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Volume 2 Supplement 1

Neural Control of Breathing

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Phylogeny of central CO2/pH chemoreception in vertebrates

The traditional view has been that respiratory chemoreceptors responsive to changes in PCO2/pH first evolved in air-breathing vertebrates at both peripheral and central sites. Levels of arterial PCO2 in water breathing fish are typically less than 2–3 torr and it has been assumed that the ventilatory responses of fish to changes in aquatic PCO2/pH were due to the effects of acidosis on haemoglobin oxygen transport. There is growing evidence, however, to suggest that fish also possess peripheral chemoreceptors responsive to changes in PCO2/pH per se that reside primarily in the gills, are innervated by the glassopharyngeal and vagus nerves, and respond primarily to changes in aquatic rather than arterial PCO2. Their distribution overlaps extensively with that of the gill O2 chemoreceptors in fish and it is not yet clear whether both responses arise from the same sensory cells. To date, there is no convincing evidence that strictly water breathing fish possess central chemoreceptors.

There is, however, growing evidence to suggest that some species of air-breathing fish possess central CO2 chemoreceptors. Central chemosensitivity has been reported in in vitro brainstem-spinal cord preparations from both a primitive (holostean) and a modern (teleost) actinopterygian (ray finned) fish. Stimulation of these putative receptors had no effect on fictive gill ventilation but stimulated fictive air breathing. Unfortunately, the fictive breathing rates of these preparations were more than 25 times the resting rates reported for intact animals raising questions about the physiological significance of changes in the fictive motor output identified as air breathing under these conditions. In the South American lung-fish (a sarcopterygian fish belonging to the lineage giving rise to higher vertebrates), on the other hand, central perfusion with mock csf of differing pH stimulated air breathing at rates similar to those seen in control animals. While these data suggest that central chemoreceptors have arisen several times in evolutionary history, hand in hand with the evolution of air breathing, this issue is not yet totally resolved.

An intriguing and related finding is that central CO2 chemosensitivity appears to develop slowly in amphibian tadpoles. It is not present in young tadpoles but develops over time. The receptors initially stimulate gill ventilation but transfer their influence to lung ventilation just prior to metamorphosis from the aquatic larval stage into the air breathing adult form. In association with this the primary location of the receptors in the brainstem shifts from a diffuse distribution to a rostral concentration. While central chemoreceptors have been demonstrated in reptiles and birds, not much is known of their properties or distribution. They have been well studied in mammals where there is growing evidence for multiple sites of central CO2/pH chemoreception and evidence to suggest that the mechanism of sensory transduction may vary both within and between receptor populations. While there has been much recent interest in the membrane channels, receptors and electrical coupling of several chemosensitive sites, this work has largely been on cells with downstream respiratory rhythmicity in preparations whose responses are very different (in terms of changes in frequency and amplitude of phrenic output) from that which is seen in intact animals.

The phylogenetic trends that are emerging indicate that the use of CO2 chemoreception for cardio-respiratory processes may have arisen much earlier than previously believed, that CO2/pH chemoreception arose in the periphery before the evolution of central CO2/pH chemoreceptors, that the sites of CO2/pH chemoreception (both peripheral and central) have increased throughout the course of vertebrate evolution and that the mechanism of CO2/pH chemotransduction may vary. The sum of the data suggests that CO2/pH chemoreceptors have arisen multiple times, at multiple sites during vertebrate evolution.


Supported by the NSERC of Canada.

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Milsom, W. Phylogeny of central CO2/pH chemoreception in vertebrates. Respir Res 2 (Suppl 1), 1.5 (2001).

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