AMER. ZOOL., 34:264-279 (1994)
Respiratory Control in the Transition from Water to Air
Breathing in Vertebrates1
NEAL J. SMATRESK
Department of Biology, University of Texas at Arlington, Arlington, Texas 76019
SYNOPSIS. Studies on extant bimodally breathing vertebrates offer us a
chance to gain insight into the changes in respiratory control during the
evolutionary transition from water to air breathing. In primitive Actinopterygian air-breathing fishes (Lepisosteus and Amid), gill ventilation is
driven by an endogenously active central rhythm generator that is powerfully modulated by afferent input from internally and externally oriented
branchial chemoreceptors, as it is in water-breathing Actinopterygians.
The effects of internal or external chemoreceptor stimulation on water
and air breathing vary substantially in these aquatic air breathers, suggesting that their roles are evolutionarily malleable. Air breathing in these
bimodal breathers usually occurs as single breaths taken at irregular intervals and is an on-demand phenomenon activated primarily by afferent
input from the branchial chemoreceptors. There is no evidence for central
CO2/pH sensitive chemoreceptors and air-breathing organ mechanoreceptors have little influence over branchial- or air-breathing patterns in
Actinopterygian air breathers. In the Sarcopterygian lungfish Lepidosiren
and Protopterus, ventilation of the highly reduced gills is relatively unresponsive to chemoreceptor or mechanoreceptor input. The branchial chemoreceptors of the anterior arches appear to monitor arterialized blood,
while chemoreceptors in the posterior arches may monitor venous blood.
Lungfish respond vigorously to hypercapnia, but it is not known whether
these responses are mediated by central or peripheral chemoreceptors. A
major difference between the Sarcopterygian and Actinopterygian bimodal
breathers is that lungfish can inflate their lungs using rhythmic bouts of
air breathing, and lung mechanoreceptors influence the onset and termination of these lung inflation cycles. The control of breathing in
amphibians appears similar to that of lungfish. Branchial ventilation may
persist as rhythmic buccal oscillations in most adults, and stimulation of
peripheral chemoreceptors in the aortic arch or carotid labyrinths initiates
short bouts of breathing. Ventilation is much more responsive to hypercapnia in adult amphibians than in Actinopterygian fishes because of
central CO2/pH sensitive chemoreceptors that act to convert periodic to
more continuous breathing patterns when stimulated.
years ago, primarily from comparative anatomical studies, developmental studies on
lungfish and amphibians and the fossil reco r d see e
(
-8- Schmalhausen, 1968 or Romer,
1970 The
salient
)features of this model are
that air-breathing organs (ABO) were first
associated with the mouth or pharynx, then
1
From the Symposium Current Perspectives on the became more deeply invaginated as ventral
Evolution Ecology, and Comparative Physiology of outpocketings of the pharynx, and ultiINTRODUCTION
A general outline for the evolution of air
breathing and the cardiovascular changes
accompanying the transition from water to
air breathing in vertebrates was developed
?3SS23?SKae^;JSSSNOf
matel becam the aired lu
r
f
e
^Hseen in
the American Society of Zoologists, 27-30 December,
amphibians. Accompanying the develop1991 at Atlanta, Georgia.
ment of the ABO, the cardiovascular system
264
CONTROL OF BIMODAL BREATHING
was modified to perfuse the gas exchange
organ, and then to separate blood that had
been oxygenated in the ABO from systemic
venous blood. As the surface area available
for aerial gas exchange increased, the gills
became reduced in size and branchial oxygen uptake became an increasingly smaller
fraction of total oxygen consumption. Branchial movements became modified to alternate between pumping water past the gills
and pumping air into the ABO. Water
pumping was eventually abandoned and the
buccal muscles were employed exclusively
as a positive pressure air pump to inflate
the lungs either in single breaths or in oscillating cycles of lung inflation.
In recent years a growing body of research
on the neural control of breathing in bimodally breathing vertebrates has let us add to
this story by asking "How did respiratory
control change during the evolutionary
transition from water to air breathing?" and
"Are there persistent ramifications of these
evolutionary changes for the control of unimodal air breathing?" Several recent reviews
provide a base for beginning to address these
questions by summarizing studies on the
distributions and roles of chemoreceptors
and mechanoreceptors that contribute to
respiratory control in vertebrates (see e.g.,
Burleson et al, 1992; Milsom, 1990; Smatresk, 1990; Shelton et al, 1986; West and
Van Vliet, 1992). This review is an initial
attempt to develop a physiological history
for the evolution of respiratory control in
the transition from water to air breathing,
based on studies of several extant bimodally
breathing vertebrates. A reasonable way to
begin developing this history, however, is
to look briefly at the control of breathing in
representative unimodal water and air
breathers.
CONTROL OF UNIMODAL WATER AND
AIR BREATHING
This section will highlight the major differences and similarities between the two
best studied groups of water and air breathers,fishand mammals. The reader is referred
to several recent reviews for more in-depth
treatment (see e.g., Burleson et al, 1992;
Feldman 1986; Fitzgerald and Lahiri, 1986;
Milsom, 1990). Ventilation in water-
265
breathing fishes and mammals is generally
regular and rhythmic. Nerve activity correlated to breathing (fictive breathing) can
be recorded from in vitro brainstem preparations, therefore rhythmic breathing in
these animals is endogenously generated
within the brainstem and does not appear
to require sensory feedback for its initiation
or maintenance (see e.g., Adrian and Buytendijk, 1931; Feldman et al, 1990; Onimara and Homma, 1987; Rovainen, 1977;
Suzue, 1984; Thompson, 1990). Recent
studies suggest that the endogenous respiratory rhythm in mammals may arise from
conditionally active pacemaker cells
embedded within the respiratory neural network (Smith et al, 1991), but the cellular
or network mechanisms of respiratory
rhythmogenesis in fishes have not been
identified. While the basic respiratory
rhythm in these unimodal breathers is
endogenously generated, afferent feedback
from sensory receptors and afferent input
from higher brain centers is needed to adapt
the rhythm to meet environmental, metabolic and behavioral demands.
In both fishes and mammals the responses
to hypoxia and hypoxemia are mediated by
peripheral chemoreceptors. In fishes, chemoreceptors resembling the glomus cells
found in mammalian carotid and aortic
bodies are located diffusely throughout the
gills, and are innervated primarily by branchial branches of cranial nerves IX and X
(Burleson and Milsom, 1990; Burleson and
Smatresk, 1990a; Burleson et al, 1992).
There appear to be two loci for these branchial chemoreceptors (Burleson and Smatresk, 19906). Stimulation of an internally
oriented group of chemoreceptors, as blood
oxygen content or Po, falls, generally
increases the amplitude and frequency of
gill ventilation. Stimulation of an externally
oriented group of chemoreceptors by aquatic
hypoxia elicits reflex bradycardia and also
stimulates ventilation frequency and amplitude. In mammals, peripheral chemoreceptors found in discrete aggregations in the
carotid body are innervated by cranial nerve
IX, while chemoreceptors found in the aortic arch and a more diffuse paraganglion system (Sinclair, 1987) are innervated by cranial nerve X. Based on their innervation
266
NEAL J. SMATRESK
d
Hyperoxla
Hyperoxlc Hypercapnla
Normoxla
Normoxlc Hypercapnla
r3
-o
1 min
FIG. 1. Buccal pressure recordings of the ventilatory responses to hypercapnia from a catfish (Ictalunispunctatus,
top panel) and a toad (Bufo marinus, bottom panel). Catfish responses were assessed during hyperoxia to be
certain that Root or Bohr effect reductions in oxygen content did not indirectly stimulate breathing. Catfish
respond to hyperoxic hypercapnia with a small but significant ventilatory stimulation, with no reduction in
arterial or venous O2 content or POj (Burleson and Smatresk, unpublished observations). Hypercapnia has a
much greater effect on ventilation in frogs and toads, causing Bufo to switch from single breath to bout breathing
patterns.
and location, the carotid and aortic body
chemoreceptors of mammals appear to be
homologous to the more diffuse branchial
chemoreceptor system in fish. The carotid
body lies in a complex vascular region that
is hyperperfused and therefore responds to
arterial PO2 change, but is relatively insensitive to changes in O2 content or blood flow.
The aortic bodies lying in the nutritive circulation of the aorta also respond to changes
in PO2, but unlike the carotid bodies, respond
vigorously to changes in oxygen delivery
brought about by varying O2 content or
blood flow. Based on these response characteristics, and the chemoreflex stimulation
of ventilation during hypoxia or hypoxemia, the carotid and aortic body chemoreceptors appear to be functionally equivalent to the externally and internally oriented
chemoreceptor of fishes.
In addition to responding vigorously to
O 2 changes, most fish respond to hypercapnic acidosis by increasing ventilation (see
Burleson et al., 1992 or Shelton et al., 1986
for review). While the basis of this response
has been extensively debated, ample evidence exists that hypercapnic or metabolic
acidosis has a direct, albeit modest, stimulatory effect on branchial ventilation which
cannot be attributed to Bohr or Root effect
reductions in O2 content in arterial or venous
blood (Fig. 1, top panel; Heisler etai, 1988;
Wood et al., 1990). Since there is no compelling evidence to suggest that fish have
central CO2/pH sensitive chemoreceptors,
as mammals do, it seems likely that the
response to hypercapnic acidosis in fish is
mediated by the peripheral (i.e., branchial)
chemoreceptors. Supporting this contention, we have recently found that branchial
nerve section abolishes the ventilatory
responses to hypercapnia in catfish (Burleson and Smatresk, unpublished data). Thus,
the branchial chemoreceptors of fishes, like
the carotid and aortic body chemoreceptors
in mammals, appear to respond to both
hypoxia and hypercapnia.
Perhaps the major difference between fish
and higher vertebrate chemoreception is that
respiratory modulation by peripheral chemoreceptors takes a back seat to the afferent
influence of the central CO2/pH sensitive
chemoreceptors. Mammalian central chemoreceptors may powerfully stimulate
CONTROL OF BIMODAL BREATHING
breathing and contribute to "respiratory
drive" even in resting animals. While these
receptors are just one of several sources of
drive (i.e., stimulating inputs) to the rhythm
generating centers in the medulla (Feldman,
1986), removal of their afferent input by
focal cooling or hypocapnia in animals
reduced to basic states by anesthesia or
decerebration leads to apnea (see e.g., Eldridge, 1980; Mitra et al, 1988). Thus, afferent activity from the central chemoreceptors may be quite important for the
maintenance of respiratory rhythms in
mammals under certain conditions.
In addition to chemoreceptors responding to oxygen or acid-base disturbance, a
variety of mechanoreceptors located along
respiratory passages or surfaces may contribute significantly to respiratory control.
Mechanoreceptors have been identified in
the gills of fish, but little is known about
their role in ventilatory control. Based on
studies of their discharge characteristics in
spontaneously breathing carp (de Graaf et
al, 1987; de Graaf and Ballintijn, 1987),
they appear to play a major role in regulating gill filament adduction and abduction
during the normal breathing cycle, thus
maintaining the integrity of the gill curtain.
Branchial mechanoreceptor information
also interacts with chemoreceptor information in higher brain centers to control
the transition from active ventilation to ram
ventilation in swimming fish, but the details
of this interaction have not been characterized (Roberts and Rowell, 1988). The best
evidence that branchial mechanoreceptors
influence respiratory timing in fish comes
from studies on carp, de Graaf and Roberts
(1991) found that externally imposed gill
arch oscillations, close to the natural ventilation frequency, entrained the rate of
respiratory motor nerve discharge and effectively phase locked the gill ventilation cycle
to the imposed cycle period. These and similar results led Milsom (1990) to suggest that
afferent input from branchial mechanoreceptors serves to stabilize breathing rhythms
and improve the ergometric cost of breathing in fishes.
In mammals, rapidly and slowly adapting
pulmonary mechanoreceptors play a major
role in the regulation of ventilation timing
267
and motor discharge patterns (see Feldman,
1986; Milsom, 1990; and Mitchell et al,
1990 for recent reviews). Mechanoreceptor
activation by lung inflation shortens the
duration of phrenic nerve discharge, hence
inspiration, without changing the shape of
the phrenic burst. The amplitude (burst
shape) and timing of upper airways motor
discharge recorded from the recurrent
laryngeal nerve, however, are both altered
by lung inflation (Feldman and Grillner,
1983). Thus, pulmonary mechanoreceptor
information has different effects on upper
and lower airways timing and motor patterns. These data suggest that afferent feedback from mechanoreceptors exerts a substantially greater influence over respiratory
rhythm and pattern generation in mammals
than it does in fishes.
CONTROL OF BIMODAL BREATHING
Based on the "endpoints" given above,
the most parsimonious explanation for the
changes in ventilatory control during the
evolutionary transition from water to air
breathing would be that rhythmic breathing
persisted through the transition, and only
modest afferent modifications were needed
to adapt the branchial rhythm generator to
meet the demands of air breathing. If we
incorporate even the most basic observations on breathing patterns in extant bimodal
breathers into this explanation, however, we
quickly see that this is not likely to be the
case. In the most primitive extant air
breathers, the air-breathing fishes, air
breathing occurs as solitary breaths at irregular intervals. Thus in its earliest stages air
breathing had little resemblance to rhythmic gill ventilation or the rhythmic airbreathing patterns of higher vertebrates. The
coexistence of regular gill ventilation with
irregular air breathing in these fish further
suggests that primitive air breathing was a
new motor pattern that did not simply
evolve from modest modifications to the
branchial rhythm generator. With this starting point, the balance of this review will
assess the limited literature available on the
neurogenesis and modulation of branchialand air-breathing patterns in several reasonably well studied Actinopterygian and
Sarcopterygian bimodal breathers to further
268
NEAL J. SMATRESK
develop our insight into the evolution of
respiratory control during the transition
from water to air breathing.
ratory neurons driving water or air breathing. However, deafferentation studies provide some insight into the need for sensory
input in the initiation and maintenance of
Control ofbimodal breathing in primitive
these behaviors. In Lepisosteus and Amia
Actinopterygian fish
sectioning the cranial nerves to the gills has
The majority of studies on the control of no effect on water-breathing patterns, but
bimodal breathing in Actinopterygian fishes abolishes air breathing and abolishes the
have been on Lepisosteus osseus or L. ocu- reflex responses to hypoxia or hypoxemia
latus (longnose and spotted gar) and Amia (Fig. 2; McKenzie et ai, 1991a; Smatresk,
calva (bowfin) members of the ginglymodi 1987). Thus, air breathing in these fishes
and halecomorphi, respectively (Lauder and appears to be critically dependent on afferLiem, 1983). These primitive bimodal ent input for its initiation, and is not the
breathers have been called living fossils, and result of an endogenously active air-breathbecause they are aquatic and arguably fac- ing rhythm generator as it is in mammals.
ultative air breathers that use swim bladder Furthermore, that branchial ventilation
"lungs," they may be good examples of early persists despite removing the major sources
stages in the transition from water to air of chemoreceptor and mechanoreceptor
breathing. Studies on the cladista (reedfish afferent feedback to the brain is consistent
and bichirs), which are even more primitive with the hypothesis that gill breathing is
Actinopterygian air breathers, would be driven by an endogenously active branchial
invaluable, but to date there has been no rhythm generator as it is in unimodal waterconcerted effort to describe the respiratory breathing fishes.
neurobiology in this group.
Because sectioning the nerves carrying
Central respiratory rhythm and pattern chemoreceptor afferent information virtugenerators in Lepisosteus and Amia.—In ally abolishes the ventilatory responses to
well aerated water Lepisosteus and Amia hypoxia and hypoxemia in Lepisosteus and
display regular and rhythmic branchial ven- Amia, branchial chemoreceptors clearly
tilation, that may be interrupted irregularly account for most, if not all, of their reflex
by single air breaths. The neural mecha- responses to hypoxia (Smatresk, 1987;
nisms generating the rhythmic branchial McKenzie et ai, 1991 a), as they do in waterventilation pattern have not been studied breathing fish. The release of endogenous
in any air-breathing fish, but it is reasonable catecholamines, however, may act in conto assume that they are essentially the same cert with these neural mechanisms to alter
as those accounting for gill breathing in any ventilation to varying degrees. Recent studActinopterygian fish. The neural origins of ies by McKenzie et al. (1991&) on Amia
air-breathing are more difficult to under- suggest that hypoxia elicits the release of
stand. Based on Liem's (1980) comparative catecholamines which may stimulate gill
studies on the mechanics of single air breaths breathing even after branchial denervation.
in various bimodally breathing fishes, air Since the stimulation of gill ventilation by
breathing appears to arise from modified exogenously administered catecholamines
coughing and suction feeding movements. persists after gill denervation, it is likely that
Thus, a central pattern generator for air catecholamines are acting directly on the
breathing may have evolved through the central neural structures controlling brancoalescence of two preexisting pattern gen- chial ventilation. Further evidence that the
erators.
branchial and air-breathing pattern generators
are separate centers is provided by the
There are no studies on fictive breathing
in isolated or in vitro brains in these air- fact that catecholamines stimulate gill venbreathing fishes that can tell us whether gill tilation but not air breathing.
ventilation and air breathing are endogeChemoafferent modulation of bimodal
nously generated, nor are there studies that breathing in Lepisosteus and Amia.—Reflex
have characterized the central anatomical and nerve section studies in both Amia and
loci and discharge characteristics of respi- Lepisosteus provide evidence that there are
269
CONTROL OF BIMODAL BREATHING
Sham Operated, Vagus Intact
Buccal
31
;ure,
Pressure,
CmH,O
+1
[ .uuu.
oh
in m
Normoxia, Po2=135 Torr
Hypoxia, Po,=17 Torr
Bilateral Vagal Section
Buccal
Pressure,
Cm H,O
inulmtmliiB Imu h ?m f w iTtirini fBiiiuifiiiimLlvntliBtttiBmtaiih'j kiflitiitttin hnLkmttui tumlmMliml i
Hypoxia, Po;=18 Torr
I
Normoxia, Po2=138Torr
t—1 mlnH
FIG. 2. Buccal pressure recordings of the responses of anesthetized, spontaneously breathing gar (Lepisosteus
oculatus) to aquatic hypoxia, before and after sectioning the branchial branches of the vagus. Hypoxia stimulates
air breathing (AB) and inhibits gill ventilation before nerve section, but after nerve section water PO2 has no
significant effects on air or water breathing, and air breathing is abolished.
internally and externally oriented branchial
chemoreceptors, as there are in other Actinopterygian fish (McKenzie et al, 1991a;
Smatresk, 1987). Cyanide localization studies (NaCN is a potent chemoreceptor stimulant) and the responses of Lepisosteus to
independent stimulation of external and
internal chemoreceptors led Smatresk et al.
(1986) to suggest that internally oriented
receptors must monitor mixed venous blood
on the afferent side of the branchial circulation. Monoamine fluorescence studies
using the Falck-Hillarp technique reveal
numerous serotonin and norepinephrine
containing cells resembling the NEC cells of
teleosts (Donald, 1987; Dunel-Erb et al.,
1982) and scattered throughout the gills of
Lepisosteus (Smatresk, unpublished data)
but a chemoreceptive function for these cells
has not been confirmed.
The responses to chemoreceptor stimulation are quite different in Lepisosteus and
Amia. Stimulation of internal chemoreceptors increases only gill ventilation in Amia,
but stimulates both gill ventilation and air
breathing in Lepisosteus (McKenzie et al.,
1991a; Smatresk et al, 1986). Stimulation
of external chemoreceptors by aquatic hypoxia or externally delivered NaCN stimulates air breathing in both fish, but increases
gill ventilation in Amia and inhibits gill ventilation in Lepisosteus (Smatresk et al,
1986). This reflex depression of gill ventilation may limit the loss of oxygen from the
gills in severely hypoxic water. Denervating
the gills abolishes the responses to hypoxia
and hypoxemia in both of these air breathing fish (McKenzie et al, 1991a; Smatresk,
1987). Based on these studies the basic chemoreceptor arrangement and innervation in
these bimodally breathing fish appears to be
similar to that of other Actinopterygians.
Stimulation of externally oriented chemoreceptors by aquatic hypoxia shifts the ventilatory emphasis from water to air breathing in both of these fish, but the quite
different effects of internal and external chemoreceptor stimulation on water and air
breathing in Amia and Lepisosteus, suggests
that the modulatory roles of the peripheral
chemoreceptors are evolutionarily malleable, helping to coordinate water and air
270
NEAL J. SMATRESK
breathing activities to match the morphological adaptations of these fish to bimodal
breathing.
There has been no systematic effort to
identify CO2 or pH sensitive chemoreceptors in air-breathing fishes, and interpreting
the modest effects of hypercapnia on ventilation patterns is complicated by the interactions of hypercapnic acidosis with arterial
O2 content and the possible release of catecholamines. For example, Amia respond
to moderately hypercapnic water with
increased gill and air breathing (Johansen et
al., 1970), but above 3% CO2 branchial ventilation is inhibited. McKenzie et al. (19916)
found that acid injections into the dorsal
aorta sufficient to drop arterial pH about
0.3 pH units stimulated air breathing and
transiently increased gill ventilation in normoxic fish, but had no effect on air breathing
and only slightly stimulated gill ventilation
in hyperoxic fish. This response is puzzling
considering that stimulation of the internally oriented chemoreceptors with intraarterial NaCN had no significant effect on
air breathing in Amia, and suggests that the
responses to hypercapnic acidosis may be
mediated by more than one group of chemoreceptors or nociceptors. If there are other
receptors contributing to the responses to
hypercapnia in Amia, however, they do not
appear to be central CO2/pH sensitive chemoreceptors, since Hedrick et al. (1991)
found that air and water breathing in Amia
were unaffected by intracranial perfusion
with hypercapnic acidic mock CSF solutions. Aquatic hypercapnia (1%) stimulates
air breathing and gill ventilation slightly in
Lepisosteus (Smatresk and Cameron,
1982a), but the time course of the ventilatory stimulation follows the time course of
arterial pH change, thus the response appears
to be due to pH rather than PCO2 per se. The
post exercise stimulation of ventilation in
Lepisosteus is also strongly correlated to
changes in arterial pH (Shipman and Smatresk, 1989). Based on these observations,
the weak responses oiAmia and Lepisosteus
to acidosis appear similar to those observed
in other Actinopterygian fishes. Lacking
evidence for central CO2/pH chemoreceptors, branchial chemoreceptors remain the
best candidates for mediating these
responses in these bimodally breathing
fishes.
Mechanoreceptor modulation of breathing in Lepisosteus and Amia.—Mechanoreceptors innervated by a visceral branch of
the vagus have been identified in the ABO
of both Amia and Lepisosteus (Milsom and
Jones, 1985; Smatresk and Azizi, 1987). In
both species, rapidly and slowly adapting
mechanoreceptors can encode the rate and
volume of ABO inflation. An obvious role
of these receptors would be to signal the
need to air breathe as lung volume declines
due to the low lung R value (ratio of CO2
to O2 exchange) in air-breathing fishes, in
order to maintain buoyancy or adequate
ABO oxygen uptake. This is clearly not the
case for Lepisosteus, however, where ABO
inflation and deflation have no significant
effect on gill ventilation or air breathing in
conscious, or anesthetized spontaneously
breathing animals, as long as ABO O2 tensions remain high (Azizi and Smatresk,
1986; Smatresk and Cameron, 1982*). ABO
inflation and deflation did, however, influence motor nerve activity to the smooth and
striated muscle in Lepisosteus lungs (Fig. 3).
Inflation decreased efferent activity (hence
muscle tone) and deflation increased activity, suggesting a myotactic-like vago-vagal
reflex that could maintain smooth or skeletal muscle tension despite lung volume
changes within the ABO. Further studies on
the roles of ABO mechanoreceptors in
Actinopterygian fish with swim bladder
lungs are needed to form a meaningful summary of their functions. If there is any value
to these mostly negative results, it is to suggest that these receptors may not be well
integrated into the respiratory control system, and may better serve non-respiratory
functions, like bouyancy regulation, in the
most primitive bimodal breathers.
Control of breathing in lungfish and
amphibians
Lungfish are often grouped with Actinopterygian air-breathing fishes when discussing ventilatory control, but they are Sarcopterygians and appear to be different
enough from the Actinopterygian fishes to
warrant either separate treatment, or inclusion with the amphibians in any discussion
CONTROL OF BIMODAL BREATHING
271
cmH 2 O
30
Vagal
Efferent
Activity,
imp-sec*1
15
deflate
cmH 2 0
30
Vagal
Efferent
Activity,
imp-sec"1
15
1 min
FIG. 3. Motor nerve activity (vagal efferent activity), recorded from a slip of the ABO branch of the vagus
innervating the smooth and skeletal muscle of the ABO in Lepisosteus oculatus is inhibited by ABO inflation
(top traces), and stimulated by ABO deflation (bottom traces).
of their respiratory neurobiology. Unlike
Lepisosteus and Amia, lungfish may be
emersed for extended periods during aestivation. Brainerd (1992) suggests that there
may be a clear separation in the basic airbreathing mechanics, hence in the central
pattern generators driving air breathing,
between the Actinopterygians and Sarcopterygians. Actinopterygians, including Lepisosteus and Amia, display a "double pulse"
breathing pattern with a distinct buccal
chamber expansion and contraction (one
pulse) for exhalation, followed by another
pulse for filling the chamber with air and
pumping it back into the ABO (Brainerd,
1992). Lungfish and some amphibians use
a single pulse for exhalation and pumping
air back into their lung, suggesting that there
may be mixing of expired and inspired gas
streams in these animals (Vitalis and Shelton, 1990). Whether this single pulse mechanism is independently evolved, primitive,
or derived from the double pulse mechanism of the Actinopterygian fishes cannot
272
NEAL J. SMATRESK
be determined at this time. In either case it
is likely that the central neural network
driving air breathing in Sarcopterygians is
organized differently than the air-breathing
pattern generator in Actinopterygian fishes,
and requires different afferent modulation
for efficient performance.
Central respiratory rhythm and pattern
generators in lungfish and amphibians.—
Larval amphibians and lungfish display
branchial and air-breathing patterns that are
similar to those described above for Actinopterygian fishes, with rhythmic branchial
ventilation interrupted periodically by singly occurring air breaths. In adult lungfish,
however, branchial ventilation is weak and
irregular, and most gas exchange occurs
across the lungs or skin. In adult anurans,
buccal ventilation appears to persist as low
amplitude movements (West and Burggren,
1982) that are largely non respiratory, except
when used for air breathing (see Fig. 1),
where more forceful buccal contractions are
used to pump air into the lungs. As the
demand for gas exchange increases, the weak
buccal oscillations are supplanted by air
breaths. Thus the branchial rhythm generator appears to persist as the buccal oscillator in lungfish and amphibians, but
becomes increasingly subservient to the
demands for air breathing. Juvenile lungfish
and larval amphibians take single air breaths
at irregular intervals, like Actinopterygians
do, but as they mature, Sarcopterygian air
breathers may use a series of rhythmic air
breaths to inflate their lungs. This suggests
that the neural network driving air breathing is modified from a central pattern generator driving single air breaths, which is
typical of Actinopterygian bimodal breathers, into something more like the central
rhythm generator seen in higher vertebrates.
This important modification to the central
respiratory control system set the stage for
the transition from periodic single breaths
to the more rhythmic and continuous
breathing patterns of higher vertebrates.
Little is known about the central sites or
mechanisms responsible for producing the
buccal and air-breathing rhythms or patterns in lungfish, but recent studies by
Walker et al. (1990) and Kogo et al. (1991)
provide evidence that water and air breath-
ing are driven by two separate but coupled
respiratory oscillators in frogs. Using isolated in vitro tadpole brains (Rana catesbianna), Walker et al. (1990) were able to
record fictive breathing corresponding to
regular and rhythmic branchial ventilation,
and noted that it was periodically interrupted by larger amplitude motor nerve discharge, corresponding to air breathing. It is
notable that air breathing in this isolated
preparation consisted only of single breaths,
rather than bouts of breathing, and suggests
that rhythmic air breathing or bout breathing patterns are acquired in later developmental stages. Using isolated in vivo and
isolated in vitro bullfrog brainstem preparations Kogo et al. (1991) identified single
cell and whole nerve fictive breathing
responses indicating that the buccal and air
breathing oscillators are independent but
coupled in adult bullfrogs. These studies
provide further support for the notion that
the air-breathing rhythm generator did not
arise simply by building around the kernel
of the branchial rhythm generator, but that
a new air-breathing rhythm generator
evolved whose activities were coupled to
the phylogenetically more primitive branchial rhythm. They also show that rhythmic
bouts of air breathing may be generated
exclusively by structures residing within the
medulla and do not require varying peripheral afferent feedback for their initiation or
maintenance.
Chemoreceptor modulation of breathing
in lungfish and amphibians.—The chemoreceptors mediating the reflex responses to
hypoxia and hypercapnia have not been
studied as thoroughly in lungfish as they
have in Lepisosteus and Amia. Small injections of NaCN given into the branchial
arches of lungfish stimulated air breathing,
and sectioning the branchial branches of the
vagus attenuated these responses (Lahiri et
al., 1970). Thus lungfish have internally oriented chemoreceptors innervated by the
vagus, as have been identified in Actinopterygian fishes. There are apparently few
external chemoreceptors, or they have
greatly attenuated effects, since lungfish do
not respond significantly to moderate
aquatic hypoxia (Johansen and Lenfant,
1968; Smatresk, unpublished observa-
CONTROL OF BIMODAL BREATHING
tions). The responses of bullfrog tadpoles to
aquatic and aerial hypoxia, however, are
similar to those ofLepisosteus, with aquatic
hypoxia depressing gill ventilation and
stimulating air breathing, while a hypoxic
atmosphere stimulates both water and air
breathing (West and Burggren, 1982, 1983).
It is not clear whether the depression of gill
ventilation during aquatic hypoxia is a direct
or indirect effect of chemoreceptor stimulation, but in general these responses suggest
that the roles of internally and externally
oriented chemoreceptors are similar in the
Actinopterygian air breathers and larval
anurans. Peripheral chemoreceptors located
in the aortic arch and carotid labyrinths and
innervated by cranial nerves IX and X have
been identified in adult anurans (Ishii and
Ishii, 1976; Ishii et ai, 1985; Van Vliet and
West, 1992). Bilateral section of the carotid
labyrinth nerves does not abolish the reflex
responses to hypoxia, thus chemoreceptors
located in the aortic arch, or in other more
diffuse loci, comprise a significant source of
chemoafferent information (West et ai,
1987). Taken collectively, these studies suggest that the innervation and basic response
characteristics of the peripheral chemoreceptors in Sarcopterygians follow the same
general plan described above for Actinopterygian fishes. As the dependence on branchial O2 uptake decreases, the gills and
branchial arteries become reduced and
internalized, becoming the carotid and aortic arches. The externally oriented chemoreceptors become arterial chemoreceptors
and the diffuse chemoreceptor system offish
appears to give way to more discrete aggregations of chemoreceptors near the carotid
bifurcations and in the aortic arch.
While hypercapnia had generally weak
and variable effects in Lepisosteus and A mia,
it vigorously stimulates air breathing in adult
lungfish and amphibians (Fig. 1). Aquatic
hypercapnia may also elicit short bouts of
two or three air breaths in lungfish, which
are not seen in response to aerial or aquatic
hypoxia (Smatresk, unpublished observations). Interestingly, aerial hypercapnia has
relatively little effect on air-breathing frequency in adult lungfish (Smatresk, unpublished observations), presumably because
CO2 taken up into the lung is rapidly lost
273
into the water across the gills and integument. The vigorous responses to hypercapnic water, and the conversion of single
breath to bout air-breathing patterns in aestivating animals that are hyperoxic and
hypercapnic, raise the possibility that lungfish have central CO2/pH sensitive chemoreceptors, but this has not been experimentally addressed. In characterizing the
afferent discharge characteristics of the
carotid labyrinth chemoreceptors in Bufo
marinus, Van Vliet and West (1992) found
that chemoreceptor discharge was stimulated by hypercapnia as well as hypoxia.
Smatresk and Smits (1991) and Branco et
al. (1991) found that stimulation of intracranial chemoreceptors with hypercapnic
acidic mock CSF solutions caused a marked
stimulation in air breathing in toads. Thus,
anuran amphibians have both central and
peripheral chemoreceptors that participate
in the responses to hypercapnic acidosis.
Central CO2/pH sensitivity appears to be
dependent on developmental stage in
amphibians, since neither water nor air
breathing was significantly stimulated by
aquatic hypercapnia in unoperated, unrestrained bullfrog tadpoles (through stage X,
Infantino, 1990), and fictive breathing
recorded in tadpole brains was not stimulated by hypercapnic acidosis (Walker et ai,
1990). Thus, central CO2/pH chemosensitivity appears to have evolved in the Sarcopterygians, but may not be fully developed in early aquatic stages of development.
How do the central and peripheral chemoreceptors modulate bimodal breathing
in amphibians? West et al. (1987) found that
hypercapnia and hypoxia had different
effects on the pattern of breathing in toads,
suggesting that central and peripheral chemoreceptors have different effects on respiratory control. To further investigate this
hypothesis, Smatresk and Smits (1991)
developed a preparation for independently
regulating central and peripheral chemoreceptor stimulation and eliminating ventilatory related oscillations in arterial gasses
in anesthetized spontaneously breathing
Bufo. Vigorous ventilatory responses to
intracranial perfusion with hypercapnic
acidic mock CSF solutions directed towards
the ventral medullary surface (but not
274
NEAL J. SMATRESK
observed when the perfusion catheter was
placed elsewhere) demonstrated that toads,
like turtles (Hitzig and Jackson, 1978), possess central CO2/pH sensitive chemoreceptors. Below a critical threshold of afferent
activity from central and peripheral chemoreceptors the toads were completely
apneic, but increasing either peripheral or
central chemoreceptor stimulation alone was
sufficient to initiate brief bouts of breathing
(see also West et al, 1987). These results
demonstrate that air breathing in anuran
amphibians is dependent on attaining a critical level of chemoafferent drive. However,
episodic breathing in Bufo is not simply the
result of negative feedback control of arterial or central pH and gases, since it persists
even when they are held constant by unidirectional ventilation. Stimulation of
peripheral chemoreceptors alone produced
brief episodes of breathing, but had relatively little effect on the total non-ventilatory period (TNVP). Stimulation of central
chemoreceptors greatly increased the number of breaths per bout, and markedly
decreased the TNVP. Thus a major effect of
central chemoreceptor stimulation appears
to be the conversion of episodic to more
continuous breathing patterns in toads. That
animals may become apneic below a certain
level of chemoreceptor afferent drive seems
to contradict the observations made above
that air breathing is the result of an endogenous rhythm generated in the absence of
afferent input, and suggest instead that central chemoreceptors may provide the drive
for fictive breathing in isolated brainstem
preparations.
Taken collectively, these studies suggest
that the evolution of central CO2/pH chemoreceptors in Sarcopterygian air breathers
may have been critical to the evolution of
endogenous air-breathing rhythms in vertebrates (Smatresk, 1990). Briefly summarized, the arguments for this hypothesis are
as follows: 1) most fish show little sensitivity
to hypercapnia, and there is currently no
compelling evidence for central chemoreceptors in any of the water- or air-breathing
fishes (Hedrick et al, 1991; Wood et al,
1990); 2) there is progressive dependence
on CO2 as a source of respiratory drive in
the transition from water to air breathing
in amphibious vertebrates; 3) the transition
from single breath to rhythmic breathing
patterns in lungfish appears to occur only
during hypercapnic acidosis (DeLaney and
Fishman, 1977); 4) stimulation of central
chemoreceptors on or near the ventral medullary surface in toads has the major effect
of converting periodic to more continuous
breathing patterns in amphibians (Smatresk
and Smits, 1991; Branco et al, 1991). A
testable correlate of this hypothesis is that
rhythmic bouts of air-breathing should only
be found in animals that have central chemoreceptors, but the distribution of central
chemoreceptors in fishes and amphibians is
not currently known.
Mechanoreceptor modulation of breathing in lungfish and amphibians. —The discharge characteristics and innervation of the
rapidly and slowly adapting lung mechanoreceptors (RARs and SARs respectively)
in lungfish and amphibians are similar to
those described for Actinopterygian bimodal
breathers, and are adequate to encode information about the rate and volume of inflation or deflation of the lung (for review see
Milsom, 1990). In addition, to SARs and
RARs, pulmonary mechanoreceptors whose
discharge is inhibited by CO2 have also been
described in lungfish and frogs (Milsom and
Jones, 1977; DeLaney^ al, 1983). Although
reflexes associated with lung inflation and
deflation have been described in urodele
amphibians (Saint-Aubain, 1982), mechanoreceptor afferent discharge characteristics
have not been described in any salamander.
While there are certainly mechanoreceptors
associated with respiratory passages and the
glottis in these bimodal breathers, little is
known about their afferent discharge characteristics or their roles in ventilatory control, aside from their roles in mediating
respiratory defense responses (Jones and
Milsom, 1982).
As for other lower vertebrates, the modulatory roles of pulmonary mechanoreceptors on the buccal and air-breathing rhythm
and pattern generators are not well understood in lungfish and amphibians. Pack et
al. (1992) found that lung inflation and
deflation powerfully modulate the ampli-
CONTROL OF BIMODAL BREATHING
tude and duration of bouts of buccal oscillations used to inflate the lungs in lungfish.
These reflexes resemble the Hering-Breuer
inspiration and expiration promoting
reflexes seen in mammals, and their results
stand in marked contrast to the lack of
response to ABO mechanoreceptor stimulation in Lepisosteus (see above). Pulmonary mechanoreceptor activity, however,
has no significant effects on gill ventilation
in lungfish, suggesting that these receptors
do not have access to the branchial rhythm
generator (Pack et ah, 1990). These observations further support the hypothesis that
the branchial and air-breathing oscillators
are independent but interacting systems.
Observations that lung inflation inhibits gill
ventilation in tadpoles, however, suggest that
the role of pulmonary mechanoreceptors on
buccal activity may be quite variable in different classes of vertebrates (West and Burggren, 1983).
In adult anurans lung deflation inhibits
buccal pumping activity, and lung inflation
given at the onset of a breath shortens the
lung inflation cycle (for review see Milsom,
1990). Removing lung mechanoreceptor
afferent input, on the other hand, increases
the duration of the breathing bout during a
lung inflation cycle, and increases residual
volume of the lung in frogs (Evans and Shelton, 1984). Based on these observations,
Milsom (1990) suggests that pulmonary
mechanoreceptor discharge regulates endinspiratory lung volume. In lungfish and
amphibians, pulmonary mechanoreceptor
activity appears to have little effect on single
breath timing, but powerfully modulates the
duration of the non-ventilatory period
between bouts, and the number of buccal
oscillations in a bout of lung inflation.
Because of this, Pack et al. (1992) suggest
that a bout of breathing during a lung inflation period may be more equivalent to a
single air breath in a mammal (which consists of a series of bursts of motor nerve
discharge in the phrenic nerve) than a single
buccal pump is. These observations taken
with the lack of afferent input on the timing
of single breaths or buccal oscillations in
bimodal breathers suggest that lung mechanoreceptors first gained access to the con-
275
trol of lung inflation in animals that had
bout breathing patterns, by regulating the
number of air breaths in a lung inflation
cycle.
STAGES IN THE TRANSITION FROM
WATER TO AIR BREATHING
Despite the many uncertainties in making
evolutionary arguments from studies on
extant species and the incomplete state of
our understanding of the respiratory neurobiology of extant bimodal breathers, even
the few studies reviewed above suggest several major changes that may have occurred
in the transition from water to air breathing
in vertebrates. Primitive bimodal breathers
probably had a ventilatory control system
similar to that of Amia. Branchial ventilation was driven by a central rhythm generator and stimulation of externally or internally oriented branchial chemoreceptors
increased gill ventilation. The coalescence
of and modifications to preexisting pattern
generators created an air-breathing pattern
generator that was activated by stimulation
of externally oriented branchial chemoreceptors during aquatic hypoxia. ABO mechanoreceptors and internally oriented chemoreceptors were probably not well
integrated into the activities of this new airbreathing pattern generator which produced
single air breaths in accordance to the level
of stimulation from externally oriented chemoreceptors.
As the dependence on aerial respiration
increased, afferent control over branchial
ventilation was modified to increase gas
exchange efficiency. Stimulation of externally oriented branchial chemoreceptors
inhibited gill ventilation amplitude, and the
actions of the branchial rhythm generator
became increasingly subservient to the
demands of air breathing. In these more efficient bimodally breathing fish, air breathing
was stimulated by both external and internal chemoreceptors, and was therefore
responsive to both environmental and metabolic challenges. Air breathing may still
have been primarily an "on-demand" phenomenon occurring as single breaths initiated by afferent input from chemoreceptors.
It might be argued that the single pulse sys-
276
NEAL J. SMATRESK
tern of air breathing, being inherently sim- demands helped to convert periodic to more
pler than the double pulse used in Actin- continuous breathing patterns. The evoluopterygian air breathers, was the primitive tion of a central rhythm generator capable
condition. The efficiency of this single pulse of driving rhythmic bouts of breathing may
mechanism may have been improved, how- also have created a new role for pulmonary
ever, by one of two evolutionary changes. mechanoreceptor afferent input. Single
The Actinopterygians separated exhalation breath timing was relatively unaffected by
from inhalation, thus improving aerial gas chemo- or mechanoreceptor input, but pulexchange with a double pulse system. There monary mechanoreceptors became imporis, in fact, some evidence to suggest that tant in controlling the initiation and duraexhalation and inhalation in Amia are sep- tion of bouts of breathing used to inflate the
arate patterns that may be coupled or may lungs.
occur independently under different conAt this point the arrangement and interditions (Hedrick and Katz, 1991). The actions between chemoreceptors, pulmobimodal breathers that gave rise to the Sar- nary mechanoreceptors and the air-breathcopterygian line, on the other hand, retained ing rhythm generator were essentially the
the single pulse system, and improved gas same as they are in most extant terrestrial
exchange by using bouts of air breathing. vertebrates. Of course the story doesn't end
Thus, bout breathing patterns may have first here. What accounted for the transition from
appeared in the Sarcopterygian line and the periodic breathing in lower vertebrates to
central neural network generating these the continuous breathing patterns in
rhythmic bouts of air breathing may be the homeotherms? How was the motor output
progenitor of the central respiratory rhythm of the central rhythm generator for air
generator in mammals.
breathing in amphibians adapted and transIn amphibious bimodal breathers, like ferred to the spinal motor nerves driving
lungfish, there was little or no response to aspiration and finally diaphragmatic
changing aquatic O 2 tensions, and the gill breathing? Do the remnants of the branchial
arches degenerated and became internal- rhythm generator continue to control upper
ized, serving primarily as shunt pathways. airways in mammals? Finally, is there a
Because of the separation of the systemic relationship between the control of abnorand pulmonary circuits in these fishes, the mal (pathological) breathing patterns in
gill-free anterior arch chemoreceptors mammals, and the periodic breathing patbecame arterial chemoreceptors, while the terns in lower vertebrates? Our ability to
posterior arch chemoreceptors monitored address these and a host of other evolusystemic venous blood. These animals no tionary questions is seriously limited by the
longer monitored the aquatic environment small base of information on the respiratory
with externally oriented chemoreceptors, neurobiology of lower vertebrates. As we
and hypoxemia rather than aquatic hypoxia expand our understanding of the control of
became the adequate stimulus for air breathing in lower vertebrates, however, we
breathing. Branchial ventilation was weakly will undoubtedly gain valuable insights into
modulated by chemoreceptors, but the these problems.
branchial oscillator became yet more closely
coupled to the actions of the air-breathing
rhythm generator. The evolution of central
ACKNOWLEDGMENTS
CO 2 /pH chemoreceptors allowed animals
I would like to thank the American Socito respond more vigorously to changes in ety of Zoologists and the National Science
acid-base balance, and added a new source Foundation for their support in organizing
of chemoreceptor drive to air breathing. The this symposium. I would also like to thank
addition of this new source of drive may Mark Burleson for his help in the preparahave been associated with the conversion
of single breath to bout breathing patterns, tion of this manuscript. Work presented in
and central chemoreceptor stimulation dur- this review was supported by NSF grant
ing hypercapnia or elevated metabolic DCB-8801846 to NJS and NIH grant
IF32HL08526-01 to M. Burleson.
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