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Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Earlsfort Terrace, Dublin 2, Ireland
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Abstract |
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(Received 23 September 2003;
; first published online 7 October 2003)
Corresponding author J. F. X. Jones: Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Earlsfort Terrace, Dublin 2. Email: james.jones{at}ucd.i.e.
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Introduction |
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O'Regan was following in a long line of Irish scientists interested in the physiology of respiration (Robert Boyle, Henry Barroft, Henry Newel Martin and Earl McCarthy).
Figure 3 is taken from O'Regan (1970) (Fig. 1 of his thesis) and is reproduced here in a modified form to show the vascular intricacies of the surgical approach taken by O'Regan. The carotid body is vascularly isolated and the venous outflow channel cannulated to measure total venous carotid body blood flow. The wet weight of the cat carotid body is only 2 mg and the blood flow is calculated by recording the time taken to fill a capillary tube. If the tube held 100 µl then it would typically take 30–60 s to fill. Given the weight of the organ this represents an enormous blood flow rate, more than 20 times that of the brain for instance. The venous blood is typically bright red since the blood flow is far in excess of that required by the metabolically active glomus cells. Eric Neil was so impressed with the young O'Regan's surgical skill that he dubbed his hands the ‘hands of Ludwig’. Carl Ludwig was one of the founding fathers of modern experimental physiology, along with Helmholtz and DuBois Reymond, and this brilliant nineteenth century physiologist was a fierce opponent of vitalism and a great experimentalist.
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Parasympathetic control (sinus nerve efferents)
O'Regan developed the following approach in order to demonstrate ongoing motor regulation of the carotid body. Single chemoreceptor afferents were peeled from the otherwise intact sinus nerve and acute section of the glossopharyngeal nerve was observed to cause an abrupt increase in chemoafferent basal activity. This indicated that there was a tonic inhibitory motor drive to the carotid body (even in the barbiturate-anaesthetized cat). Single efferent activity could also be recorded in this preparation and O'Regan explored the kind of stimuli that evoked increased activity in the efferents. Adrenaline proved to be a particularly good stimulant and hypoxia was also effective (Neil & O'Regan, 1971b). Since hypoxia increased the activity of both afferents and efferents, the concern was raised that centrifugal activity might represent antidromically conducted spikes of afferent fibres (in a variation of an ‘axon reflex’). However this hypoxia-sensitive centrifugal activity was abolished by section of the glossopharyngeal nerve; a procedure that should not affect sensory fibres with or without collaterals. The next experiment proved to be particularly fruitful. A set of bipolar stimulating electrodes were placed on the glossopharyngeal nerve to activate sinus efferents whilst single chemoreceptor activity from an otherwise intact sinus nerve and total venous carotid body blood flow were monitored continuously. A dramatic decrease in chemosensory discharge and an increase in blood flow were observed. The fact that the blood flow change could not be temporally correlated with the activity profile, together with the fact that only the vascular effect was atropine-sensitive, led Neil & O'Regan (1971a) to conclude that the parasympathetic control of the carotid body was effected by a vascular and a non-vascular mechanism.
Efferent inhibition and artifacts
In the experiments involving close stimulation of the glossopharyngeal nerve there was a potential source of artifact. The proximity of the cathodal excitation point to the saline wick electrode that registered single chemosensory activity could lead to current spread and consequently the antidromic depression of sensory fibres. Neil & O'Regan (1971a) were fully aware of this problem and addressed it by placing procaine-soaked pledgets between stimulating and recording electrodes. This manoeuvre abolished the electrically evoked inhibition of sensory discharge indicating that current spread was not occurring at the low voltages used. However, others were not convinced and Goodman (1975) from Oxford wrote a diatribe about the hazards of close stimulation, and the running title of his paper was ‘Efferent inhibition and artifacts’. The following extract is taken from the transcript of the discussion period following Goodman's paper at the 1973 Bristol meeting of the International Society for Arterial Chemoreception (ISAC, as it later became known).
O'Regan: ‘I am prepared to admit that adventitious excitation may occur but I cannot see how you can say that it definitely occurred in our experiments. The only reason that you suggest that we were getting antidromic invasion was that we were getting a greater than 50% reduction in discharge. What also surprised me in view of the conclusions you draw is that you didn't monitor carotid body blood flow.’
Goodman:‘I didn't fancy measuring blood flows very much.'
It appears that in this field there was only one pair of Ludwig-like hands. The demonstration of the same effect in the aortic nerve by Neil & O'Regan (1971a) should have alleviated Goodman's concern about current spread between stimulating and recording electrodes since here the distance between electrode pairs is much greater than in the case of the sinus nerve. However, one decisive experimental preparation destroyed Goodman's argument because O'Regan managed to demonstrate chemosensory inhibition whilst activating sinus efferents without electricity (O'Regan, 1976). In this series of experiments the carotid body was rendered ischaemic and this caused carotid sinus nerve discharge to increase but the discharge was promptly inhibited following an injection of the sinus efferent activator adrenaline. The important point about this experiment is that sinus efferent inhibition occurred in the complete absence of blood flow. In other words, the non-vascular mechanism is powerful. This experiment was conducted to ensure zero blood flow; simply clamping the common carotid artery is not sufficient. The critical closing pressures might be altered following adrenaline and arterio-venous pressure differences could develop. Pressure differences cause flow. By opening the external carotid artery to the atmosphere after common carotid artery clamping and measuring total carotid body blood flow, O'Regan ensured that his experiment was not subject to these lingering doubts. This was to become the hallmark of an O'Regan experiment: an increase in technical virtuosity with a decrease in interpretative difficulty.
Sympathetic control
Sympathetic fibres project to the carotid body from the superior cervical ganglion via three principal routes: ganglio-glomerular nerve, external carotid nerve, and recurrent sympathetic fibres in the carotid sinus nerve. All these postganglionic fibres may be activated by electrically stimulating the cervical sympathetic chain that contains the sympathetic preganglionic axons. Stimulation of the cervical sympathetic chain causes a reduction of total venous carotid body blood flow (sensitive to 
adrenoceptor blockade) and most commonly an excitation of carotid body afferents (O'Regan, 1981). This pattern is the opposite of that evoked by parasympathetic stimulation and it is possible that these two limbs of the autonomic nervous system act as antagonistic influences on sensation in the carotid body (Table 1).
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The total venous blood flow of the carotid body is a combination of flow shunted away from the organ and perfusion of the glomus. Acker & O'Regan (1981) measured the effect of the autonomic nervous system on these parameters. Mirabile dictu, local blood flow and tissue PO2 were completely unaffected by both parasympathetic and sympathetic stimulation that was potent enough to alter total blood flow. This indicates that non-vascular mechanisms are responsible for the alterations in neural traffic seen during electrical stimulation of the autonomic nerves and that the brainstem is primarily concerned with regulation of shunt vessel diameter. The purpose of this focused regulation of shunt blood flow is obscure.
The carotid body perfused with cell-free solutions
Joels & Neil (1968) reported a remarkable serendipitous discovery on the revitalizing action of blood on physiological saline-perfused carotid bodies. During the course of one experiment they noticed that after some blood had accidentally escaped into a cell-free perfusate, the resting discharge increased and the responses of carotid body afferents to various chemostimulants were enhanced. It was not accident alone that favoured these investigators but accident and sagacity, in the manner of Walpole's Three Princes of Serendip who made discoveries of things they were not in quest of. O'Regan (1979b) re-investigated this phenomenon and showed impressive restoration of responsiveness to cyanide by blood even after prolonged perfusion with cell-free media. An accompanying paper (O'Regan, 1979a) showed the dramatic decline in oxygen consumption of the carotid body of the cat when perfused with cell-free solutions. Re-admission of blood after a period of saline perfusion had a stimulating action on the levels of oxygen consumption, as observed in the case of improved afferent chemosensitivity. Plasma or oncotic agents did not reproduce the action of whole blood. These two papers clarified previous inconsistencies in the literature concerning the levels of carotid body oxygen consumption. The method and duration of perfusion and the nature of the perfusate dictate the numerical value of oxygen consumption. O'Regan has once again left us with a mystery, in this case the mechanism whereby some unidentified component of the blood (in its cellular fraction) affects the basal metabolism of glomus cells.
Envoi
I trust this brief discussion of the contribution of Ronan O'Regan to the physiological sciences has left the reader with a flavour of the beautiful enigma that is the carotid body.
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Footnotes |
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References |
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TopAbstractIntroductionReferences |
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Biscoe
TJ
&
Sampson
SR (1968). Rhythmical and non-rhythmical spontaneous activity recorded from the central cut end of the sinus nerve. J Physiol
196, 327–338.
Decastro F (1926). Sur la structure et l'innervation de la glande intercarotidienne (glomus caroticum) de l'homme et des mammiferes, et sur un nouveau systeme d'innervation autonome du nerf glossopharyngien. Trab Laboratory Invest Biol University Madrid 24, 365–432.
Goodman NW (1975). Efferent inhibition of arterial chemoreceptors and stimulation of the sinus nerve. In The Peripheral Arterial Chemoreceptors, ed. Purves, MJ, pp. 241–251. Cambridge University Press, Cambridge.
Joels N & Neil E (1968). The idea of a sensory transmitter. In Wates Foundation Symposium on Arterial Chemoreceptors, ed. Torrance RW, pp 153–178. Blackwell Scientific Publications, Oxford and Edinburgh.
Neil
E
&
O'Regan
RG (1971a). The effects of electrical stimulation of the distal end of the cut sinus and aortic nerves on peripheral arterial chemoreceptor activity in the cat. J Physiol
215, 15–32.
Neil E & O'Regan RG (1971b). Efferent and afferent impulse activity recorded from few-fibre preparations of otherwise intact sinus and aortic nerves. J Physiol 215, 33–47.
O'Regan RG (1970). Studies on oxygen usage of the carotid body and the effects of efferent nerves on arterial chemoreceptor function in the cat. PhD Thesis, University of London.
O'Regan RG (1976). Efferent control of chemoreceptors. In Morphology and Mechanisms of Chemoreceptors, ed. Paintal, AS, pp. 229–247. Navchetan Press Ltd, New Delhi.
O'Regan RG (1979a). Oxygen usage of the cat carotid body perfused with cell-free solutions. Ir J Med Sci 148, 69–77.[Medline]
O'Regan RG (1979b). Responses of the chemoreceptors of the cat carotid body perfused with cell-free solutions. Ir J Med Sci 148, 78–85.[Medline]
O'Regan
RG (1981). Responses of carotid body chemosensory activity and blood flow to stimulation of sympathetic nerves in the cat. J Physiol
315, 81–98.
Von Euler US, Liljestrand G & Zotterman Y (1939). The excitation mechanism of the chemoreceptors of the carotid body. Skand Arch Physiol 83, 132–152.
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