FBM in mild hypoxia are discussed in terms of central respiratory mechanisms excited by hypoxia, as opposed to the well-documented mechanisms which inhibit FBM in more intense hypoxia.

Animals↗

PubMed1989

The effect of chronic hypoxia upon the development of respiratory chemoreflexes in the newborn kitten.

1. We have studied the reflex respiratory responses to two-breath alternations of fractional inspired oxygen (FI,O2) in normoxic (reared in room air) and chronically hypoxic kittens (born into and reared in an FI,O2 of 0.13-0.15) on post-natal days 1, 2-3, 4-8 and 9-14. 2. Respiration was measured non-invasively in the unanaesthetized kittens. Test runs (with alternations of FI,O2 between 0.21 and 0.14) and control runs (with an FI,O2 of 0.21) were carried out during quiet sleep. 3. The degree of alternation in tidal volume, inspiratory time, expiratory time, frequency, drive, timing and instantaneous ventilation components of the respiratory response was compared during control and test runs. 4. There was little response to control runs in either group at any post-natal age. 5. In normoxic kittens we found no significant reflex response in any respiratory variable to test runs before day 4. However significant alternation was found in expiratory time, frequency and ventilation at days 4-8 and in tidal volume at days 9-14. 6. In chronically hypoxic kittens there were no significant differences between control and test runs at any of the ages studied. 7. In the normoxic group increases in the response with post-natal age probably reflect post-natal increases in the sensitivity of the peripheral chemoreceptors. The lack of development in the chronically hypoxic group may indicate abnormal function or delayed maturation of the peripheral chemoreceptor sensitivity to hypoxia. 8. The results suggest that the method can be used to detect developmental and pathological changes in the arterial chemoreflex.

Animals↗

PubMed1989

Re-setting of the hypoxic sensitivity of aortic chemoreceptors in the new-born lamb.

We tested to see whether the steady-state hypoxic sensitivity of aortic chemoreceptors was re-set during the first 2-3 weeks of post-natal life. Aortic chemo-receptor activity was recorded from the distal end of the cut aortic branch of the cervical vagus in pentobarbitone - anesthetized, new-born lambs. Two groups were studied, the first aged 1-4 days and the second aged 10-19 days. Chemoreceptor discharge increased as hyperbolic function with increasing isocapnic hypoxia in both groups and we quantified the position and the shape of this response curve. It was shifted to the right significantly in the older group of lambs, the mean vertical asymtote increasing from 10.00 to 27.95 torr PO2. No significant difference was found in the horizontal asymotote or in the 'shaping term' between the two groups. The greatest differences between the stimulus-response curves of the two groups of animals with respect to the mean level of discharge and the slope of the curve occurred when PaO2 was below ca. 50 torr. The aortic chemoreceptors of older lambs were unable to maintain a sustained discharge at arterial PO2 values below ca. 30 torr. In contrast, in the younger group PO2 often had to be reduced below this level before discharge increased significantly. We conclude that, like the carotid chemoreceptors, aortic chemoreceptor sensitivity is re-set over the first few weeks of life. The re-setting may contribute to the increase in the ventilatory response to hypoxia which occurs over this period.

Action Potentials↗

PubMed1989

Almitrine inhibits breathing movements in fetal sheep in utero.

Whilst hypoxia stimulates fetal peripheral chemoreceptors, fetal breathing movements do not increase as hypoxia also has central effects. We wondered whether specific stimulation of the arterial chemoreceptors by almitrine would produce a stimulation of fetal breathing movements. When almitrine was given to 5 intact and 3 peripherally-chemodenervated fetal sheep in utero, fetal breathing movements rapidly ceased for 1-12 h. There was also a decrease in the amount of time spent in low voltage electrocortical activity. The effects of almitrine are therefore similar to those of hypoxia, and are independent of the peripheral chemoreceptors. Thus it may be a valuable tool in the study of the control of fetal breathing.

Almitrine↗

PubMed1989

The incidence of breathing movements of fetal sheep in normoxia and hypoxia after peripheral chemodenervation and brain-stem transection.

The incidence of fetal breathing movements and low voltage electrocortical activity was measured in three groups of fetal sheep, at 123-137 days gestation. The first group (transected & denervated) had the brainstem transected at the level of the colliculi and also had peripheral arterial chemodenervation. The second group (denervated) had a sham brain-stem transection and peripheral arterial chemodenervation. The third group (sham-operated) had sham brain-stem transection and sham peripheral chemodenervation. No differences were observed in the incidence of fetal breathing movements or low voltage electrocortical activity between the sham-operated and the denervated groups in normoxia, or in hypoxia when all these fetuses became apnoeic. There were however differences between these 2 groups and the transected & denervated group, in which fetal breathing movements where dissociated from electrocortical activity and which in some fetuses were continuous. During isocapnic hypoxia 3 of 8 transected & denervated fetuses made fetal breathing movements. We discuss the problems of interpreting data from brain-stem transected fetuses, but conclude that the evidence reveals no tonic influence of the peripheral arterial chemoreceptors on fetal breathing movements.

Animals↗

PubMed1988

Effects of pilocarpine on breathing movements in normal, chemodenervated and brain stem-transected fetal sheep.

1. We examined the effects on fetal breathing movements (FBM) and electrocortical activity (ECoG) of the administration of pilocarpine to three groups of fetal sheep in utero: one group had peripheral chemodenervation; one group had peripheral chemodenervation and transection of the brain stem at the level of the colliculi; a third group of sham-operated animals acted as a control. 2. Pilocarpine induced a period of FBM characterized by their high amplitude (ca. 24 mmHg) and low frequency (ca. 0.65 Hz). It also produced low-voltage ECoG. These effects were seen both in normoxia and in hypoxia. They were independent of the ECoG state in which the drug was given. 3. In normoxia, pilocarpine-induced FBM were blocked by cholinergic antagonists which enter the central nervous system, atropine sulphate and scopolamine hydrobromide, but were either unaffected or were reduced in amplitude by antagonists with restricted access to the central nervous system, atropine methylnitrate and scopolamine methylbromide. In hypoxia, atropine sulphate and scopolamine hydrobromide again blocked FBM but now scopolamine methylbromide and atropine methylnitrate blocked the FBM in 42% of trials. In the remaining trials FBM remained virtually unchanged. 4. No differences were observed in the effects of pilocarpine on FBM or ECoG between chemodenervated fetuses and those which had been sham-operated. 5. In fetuses with transection of the brain stem, breathing was continuous irrespective of the ECoG. Pilocarpine increased the amplitude of FBM but did not alter the frequency of these FBM. These effects occurred both in normoxia and in hypoxia. 6. We conclude that pilocarpine produces effects on fetal behaviour via at least two sites in the central nervous system. One site lies in the pons or medulla and is responsible for the stimulation of FBM. The other site is above the level of the colliculi and is responsible for producing sustained low-voltage ECoG. These effects do not require the integrity of the peripheral chemoreceptors and we find no evidence to support the previous suggestion that the action of pilocarpine is via stimulation of these receptors.

Animals↗

PubMed1988

Stimulation of breathing movements by L-5-hydroxytryptophan in fetal sheep during normoxia and hypoxia.

1. In fetal lambs in late gestation, systemic infusion of L-5-hydroxytryptophan (L-5-HTP) during normoxia greatly increases the incidence of fetal breathing movements (FBM) and high-voltage electrocortical activity (HV ECoG). It also induces FBM during HV ECoG and increases blood pressure. To investigate its mechanism of action, L-5-HTP was administered in conjunction with the 5-hydroxy-tryptamine (5-HT) antagonists ketanserin or cyproheptadine. L-5-HTP was also infused with or without the antagonists during hypoxia, to test whether it would overcome the inhibition of FBM by hypoxia. 2. When L-5-HTP was given in normoxia, cyproheptadine blocked and ketanserin reduced the increase in blood pressure, both drugs blocked the stimulation of FBM, but neither drug prevented the induction of prolonged episodes of HV ECoG. 3. In hypoxia, L-5-HTP similarly stimulated FBM. This effect was also blocked by cyproheptadine and was delayed by ketanserin. 4. The antagonism of the effects of L-5-HTP on blood pressure and the incidence of FBM in normoxia and hypoxia is consistent with the action of L-5-HTP via 5-HT receptors. At present there is no clear explanation of the mechanism by which L-5-HTP induces HV ECoG.

5-Hydroxytryptophan↗

PubMed1988

Carotid baroreceptors in fetal and newborn sheep.

The responses of single carotid baroreceptor afferents were determined in anaesthetized fetal lambs at 88-113 and 131-144 days gestation, and in newborn lambs 1-8 and 30-40 days old. The baroreceptors discharged in synchrony with the arterial pressure pulse and increased their discharge rate as pressure was raised by compression of the abdominal aorta. When step increases in pressure were applied to the vascularly isolated carotid sinus, baroreceptor discharge increased abruptly and then showed adaptation to a steady state level. Basal mean arterial pressure increased from 49.1 in the young fetuses to 87.5 mm Hg in the 30- to 40-day-old lambs without an accompanying increase in basal baroreceptor discharge expressed absolutely or as a function of maximum discharge for each unit. The slope of the steep portion of the stimulus-response curve decreased with gestational age from 7.89 +/- 1.57 (mean +/- SE) at 88-113 days gestation to 1.82 +/- 0.37% nerve activity.mm Hg-1 in the 30- to 49-day-old lambs. Dynamic and steady state response curves were determined using step increases in carotid sinus pressure in two fetal lambs of 135 days gestation and two lambs 8 days old. Both the dynamic and the steady state curves were less steep in the older lambs. We conclude that the sensitivity of the carotid baroreceptors is reset as arterial pressure increases throughout the last third of gestation and the first postnatal month. This resetting is seen as a shift to the right of the response curve and a decrease in its slope.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1988

The importance of baro- and chemoreflexes in the control of the fetal cardiovascular system.

The information gained about the afferent traffic from carotid arterial baro- and chemoreceptors by direct recordings made in the sheep fetus is reviewed. Less is known about aortic baro- and chemoreceptor discharge during this period, and virtually nothing is known about the discharge of other vagal mechano- or chemoreceptor afferents. Knowledge about the functional integrity of sympathetic and parasympathetic efferent pathways is reviewed. Then the various methods which have been used for assessing fetal baro- and chemoreflexes are discussed: the crucial problem here is that there are no techniques available for either increasing or decreasing the discharge of these receptors specifically. Because they have been widely used, however, and are of clinical importance, the effects upon the fetal circulation of hypoxia and asphyxia are reviewed specifically. The relative contributions of baro- and chemoreflexes in producing these effects are considered against the background of the plethora of other processes which operate under these conditions.

Animals↗

PubMed1988

Effects on carotid chemoreceptor resetting of pulmonary ventilation in the fetal lamb in utero.

We tested the hypothesis that postnatal resetting of the carotid chemoreceptors is initiated by, and is dependent on, the rise in arterial PO2 (PaO2) which normally occurs after birth as air breathing is established. Previous studies had indicated that this resetting takes at least 24 h. We applied a technique for ventilation of the lungs of fetal sheep in utero to 3 groups of fetuses of 140-142 days gestational age: group 1 were exposed to normocapnic hyperoxia (mean PaO2 179.9 +/- 22.2 mmHg) for 27.4 +/- 0.9 h; group 2 were exposed to normocapnic hyperoxia (mean PaO2 229.4 +/- 77.5 mmHg) for 7.0 +/- 0.3 h; group 3 were ventilated for 21.6 +/- 3.3 h with a nitrogen/CO2 mixture to maintain PaO2 and PaCO2 within the normal fetal range. At the end of the ventilation period the fetuses were delivered by caesarean section, anaesthetized, paralysed and ventilation was continued. The responses of single or few fibre carotid chemoreceptor preparations to isocapnic hypoxia were then determined. To compare their response curves quantitatively, hyperbolic curves were fitted to the data. No significant differences between any of the groups were found in the vertical or the horizontal asymptotes. There was no difference in the slope of the hyperbolic line between group 2 and group 3. However, this slope was significantly greater for Group 1 than for either group 2 or group 3. Our results show that a period of hyperoxia of 24-31 h in utero, although not a similar period of normoxic ventilation, initiates the process of carotid chemoreceptor resetting.

Animals↗

PubMed1987

Breathing activity in fetal sheep during mechanical ventilation of the lungs in utero.

Effects of mechanical ventilation of the lungs of fetal lambs in utero are described. Feasibility studies were performed acutely on four fetuses at 140-142 days gestational age. Five fetuses were prepared for chronic experiments at 122-128 days gestation. Mechanical ventilation was used to produce changes in fetal blood gases for periods of up to 24 h in acute preparations or for repeated periods of 3-9 h on consecutive days in chronic preparations. This technique permits the study of fetal lambs in utero under conditions which normally occur after birth without producing maternal changes or using anesthesia and whilst the umbilical circulation remains open. Four situations were examined using ventilation in these chronic preparations: (1) expansion of the lungs whilst maintaining fetal normoxia and normocapnia; (2) fetal normoxia and hypocapnia; (3) hyperoxia and normocapnia; (4) hyperoxia and hypocapnia. None of these situations produced continuous fetal breathing, either during ventilation or after switching off the ventilator. We conclude that they do not provide appropriate stimuli to mimic those which normally produce continuous breathing after birth.

Animals↗

PubMed1987

Determinants of the onset of continuous air breathing at birth.

We used mechanical ventilation of the fetal lungs in utero on 11 fetal lambs at 140-145 days gestation to alter fetal blood gases and thus separate the influences of PaO2 and PaCO2 on extrauterine breathing after cord clamping. The fetus was delivered either into a 40 degrees C saline bath or onto a cold table. Mechanical ventilation was stopped 2 min after delivery and the time to onset of continuous air breathing was observed. Also two fetuses were ventilated in utero 5 or more days after chronic instrumentation at 127 days gestation; in these animals the time to onset of breathing (diaphragm EMG) was recorded after stopping the ventilator and occluding the cord. We conclude: (a) hypercapnia is a stimulus to breathing even in hyperoxia and at 40 degrees C; (b) hypocapnia delays the start of extrauterine breathing in hyperoxia at 40 degrees C; (c) hypoxia inhibits breathing in the absence of hypercapnia or cold; (d) cold overrides the effects of hypocapnia in normoxia or moderate hypoxia.

Animals↗

PubMed1987

Maturation of the respiratory response to acute hypoxia in the newborn rat.

1. We used a non-invasive method to measure the breathing of conscious newborn rat pups continuously and studied the maturation of the respiratory response to reductions in inspired O2 fraction (FI,O2) from 0.21 to 0.15, 0.12 or 0.08 for 6 min. Newborn rats, like many other species, showed a "biphasic" respiratory response, ventilation (VE) increasing during the first 1-2 min of hypoxia (phase 1) and then falling towards control, or below it, over the next 4 min (phase 2). 2. The secondary fall in VE decreased with age up to 14 days. The presence of a significant fall in VE in phase 2 depended on the FI,O2 to which the pups were exposed acutely; the lower the FI,O2 the greater the age at which a biphasic VE response was observed. 3. Our results are discussed in terms of two opposing components which determine VE during acute hypoxia in the neonate: (a) a fast arterial chemoreceptor-mediated stimulation of VE and (b) a slower central nervous component which inhibits VE, possibly a persistence of a suprapontine mechanism which inhibits fetal breathing movements during hypoxia in utero. Both of these components undergo maturation after birth.

Animals↗

PubMed1987

Effects of chronic hypoxia from birth on the ventilatory response to acute hypoxia in the newborn rat.

1. Newborn rats and their mothers were exposed from birth in a normobaric environmental chamber to an inspired O2 fraction (FI,O2) of 0.13-0.15 for 5-10 weeks. 2. The respiratory response to reducing FI,O2 to 0.12 or 0.08 for 6 min was measured in the conscious chronically hypoxic rat pups on post-natal days 5 and 14 and again at 5-10 weeks of age. On days 5 and 14 the responses were compared to those of normoxic control pups also exposed acutely to an FI,O2 of 0.12 or 0.08. 3. No significant respiratory response to the acute reduction in FI,O2 was found in the chronically hypoxic pups on post-natal days 5 and 14, whereas the normoxic pups showed a "biphasic" respiratory response on day 5 and a sustained ('adult') response on day 14. A "biphasic" respiratory response to an FI,O2 of 0.08, but not to an FI,O2 of 0.12, was seen in the chronically hypoxic pups at 5-10 weeks of age. 4. At 5-10 weeks recordings from the carotid sinus nerve were made in anaesthetized, paralysed and artificially ventilated rats. The isocapnic hypoxic response curves of chronically hypoxic rats were not significantly different from those of age-matched normoxic rats. 5. Our results suggest that limiting the rise in arterial O2 pressure which usually occurs at birth alters the ventilatory response to acute hypoxia by post-natal day 5 and this alteration is still evident at 5-10 weeks of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

The effects of doxapram on breathing, heart rate and blood pressure in fetal lambs.

In experiments to assess its value in the study of fetal arterial chemoreceptor reflexes, doxapram (0.5 - 2 mg i.a.) given to unanaesthetized fetal lambs in utero in low voltage electrocortical activity stimulated fetal breathing in 73% of trials. The response began within a few seconds and lasted up to 5 min. This response to doxapram was present in intact or mid-collicular brainstem transected fetuses and after bilateral section of the carotid sinus nerves and cervical vagosympathetic trunks (denervation). In intact and brainstem transected fetuses, doxapram injections were followed by a modest rise in arterial pressure and a small fall in heart rate. After denervation the rise in arterial pressure was fourfold and the heart rate increased. Electrocortical activity and limb movements were not affected in any group of lambs, and fetal breathing was not induced during isocapnic hypoxia. It is concluded that doxapram stimulates fetal breathing by a central action below the pons, and that it can therefore not be used to study peripheral arterial chemoreceptor function in utero.

Animals↗