Respiratory and cardiovascular responses to hyperoxia, hypoxia and hypercapnia in the renal hypertensive rabbit: role of carotid body chemoreceptors.

We tested the hypothesis that in renal hypertension the increased peripheral vascular resistance of neurogenic origin might be due to a reflex through resetting of the carotid body chemoreceptors. The reflex respiratory and cardiovascular functions of the carotid bodies were studied in a one-kidney wrapped hypertension model in conscious rabbits, and compared with a control group of animals, by breathing 100% oxygen, three hypoxic gas mixtures to which were added sufficient CO2 to maintain the PaCO2 constant, and 2 and 4% CO2 in 21% O2 and N2. In the control state (breathing room air) the renal hypertensive animals had a slightly higher respiratory minute volume, a higher level of arterial blood pressure and increased calculated systemic vascular resistance, compared with the normal group, but there was no difference in cardiac output. Hyperoxia had no consistent effect on respiration, heart rate or arterial blood pressure. Increasing degrees of isocapnic hypoxia caused the same degree of hyperventilation and bradycardia in both groups of animals. The arterial blood pressure did not change in either group but there was a transient increase in systemic vascular resistance in the renal hypertensives breathing 9 and 7.5% O2. The respiratory responses to 2 and 4% CO2 were similar in the two groups of animals. In the renal hypertensive animals, serial sections of the carotid bodies showed pathological changes, including subendothelial proliferation in vessels supplying the carotid bodies with narrowing of their lumens, fragmentation of the elastic laminae of the media, hypertrophy of the smooth muscle and extensive fibrosis with occasional haemorrhages. The capillaries, however, were normal. The rostral-caudal lengths of the carotid bodies were similar in the two groups. In view of our findings we conclude that the relatively normal carotid chemoreceptor responses in renal hypertensive rabbits may, in part at least, be the result of the carotid body blood flow through the partially occluded vessels being maintained at near normal levels by the elevated blood pressure.

The volume of the carotid body and periadventitial type I and type II cells in the carotid bifurcation region of the fetal cat and kitten.

The bilateral distribution of carotid body type I cells was investigated in 6 fetuses (gestational age 95%) and 9 newborn kittens (aged 1 day to 4 days) by serially sectioning the carotid bifurcation regions. In most specimens type I cells occurred in close proximity to the wall of the occipital artery or one of its small proximal branches within a division of connective tissue with definable but irregular borders. This combination of type I cells and connective tissue constituted the principal mass of the carotid body. Using an interacting image analysis system, the area of the carotid body in each serial section was measured by accurately contouring its perimeter. The volume of the carotid body was calculated by multiplying the sum of the areas of the serial sections by the thickness of the section. The volume of the carotid body was 0.052 +/- 0.018 mm3 in the fetuses and 0.025-0.117 mm3 in the 1-4 day old kittens. A degree of symmetry in the values for the volume of the right and left carotid body was found. Caudally, and separate from the principal mass of carotid body type I cells, isolated groups of periadventitial type I cells were noted in the connective tissues around the occipito-ascending pharyngeal trunk, origin of the occipital artery and rostral end of the common carotid artery in 7 out of 12 specimens from fetal cats and 11 out of 18 specimens in newborn kittens. The volumes of the periadventitial groups of cells ranged between 25-1,365 micron3 in fetuses and 10-1,351 micron3 in kittens.

Carotid chemoreceptor reflex cardioinhibitory responses: comparison of their modulation by central inspiratory neuronal activity and activity of pulmonary stretch afferents.

The differential nature of the modulation of excitatory inputs from various cardiovascular receptor groups by pulmonary stretch afferents, driven by lung inflation, and the central inspiratory neuronal activity, has been demonstrated. At levels of activity of pulmonary stretch afferents and of central inspiratory drive that almost completely suppress the bradycardia of stimulation of the carotid bodies, the response to stimulation of the arterial baroreceptors and cardiac C fibre endings was reduced by 30-58%. In contrast, the bradycardia evoked by pulmonary C fibre stimulation was not significantly affected by either respiratory mechanism.

Some reflex cardioinhibitory responses in the cat and their modulation by central inspiratory neuronal activity.

1. Cats were anaesthetized with a mixture of chloralose and urethane, and were artifically ventilated. 2. An open pneumothorax was provided by two large-bore tubes which were sealed in the sixth intercostal space on each side. They were connected to a Fleisch pneumotachograph. Phasic changes in central inspiratory neuronal activity were measured quantitatively as changes in the volume of the pneumothorax during temporary interruption of artificial respiration, the volume of the lungs being held constant at their end-expiratory level. In this way the activity of slowly adapting pulmonary stretch receptors was maintained constant. 3. Reflex cardioinhibitory responses were elicited by stimulation of (a) the carotid body chemoreceptors by intracarotid injections of cyanide; (b) the arterial baroreflex by controlled elevations of the blood pressure; (c) cardiac receptors by left atrial injections of veratridine; and (d) pulmonary C fibres (including J receptors) by right atrial injections of phenylbiguanide. 4. The effects of central inspiratory neuronal activity on pulse interval were assessed by comparing the values observed during the inspiratory and expiratory phases of the respiratory cycle in the control state and during stimulation of each cardiovascular receptor group. 5. The carotid chemoreceptor-induced bradycardia measured during the expiratory phase of respiration was reduced during inspiration to a value of about 15% of control. The central inspiratory drive was less effective in altering the reflex responses from the arterial baroreceptors and cardiac receptors, the corresponding values being 42 and 51% respectively. 6. In contrast, the bradycardia evoked by pulmonary C fibre stimulation was not significantly affected by the central inspiratory drive. 7. The differential nature of the modulation by the central inspiratory drive occurred independently of the integrity of the sympathetic nerve supply to the heart indicating that the cardiac efferents involved were largely fibres in the vagus nerves. 8. The possible explanation of these results in terms of central mechanisms is discussed.

Cardiovascular responses to stimulation of pulmonary C fibres in the cat: their modulation by changes in respiration.

1. In cats anaesthetized with a mixture of chloralose and urethane, stimulation of pulmonary C fibres by right atrial injections of phenylbiguanide caused, after a latency of about 3 s, a reduction in pulmonary ventilation or apnoea, bradycardia and systemic hypotension, confirming previous work. 2. A decrease in femoral artery perfusion pressure also occurred under conditions in which the hindlimb was vascularly isolated, the blood flow was maintained constant and the inferior vena caval pressure did not change. This indicates a reduction in vascular resistance due to vasodilatation. The response was unaffected by atropine and propranolol, but was reduced or abolished by guanethidine, hexamethonium and denervation of the limb, indicating that it is due to a reduction in activity in sympathetic vasoconstrictor fibres. 3. Similar cardiovascular responses were observed when the arterial blood pressure was maintained constant, and also in artificially ventilated animals. 4. Evidence is presented that the receptors responsible for the respiratory and cardiovascular responses to right atrial injections of phenylbiguanide lie in the pulmonary vascular bed. 5. When the pulmonary C fibres were excited during a period of apnoea which was induced reflexly by electrical stimulation of the central end of a superior laryngeal nerve, there were no consistent differences in the size of the cardiac or vascular responses compared to the control responses in the absence of the laryngeal input. This result occurred irrespective of the size of the control ventilatory response to phenylbiguanide. 6. By contrast in the same experiments, the cardio-inhibitory and vasoconstrictor responses to excitation of the carotid body chemoreceptors were invariably potentiated by electrical stimulation of a superior laryngeal nerve, as found previously. 7. The possible central mechanisms responsible for the differential modulation of pulmonary C fibre and carotid chemoreceptor reflexes by respiration are discussed.

Respiratory modulation of carotid and aortic body reflex left ventricular inotropic responses in the cat.

1. The reflex changes in the inotropic state of the left ventricle, measured as the dP/dt max (maximum rate of change of pressure), occurring in response to selective stimulation of the carotid and aortic body chemoreceptors by sodium cyanide, were studied in the cat anaesthetized with a mixture of chloralose and urethane. 2. The animals were artificially ventilated with an open pneumothorax. The heart rate and mean arterial blood pressure were maintained constant. 3. With on-going central respiratory activity, stimulation of the carotid bodies caused an increase in respiratory movements. Variable changes in left ventricular dP/dt max occurred, the predominant response being an increase. The mean change was 8.3 +/- 2.9 % from a control value of 6850 +/- 450 mmHg s-1. Stimulation of the aortic bodies resulted in a smaller increase in respiration or no effect, but a significant increase occurred in left ventricular dP/dt max of 19.6 +/- 2.9 % from a control value of 6136 +/- 228 mmHg s-1. No significant changes in left ventricular end-diastolic pressure occurred in response to stimulation of either group of chemoreceptors. 4. Tests of chemoreceptor stimulations were repeated during temporary suppression of the secondary respiratory mechanisms: the central respiratory drive was suppressed reflexly by electrical stimulation of the central cut ends of both superior laryngeal nerves and lung stretch afferent activity was minimized by stopping artificial respiration. Carotid body stimulation again evoked variable responses, the predominant now being a reduction in left ventricular dP/dt max of 3.1 % from a control value of 5720 +/- 320 mmHg s-1, which was significantly different to that occurring during on-going spontaneous respiration. Aortic body stimulation caused an increase in left ventricular dP/dt max similar to the response during on-going spontaneous respiration. 5. The positive inotropic responses were mediated via the sympathetic nervous system, as indicated by their abolition as a result of intravenous injections of the beta-adrenoceptor blocking agent, propranolol. 6. It is concluded that the carotid bodies exert a small variable effect on left ventricular dP/dt max, the predominant positive inotropic response being due to the concomitant neurogenic effects of the increase in respiration. In contrast, the positive inotropic response to excitation of the aortic chemoreceptors is not respiratory modulated.

An analysis of the reflex systemic vasodilator response elicited by lung inflation in the dog.

1. A maintained inflation of the lungs caused a reflex reduction in total systemic vascular resistance in anaesthetized dogs under conditions in which the systemic circulation was perfused at constant blood flow and the arterial blood P(O2) and P(CO2) were maintained constant.2. The fall in systemic arterial perfusion pressure evoked by inflation of the lungs was accompanied by an increase in blood flow to the lower limbs and a reduction in their calculated vascular resistance. Since the fall in resistance occurred when the limb was perfused either at constant pressure or at constant blood flow, it must be due to vasodilatation.3. Lung inflation caused vasodilatation in skin, muscle, and in the splanchnic vascular bed. The responses in vertebral circulation were, however, small and variable.4. The vasodilator responses in the vascular territories studied were reflex in nature, being abolished by cutting the cervical vagosympathetic nerves, in which run the afferent fibres, or by interrupting the sympathetic pathways to the blood vessels.5. In the intact limb, muscle, skin and splanchnic vascular bed, the vasodilator responses to lung inflation were unaffected by atropine or propranolol, but were abolished by hexamethonium, dibenyline and bretylium tosylate, indicating that they were due predominantly to a reduction in the activity in sympathetic adrenergic vasoconstrictor fibres.

The effects of artificial lung inflation on reflexly induced bradycardia associated with apnoea in the dog.

1. The cardiac effects of artificial inflation of the lungs were studied during reflexly induced apnoea and bradycardia in anaesthetized dogs.2. Reflex apnoea and bradycardia were induced (a) by stimulation of the larynx with water or by electrical stimulation of afferent fibres in the superior laryngeal nerve, or (b) by combined stimulation of the superior laryngeal nerve and carotid body chemoreceptors.3. During combined stimulation of the laryngeal and carotid body inputs, the activation of respiration normally evoked by chemoreceptor stimulation was inhibited whereas the chemoreceptor cardio-inhibitory reflex was facilitated leading to periods of temporary cardiac arrest.4. In spontaneously breathing animals and in those artificially ventilated, lung inflation invariably caused tachycardia.5. Rhythmic artificial inflation of the lungs during the apnoeic period produced by the laryngeal input or by a combination of the laryngeal and chemoreceptor inputs wholly or partly reversed the bradycardia. This occurred using lung inflation volumes within the range of the normal tidal volume and inflation pressures of less than 12 mmHg; the response was independent of the composition of the gas used for inflating the lungs, and occurred at constant P(a, O2) and P(a, CO2). Lung inflation carried out during a reflexly induced arrest of the heart immediately restarted the heart and was accompanied by an exaggerated sinus arrhythmia.6. Evidence is presented that the observed effects of artificial lung inflation are reflex in origin with the vagus nerves as the main afferent and efferent pathways.7. Electrical stimulation of the central end of the cut pulmonary branches of the thoracic vagosympathetic nerves also caused tachycardia and had the same effects as lung inflation in modifying the reflexly induced bradycardia.8. Some clinical implications of these results are discussed.

Role of carotid-body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest.

Stimulation of the carotid-body chemo-receptors by asphyxia during an apnoeic episode may contribute to the vagally mediated cardiac arrest and sudden death that sometimes occurs in man. Apnoeic asphyxia may be induced centrally or reflexly by stimulation of upper airways receptors. Conditions associated with apnoeic asphyxia and in which the risk is likely to be greatest include intubation, laryngoscopy and bronchoscopy; accidents involving underwater swimming; inhalation of sympathomimetic amines in aerosols by asthmatic patients; and chronic hypoventilation syndromes. These reflexes may be responsible for some victims of sudden infant death syndrome. Stimulation of the carotid bodies normally produces hyperventilation and bradycardia. When apnoea occurs centrally or reflexly, carotid chemoreceptor excitation resulting from asphyxia now causes a much enhanced bradycardia and even cardiac arrest, but paradoxically does not usually affect respiration. These reflexes and their interactions normally serve protective and purposeful functions, but may under certain circumstances become exaggerated and put the patient's life at risk.

Modification by lung inflation of the vascular responses from the carotid body chemoreceptors and other receptors in dogs.

The reflex effects of increasing pulmonary ventilation on the responses of the hind-limb and systemic vascular resistances to stimulation of the carotid body chemoreceptors and carotid sinus baroreceptors and to distension of the urinary bladder have been studied in the anaesthetized dog. A preparation was used incorporating total cardiopulmonary bypass to maintain the arterial blood gas composition constant when alterations in pulmonary ventilation were made. The regions of both carotid bifurcations, the arch of the aorta and the cerebral circulation were independently perfused at constant pressure so as to exclude secondary reflexes from arterial baroreceptors. Four levels of pulmonary ventilation were used: 0.095, 0.285, 0.475 and 0.665 l min-1 kg-1 body weight, at a constant frequency of 19 cycles min-1. Increasing the pulmonary ventilation per se in steps from 0.095 to 0.665 l min-1 kg-1 resulted in a significant progressive reduction in hind-limb and systemic vascular resistances which were shown to be due to a reflex from the lungs. Stimulation of the carotid body chemoreceptors by hypoxic hypercapnic blood resulted in an increase in hind-limb and systemic vascular resistances when carried out at each of the four levels of pulmonary ventilation. The size of the increases in vascular resistances, however, was progressively and significantly reduced as the pulmonary ventilation was increased. This partial inhibition of the carotid body reflex vasoconstrictor response was dependent on the innervation of the lungs. Stimulation or unloading of the carotid sinus baroreceptors by altering the perfusion pressure in the vascularly isolated carotid bifurcation regions caused a significant decrease and increase respectively in hind-limb and systemic vascular resistances at all four levels of pulmonary ventilation. Unlike the responses to chemoreceptor stimulation, the size of these responses was unaffected by the level of pulmonary ventilation. Distension of the urinary bladder resulted in a significant increase in hind-limb and systemic vascular resistances. The size of these responses was also unaltered by changing the level of pulmonary ventilation. These results indicate that there is an interaction between the inputs from the lungs and the carotid body chemoreceptors in the control of hind-limb and systemic vascular resistances. In contrast the inputs from the carotid sinus baroreceptors and the urinary bladder were unaffected by the input from the lungs.

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.