Ventilatory compensation of the alkaline tide during digestion in the snake Boa constrictor
1 Departamento de Zoologia, Universidade Estadual Paulista, 13506-900, Rio
Claro SP, Brazil
2 Department of Zoophysiology, Aarhus University, 8000 Aarhus C,
Denmark
* Author for correspondence (tobias.wang{at}biology.au.dk)
Accepted 26 January 2004
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Summary |
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The increase in oxygen consumption of omeprazole-treated snakes after ingestion of 30% of their own body mass was quantitatively similar to the response in untreated snakes, although the peak of the metabolic response occurred later (36 h versus 24 h). Untreated control animals exhibited a large increase in arterial plasma HCO3 concentration of approximately 12 mmol l1, but arterial pH only increased by 0.12 pH units because of a simultaneous increase in arterial PCO2 by about 10 mmHg. Omeprazole virtually abolished the changes in arterial pH and plasma HCO3 concentration during digestion and there was no increase in arterial PCO2. The increased arterial PCO2 during digestion is not caused, therefore, by the increased metabolism during digestion or a lower ventilatory responsiveness to ventilatory stimuli during a presumably relaxed state in digestion. Furthermore, the constant arterial PCO2, in the absence of an alkaline tide, of omeprazole-treated snakes strongly suggests that pH rather than PCO2 normally affects chemoreceptor activity and ventilatory drive.
Key words: reptile, snake, Boa constrictor, feeding, postprandial period, acidbase balance, gastric acid secretion, alkaline tide, omeprazole, ventilation, ventilatory control
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Introduction |
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While it seems plausible that the respiratory compensation of pH during the
postprandial period serves a homeostatic function by preventing disturbances
of acidbase balance to protect enzyme function and metabolic processes,
the underlying regulation of acidbase balance is not well understood.
In fact, because digestion is associated with large metabolic increments it is
possible that the rise in PaCO2 merely reflects
an ineffective ventilatory compensation to the increased metabolic rate that
fortuitously acts to regulate pHa. As an alternative, it has been suggested
that increased PaCO2 during digestion in humans
is caused by the induction of a more relaxed state with low responsiveness to
ventilatory stimuli (e.g. Higgins,
1914), as has been observed during sleep.
To study whether pHa or PCO2 constitute the
regulated variable during digestion, we used pharmacological inhibition of
gastric acid secretion. We studied the snake Boa constrictor because
it is able to ingest large meals and exhibits large postprandial ncreases in
metabolism (Secor and Diamond,
2000; Toledo et al.,
2003
). Gastric acid secretion was inhibited by oral administration
of the specific proton-pump inhibitor omeprazole. Omeprazole is a weak base
with a pKa of about 4 that concentrates in acidic compartments, such as the
secretory canaliculus of the parietal cells, where it undergoes an
acid-catalysed transformation to a sulphonamide
(Fellenius et al., 1981
;
Sachs et al., 1995
;
Huang and Hunt, 2001
). The
converted sulphonamide reacts with cysteine groups of the
H+,K+-ATPase and leads to specific inhibition of gastric
acid secretion (Fellenius et al.,
1981
; Sachs et al.,
1995
; Huang and Hunt,
2001
). Hence, administration of omeprazole should greatly diminish
the postprandial rise in plasma HCO3. If
inhibition of the alkaline tide also abolishes the postprandial rise in
PaCO2, in spite of increased metabolism, it
would appear that the relative hypoventilation normally observed during
digestion represents regulation of pHa. If, however,
PaCO2 increases in the absence of an alkaline
tide, it would seem that the postprandial period is associated with a
state-dependent increase in the PaCO2-set-point
for ventilatory regulation.
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Materials and methods |
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Administration of omeprazole
Eleven snakes were treated with omeprazole to inhibit gastric acid
secretion. Omeprazole was dissolved in methylcellulose (1.5%) and
administrated orally through a soft rubber tube inserted into the stomach
through the mouth. We applied a dose of 60 µmol kg1 (22
mg kg1, given as 2 ml kg1 snake) every 48
h for 8 days (i.e. four administrations). A final dose was administered a few
hours before feeding.
Measurements of the rate of oxygen uptake during digestion
Rates of O2 uptake
(O2) were
measured during fasting and after ingestion in a group of untreated animals
and a group of snakes treated with omeprazole. Both groups ingested rodent
meals of 30±3% of their body mass. Having determined the mass of the
fasting snakes, they were placed in hermetically closed respirometers with a
volume of 11.5 l maintained within a climatic chamber (Fanem, SP,
Brazil) kept at 30°C throughout the experiment.
O2 of individual
snakes was measured continuously for no less than 24 h prior to feeding. This
period provided stable and repeatable values for
O2 that were
averaged to obtain resting metabolic rate (RMR). Occasional high values for
O2 that
reflected spontaneous activity were eliminated. Following respirometry, the
chambers were opened and the snakes were offered live rats that they readily
killed by constriction. Following ingestion, the metabolic measurements were
continued until
O2 had returned
to RMR levels.
O2 was
measured by an automised, intermittently closed, respirometry system (Sable
System, TR-RM8; Salt Lake City, UT, USA). Briefly, the system was programmed
to ventilate each respirometer with fresh air (open phase) for 70 min, while
measuring the rate of oxygen depletion during a 10 min closed phase while dry
air (water vapour had been removed with drierite) was re-circulated through an
oxygen analyser (PA-1, Sable System). The output from the gas analyser was
collected on data acquisition system (Sable System, DATACAN V) and
O2 was
calculated from the rate at which the oxygen concentration decreased during
the closed phase. The rate of decay was linear, with r2
>0.9.
During digestion, body mass increases as food is assimilated. To calculate
mass-specific O2
rates, we assumed that assimilation amounted to 50% of the ingested meal and
that the snake's body mass increased linearly over the initial 10 days (for a
discussion of these assumptions, see
Overgaard et al., 2002
).
Arterial cannulation
Six untreated and six omeprazole-treated snakes were surgically
catheterised for determination of arterial blood gases. The surgery was
performed under CO2 anaesthesia (see
Wang et al., 1993). When the
animals no longer responded to pinching of the skin, the vertebral artery or
the caudal portion of the dorsal aorta was accessed through a 5 cm
ventrolateral incision. The vessels were cannulated occlusively with PE90
containing heparinised saline and catheters were excised through the back and
secured to the skin with sutures. This procedure took 2030 min and all
animals appeared to regain normal activity levels within an hour after
surgery. Each snake was given an intraperitonial injection of antibiotic
enrofloxacin (Baytril®; 23 mg kg1) to prevent
infection and was allowed to recover for a minimum of 18 h at 30°C before
blood samples were taken.
Experimental protocol for blood gas determinations during digestion
Snakes were maintained individually within plastic boxes (60 cmx30
cmx15 cm) at 30±1°C (the preferred body temperature of
Boa constrictor; McGinnis and
Moore, 1969) within a temperature-controlled chamber. To minimise
disturbance of the snakes, the catheters were passed through an opening in the
top of the box and out of the climatic chamber at least 60 min prior to blood
sampling. When blood samples had been collected from fasting snakes, each
snake was fed a meal of freshly killed rats, which they struck and constricted
before swallowing. The snakes normally ate two rats, and the meals constituted
28±7% (range 1845%) of body mass. Some of the omeprazole-treated
snakes did not eat voluntarily and had to be force-fed.
Measurements of arterial acidbase parameters, PO2 and haematocrit
All blood samples (0.81.0 ml) were sampled anaerobically and
analysed within 2 min after being collected. Blood pH was measured with a
capillary pH electrode connected to a PHM 73 (Radiometer, Copenhagen, Denmark)
maintained at 30°C in a BMS Mk 3 electrode unit (Radiometer). The pH
electrode was calibrated several times a day with Radiometer precision buffers
(S1500 and S1510). Total CO2 content of freshly separated plasma
(ct[CO2]pl) was measured according to Cameron
(1971). Arterial
PCO2 (PaCO2) was
calculated using the rearranged HendersonHasselbalch equation:
![]() | (1) |
![]() | (2) |
Data analysis and statistics
Effects of digestion on blood gas composition and oxygen consumption,
within each set of experimental treatments, were analysed with a one-way
analysis of variance (ANOVA) for repeated measures, followed by a post
hoc StudentNewmanKeuls test to identify means that were
significantly different. Differences in fasting values for untreated control
snakes and snakes treated with omeprazole were compared with a Student's
t-test. A Student's t-test was also used when comparing
maximal metabolic changes during digestion in untreated and omeprazole-treated
snakes. Differences were considered to be statistically significant when
P<0.05 and all results are presented as means ± 1
S.E.M.
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Results |
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Plasma HCO3 concentration of untreated control animals increased from a fasting level of 13.9±1.0 mmol l1 to 25.9±0.9 mmol l1 within 12 h after ingestion and remained elevated for the remainder of the experiment (Fig. 2, opensymbols). Arterial pH of fasting untreated control animals was 7.519±0.016, and increased significantly to a maximal value of 7.641±0.014 at 24 h after ingestion. Digestion was also associated with a significant increase in PaCO2 from a fasting level of 16.3±0.9 to 26.4±1.1 mmHg at 12 h post feeding. Using a Davenport diagram (Fig. 3), we estimate that pHa would have increased to approximately 7.75 if PaCO2 had remained at the fasting level during digestion (see red line in Fig. 3). Conversely, to maintain pHa of the fasting level, PaCO2 would have had to increase to 34 mmHg (see blue line in Fig. 3).
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|
Fig. 2 also includes the arterial acidbase parameters of the omeprazole-treated animals. The fasting acidbase parameters of this group of snakes differed somewhat from the control group. Thus, the omeprazole-treated animals had a significantly higher pHa (7.616±0.020) as well as significantly higher PaCO2 and plasma [HCO3] (19.9±1.6 mmHg and 21.0±1.8 mmol l1, respectively) compared with untreated snakes. Following ingestion, there were no significant changes in pHa, and there only very small, and not statistically significant, increases in PaCO2 and plasma [HCO3] (Fig. 2).
There were no changes in arterial PO2 or haematocrit during digestion in any of the two experimental groups (Table 1), but haematocrit values of the untreated control snakes were significantly higher than those of the omeprazole-treated snakes.
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Discussion |
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The metabolic response to digestion
Boa exhibited the well-established rise in oxygen uptake after
feeding (e.g. Benedict, 1932;
Secor and Diamond, 1995
,
2000
;
Andrade et al., 1997
). Oxygen
uptake of untreated snakes increased three-to fourfold and reached maximal
levels of 46 ml O2 kg1
min1. The factorial increase and the peak rates are somewhat
lower than most values reported for Boa constrictor and Python
molurus following similar meal sizes at 30°C
(Secor and Diamond, 1995
;
Overgaard et al., 1999
,
2002
;
Secor et al., 2000
;
Toledo et al., 2003
). The
lower factorial scope is, at least partially, due to the relatively high RMR
in our study compared to previous measurements on Boa
(Chappell and Ellis, 1987
;
Secor and Diamond, 2000
; cf.
Toledo et al., 2003
), but
maximal
O2
during digestion was lower than reported by Secor and Diamond
(2000
) (see also
Toledo et al., 2003
).
RMR was lower in omeprazole-treated snakes, but because the untreated
snakes had a lower mass than the omeprazole-treated snakes, it is unlikely
that the difference in RMR is due a direct effect of omeprazole.
Omeprazole-treated animals were able to digest the ingested prey and the
factorial increase in metabolism was similar to that of untreated animals.
However, maximal
O2 occurred
somewhat later in omeprazole-treated snakes, which may reflect a lower rate of
food degradation within the stomach in the absence of acid secretion. In
mammals, the rate and efficiency of digestion is not markedly affected by
omeprazole (e.g. Evenopoel,
2001
), and it has been suggested that gastric acid secretion is
more important for reducing infections transmitted over the gut than for
digestion (e.g. Sanford,
1992
). However, in snakes and other animals that ingest large and
intact prey, it seems likely that gastric acid secretion serves an important
role in digestion and by initiating the breakdown of the large meals within
the stomach.
Secor (2003) recently
estimated that gastric production and secretion of HCl and enzymes account for
more than half of the energetic costs of digestion in Python. In this
case, one would expect that inhibition of gastric acid secretion should
significantly reduce SDA of omeprazole-treated snakes. However, since it is
possible that gastric acid secretion was restored later into the digestive
period, our study may not be able to reveal anything about the costs of
gastric function during digestion.
Effects of digestion on arterial acidbase parameters and oxygen levels
The changes in arterial acidbase balance during the postprandial
period are consistent with previous studies on snakes and other ectothermic
air-breathing vertebrates (Wang et al.,
1995,
2001
;
Overgaard et al., 1999
; Busk
et al.,
2000a
,b
;
Overgaard and Wang, 2002
;
Andersen and Wang, 2003
).
Plasma HCO3 concentration of untreated snakes
increased by approximately 13 mmol l1
(Fig. 2). This is larger than
the 6 mmol l1 increase that has been observed previously in
similarly-sized Python (Overgaard
and Wang, 2002
; see also
Overgaard et al., 1999
), but
similar to that observed in Alligator, Rana and Bufo (Busk
et al.,
2000a
,b
;
Andersen and Wang, 2003
). The
alkaline tide of Boa lasted considerably longer than in
Python, where most of the acidbase changes occur within the
first 48 h after ingestion (Overgaard et
al., 1999
). The magnitude of the alkaline tide represents the
temporal and quantitative difference in gastric acid secretion and the
subsequent base output by the pancreas and the intestine when food is passed
from the stomach to the intestine. It is possible that Boa and
Python differ in the speed at which these processes proceed. Indeed,
it seems that Python does pass a larger portion of meal to the
intestine within the initial 24 h of digestion compared to Boa
(Secor and Diamond, 2000
).
In spite of the increased plasma HCO3
concentration, pHa only increased by 0.12 pH units because the elevated
PaCO2 countered the metabolic alkalosis. A
similar pattern has been observed in all studies on amphibians and reptiles
where blood samples were obtained through chronic cannulation on minimally
disturbed animals (Wang et al.,
1995,
2001
;
Overgaard et al., 1999
; Busk
et al.,
2000a
,b
;
Overgaard and Wang, 2002
). A
smaller, but qualitatively similar respiratory compensation, has also been
observed in cats (Ou and Tenney,
1974
) and humans (e.g.
Higgins, 1914
;
Erdt, 1915
;
Van Slyke et al., 1917
). The
increased PaCO2 seems to be caused by a
relative hypoventilation, where lung ventilation does not increase
proportionally to CO2 production
(Glass et al., 1979
;
Wang et al., 1995
;
Hicks et al., 2000
;
Secor et al., 2000
). We have
previously speculated that the relative hypoventilation implies that
amphibians and reptiles control pHa and not
PaCO2 during the postprandial period (e.g.
Wang et al., 2001
).
The relatively low PaO2 of Boa is
common for reptiles and can be explained by admixture of systemic venous blood
to the arterial blood within the undivided ventricle (Right-to-Left
(RL) cardiac shunt; e.g. Wang and
Hicks, 1996). The sizable RL cardiac shunt of reptiles
means that PaCO2 and
PaO2 are determined by different parameters, so
that PaCO2 can increase without concomitant
decreases of PaO2. Thus, because the
capacitance of CO2 in blood is much higher than that of oxygen,
PaCO2 is primarily determined by lung
PCO2, whereas
PaO2 is primarily determined by the degree of
admixture and venous oxygen levels (reviewed by
Wang and Hicks, 1996
;
Wang et al., 2001
).
Effects of inhibiting gastric acid secretion on arterial acidbase status during fast and digestion
Fasting omeprazole-treated animals had higher pH,
PaCO2 and plasma
HCO3 concentration than untreated control snakes.
While this may be a direct effect of omeprazole on acidbase balance of
fasting animals, it may also be caused by seasonal changes since the two sets
of experiments were conducted at different times of the year. In rats,
omeprazole treatment over several months does not affect arterial
acidbase status (T. Wang, P. Norlen and R. Haakanson, personal
observation). Irrespective of the differences in acidbase status of
fasting snakes, omeprazole greatly reduced the changes in arterial
acidbase parameters seen during digestion. The marked reduction of the
alkaline tide is consistent with omeprazole being effective in blocking
gastric acid secretion. If gastric acid secretion was completely blocked by
omeprazole, it may have been expected that the snakes would display a
postprandial decrease in plasma HCO3
concentration (i.e. decreased SID) as pancreatic base production is stimulated
by the entrance of chyme to the intestine. Part of the increased pancreatic
base output during digestion occurs in response to acidification of the small
intestine, but in some mammals, the base output increases even when gastric
acid secretion is inhibited (Vaziri et
al., 1980). As discussed previously, we cannot ascertain whether
gastric acid secretion was fully blocked and it is possible that the stable
plasma HCO3 concentration throughout digestion
reflect equimolar gastric acid output and pancreatic base secretion.
Inhibition of gastric acid secretion and the alkaline tide abolished the
postprandial increase in PaCO2 even though
metabolic rate increased similarly to untreated control snakes
(Fig. 1). Thus, the increased
PaCO2 during digestion is not caused by
inefficient ventilatory response to elevated metabolism, or a more relaxed
state during the postprandial period
(Higgins, 1914). Instead, our
data strongly suggest that the ventilatory compensation of the alkaline tide
represents a regulated response that serves to maintain pHa and not
PaCO2.
The ventilatory responses to acidbase disturbances in reptiles are
complex and involve different receptors (e.g.
Milsom, 1995), and all of
these may be involved in the respiratory compensation during digestion. It is
not well known whether reptiles regulate pH or
PCO2, but immediately after an acutely imposed
acidosis by exercise or infusion of lactic acid in resting lizards, it seems
that ventilation is geared towards regulation of
PaCO2
(Mitchell and Gleeson, 1985
).
However, with chronic alkalosis by systemic infusion of bicabonate, pHa seems
to be regulated (Jackson,
1969
). Central chemoreceptors exert an important contribution to
ventilatory responses to acidbase disturbances in reptiles
(Hitzig and Jackson, 1978
;
Branco and Wood, 1993
). In
mammals, the central chemoreceptor is not as sensitive to metabolic
acidbase disturbances of arterial blood as they are to respiratory
disturbances, because the bloodbrain barrier, separating blood from the
cerebrospinal fluid (CSF), is rather impermeable to ions, but permeable to
CO2 (e.g. Fencl,
1986
). It is likely that a similar mechanism operates in reptiles,
but the slow time course of the alkaline tide may allow for the metabolic
alkalosis to be transmitted from the blood to the CSF. Alternatively, it is
possible that pH-sensitive peripheral chemoreceptors contribute to the
ventilation compensation. Finally, elevated lung and endtidal
PCO2 during digestion may stimulate lung and
upper airway receptors that may regulate ventilation whenever metabolic rate
is increased (e.g. Furilla,
1991
; Furilla et al.,
1991
). Clearly the role of the different receptors needs to be
further understood to provide a mechanistic explanation of the regulation of
arterial pH during digestion in snakes.
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Acknowledgments |
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