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First published online May 8, 2007
Journal of Experimental Biology 210, 1687-1699 (2007)
Published by The Company of Biologists 2007
doi: 10.1242/jeb.001925
Review Article |
Tribute to P. L. Lutz: cardiac performance and cardiovascular regulation during anoxia/hypoxia in freshwater turtles
1 National Environmental Research Institute, Aarhus University, Silkeborg,
Denmark
2 Department of Zoophysiology, Aarhus University, 8000 Aarhus C,
Denmark
* Author for correspondence (e-mail: tobias.wang{at}biology.au.dk)
Accepted 5 February 2007
 |
Summary |
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 TOP Summary The anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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Key words: reptile, overwintering, hibernation, heart rate
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The anoxia tolerant turtle |
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TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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). Because of the
very low metabolic rate, induced by low temperature and entrance to a
hypometabolic state, cutaneous gas exchange can partially or fully suffice to
maintain aerobic respiration when the water is normoxic
(Belkin, 1968a;
Ultsch, 1985;
Herbert and Jackson, 1985a;
Jackson et al., 2001;
Jackson et al., 2004;
Ultsch, 2006). However, when
the overwintering turtles encounter low oxygen levels or complete anoxia in
the water, anaerobic metabolism is pivotal for maintaining physiological
functions. Not surprisingly, these species of freshwater turtles are endowed
with extraordinary capacities for surviving the lack of oxygen. Indeed,
several species of freshwater turtles can survive for months in cold anoxic
water (e.g. Ultsch and Jackson,
1982; Ultsch,
1985; Ultsch et al.,
1999; Jackson,
2000; Reese et al.,
2002; Ultsch,
2006). Thus, together with the Crucian carp, which survives
prolonged anoxia during the winter in Scandinavian lakes, freshwater turtles
exhibit the highest known anoxia tolerance among vertebrates
(Lutz and Nilsson, 1997).
Due to their exceptional anoxia tolerance, freshwater turtles have
frequently been used as `August Krogh' animals to investigate mechanisms that
confer anoxia tolerance. Most of these studies have been performed on the
painted turtle C. picta and the red-eared slider T. scripta.
In contrast to Crucian carp, which maintains physical activity when exposed to
prolonged anoxia, the turtles become lethargic and are in a near-comatose
state where energy expenditure on many physiological functions is greatly
reduced (Lutz and Nilsson,
1997; Jackson,
2000). Turtles reduce their metabolic rate tenfold during anoxia
(Jackson and Schmidt-Nielsen,
1966; Jackson,
1968), and a similar anoxic depression of metabolism has also been
characterised in isolated hepatocytes
(Buck and Hochachka, 1993).
Apart from the direct savings from avoiding physical activity, anoxia is also
associated with marked reductions in activities of ion-motive ATPases in the
membrane and in protein synthesis (Buck
and Hochachka, 1993; Hochachka
et al., 1996; Jackson,
2000; Fraser et al.,
2001). The heart, nevertheless, continues to pump and transport
nutrients, hormones and waste products between the various organs of the body,
although heart rate and cardiac work are severely reduced
(Herbert and Jackson, 1985a;
Hicks and Wang, 1998;
Hicks and Farrell, 2000a;
Stecyk et al., 2004).
For obvious reasons the nervous and cardiovascular systems have received
most interest in the hypoxic turtle. Peter Lutz's research primarily
contributed to our understanding of the sustained nervous function in the
absence of oxygen. However, the tight correlation to continued cardiovascular
function is nicely illustrated by the finding that pulmonary ventilation,
reflecting continued function of the central nervous system, continues 14
times longer in anoxic turtles with an intact cardiovascular system compared
with turtles where blood flow was artificially stopped
(Belkin, 1968b). Here we review
the mechanism that allows the turtle heart to continue to function under
anoxic conditions.
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Comparative hypoxia tolerance of cardiac function |
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TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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;
Wasser, 1996;
Boutilier and St-Pierre, 2000;
Boutilier, 2001). While these
mechanisms appear qualitatively similar among vertebrates, they differ
quantitatively and temporarily, and there are large variations in the extent
to which vertebrates can maintain physiological functions during and following
severe oxygen lack.
The variability in the effects of anoxia on cardiac contraction is
illustrated in Fig. 1, where
the relative reduction in twitch force developed by isolated and electrically
paced cardiac strips during anoxia is shown for various vertebrates. The
turtle is among the best at preserving contractility during anoxia. However,
the European viper, which hibernates at low temperature, also possesses a
heart muscle with a pronounced anoxia tolerance, although it is unlikely that
it experiences hypoxia during hibernation
(Gesser and Poupa, 1978). In
contrast, the heart muscle from tropical species, pythons and alligators, is
much more sensitive (Zaar et al.,
2007) (H.G. and T.W., unpublished results). It might therefore be
speculated that the tolerance to oxygen lack in turtle and viper hearts
represents an adaptation to hibernation at low temperature, as it does not
seem to be a general feature of the reptilian heart. Similarly, the anoxia
tolerance of the edible frog was higher than that of the tropical Bufo
marinus, and within fish, the best-preserved performance was found in
species known to have a high hypoxia tolerance. A comparison within reptiles
also indicates that diving reptiles, where hypoxia may develop during
prolonged breath-hold diving, are not necessarily endowed with a high cardiac
anoxia tolerance, since the ventricle of the American alligator exhibits a low
tolerance to oxygen lack (H.G. and T.W., unpublished results). Clearly, the
anoxia tolerance of hearts from more reptiles with different natural histories
needs to be studied and analysed within an appropriate phylogenetic context.
Interestingly, in a comparison of the anoxia tolerance of more than 60 species
of reptiles, assessed as the time in which ventilation persisted in an
oxygen-free atmosphere, Belkin (Belkin,
1963) found that turtles were much more tolerant than other
reptiles. However, because anoxia tolerance was common to both terrestrial and
aquatic species, he concluded that the exceptional anoxia tolerance of turtles
is of taxonomic origin rather than being based on natural history, and he also
suggested that the high plasma buffer values of turtles could be of
importance.
Within a single species, differences in anoxia tolerance may also exist
between the two sides of the ventricle because oxygen-poor blood from the
systemic veins largely enters the cavum pulmonale, while oxygenated blood
returning from the lungs predominately enters the cavum arteriosum. The
differences in in vivo oxygenation of the two parts of the ventricle
should be particularly pronounced in animals with anatomical or functional
separation of the ventricles, but in neither pythons nor alligators was it
possible to discern differences in the hypoxia tolerance in isolated
ventricular strips from the two sides of the heart
(Fig. 1)
(Zaar et al., 2007) (H.G. and
T.W., unpublished).
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Energetic and cardiac requirement during anoxia |
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TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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).
This may be due to cessation of protein synthesis during anoxia
(Fraser et al., 2001), but
other mechanisms may also contribute. The metabolic depression of the cardiac
myocytes is accompanied by a comparable reduction of functional demand on the
heart, which lowers the amount of energy required for the contractile proteins
and ATPases. There is probably a cellular hierarchy so that some energy
demanding processes such as protein synthesis might be downregulated to a
disproportionately large extent or even put on stand-by during anoxia
(Hochachka et al., 1996;
Fraser et al., 2001;
Boutilier, 2001;
Jackson, 2002), whereas
processes crucial for cell survival such as the Ca2+ homeostasis
are excellently defended (Wasser,
1996). Fig. 2
illustrates how energy producing and energy consuming processes are affected
by the transition from oxygenated to anoxic conditions. Overall, it seems that
energy consumption of the anoxic turtle is depressed sufficiently to
compensate for the tenfold reduction in ATP production mol–1
glucose that accompanies the transition from aerobic to anaerobic metabolism.
Accordingly, it has been suggested that downregulation of energy consumption
rather than the capacity for anaerobic metabolism explains the hypoxic
tolerance of the turtle heart (e.g.
Farrell et al., 1994).
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In vivo cardiovascular performance in anoxic turtles |
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TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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), who
documented a slow onset of bradycardia upon enforced submersion in anoxic
water over 24 h at 22°C. The slow decline in heart rate differs from
voluntarily diving turtles, where heart rate decreases immediately upon
submersion (e.g. White and Ross,
1966; Wang and Hicks,
1996), and can most likely be ascribed to physical activity and
stress. Despite the differences between voluntary and enforced diving at the
onset of submersion, most studies on the effects on cardiovascular function
during anoxia have been performed on forcefully submerged turtles. While the
cardiovascular status manifested when the turtles have become inactive or even
comatose is unlikely to differ between voluntary and forced submersion, the
initial phase is undoubtedly influenced by the manner in which the experiment
is performed.
There is a progressive decline of the heart rate and arterial pressure in
anoxic turtles at temperatures between 3 and 20°C
(Herbert and Jackson, 1985a).
Heart rate declined at all temperatures, but bradycardia develops slower at
low temperatures, which is consistent with the lower metabolism allowing for a
longer survival time and a larger anoxia tolerance
(Musacchia, 1959;
Herbert and Jackson, 1985a;
Herbert and Jackson, 1985b).
Similar effects of temperature have been reported in subsequent studies on
intact turtles (Hicks and Farrell,
2000a; Stecyk et al.,
2004), and in situ perfused hearts of turtles and other
ectothermic vertebrates (Farrell et al.,
1994; Overgaard et al.,
2004). The bradycardia causes reductions in systemic blood flow as
stroke volume remains relatively unchanged, and anoxia is associated with a
complete cessation of pulmonary blood flow
(Millen et al., 1964;
Hicks and Wang, 1998;
Hicks and Farrell, 2000a;
Hicks and Farrell, 2000b;
Stecyk et al., 2004). The
constriction of the pulmonary vascular bed is not due to increased vagal
activity, because atropine is without effect on pulmonary blood flow in the
anoxic turtle (Hicks and Wang,
1998). Thus, it is most likely explained by hypoxic pulmonary
vasoconstriction within the peripheral circulation of the lungs
(Crossley et al., 1998). The
benefit of this response may be to save energy otherwise used to perfuse the
lungs during the anoxic period where pulmonary oxygen uptake is
impossible.
Examples of heart rate as well as flow, pressure and resistance in the
systemic circulation of turtles exposed to anoxia at low temperature are shown
in Fig. 3. Apart from the
hypoxic bradycardia and the decline in systemic blood flow, anoxia only causes
a slight hypotension because systemic vascular resistance increases
several-fold. This rise in resistance has been shown in several studies and
occurs over a broad range of temperatures
(Hicks and Farrell, 2000a;
Hicks and Farrell, 2000b;
Stecyk et al., 2004), and is
probably to prevent systemic pressure declining below the critical closing
pressure. The mechanisms underlying the systemic vasoconstriction have not
been identified and cannot be explained by an increased sympathetic tone on
-adrenergic receptors, although the sympathetic tone may contribute at
high temperatures (Stecyk et al.,
2004). It is unlikely that the tone of endogenously produced
nitric oxide is so high that cessation of NO synthesis during anoxia can
explain the marked constriction, and endothelin does not appear to mediate
constriction in turtles (Crossley et al.,
2000; Skovgaard et al.,
2005). Also, while anoxia per se clearly leads to
constriction of systemic blood vessels from some ectothermic vertebrates
(Olson et al., 2001), the
systemic vasculature of anaesthetised turtles vasodilates upon short exposure
to hypoxia (Crossley et al.,
1998). Nevertheless, it would be of considerable interest to study
the effects of anoxia on systemic resistance vessels from turtles using a
myograph. It is possible that a passive lowering of the diameter of the
resistance vessels in response to the lower systemic blood pressure
contributes and that the systemic circulation, in that sense, behaves as a
Starling resistor. This possibility could be investigated through artificial
perfusion of the systemic vasculature.
|
). Blood
flows to digestive and urogenital organs were reduced as previously shown in
anaesthetised turtles (Davies,
1989), which is consistent with marked reduction of renal function
in anoxia (Warburton and Jackson,
1991; Jackson et al.,
1996). In cold anoxic turtles the relative proportion of perfusion
of the shell increased, and so did the relative perfusion of the liver. These
results indicate that perfusion of the liver, which is the major glycogen
store, is important for the anaerobic metabolism during anoxia (see
Warren et al., 2006).
Likewise, the increased perfusion of the shell fits nicely with its role in
buffering the lactate acidosis by carbonates and the direct complex binding of
lactate within the shell (reviewed by
Jackson, 2000;
Jackson, 2002)
(Fig. 2). The cold anoxic
turtles did not increase relative or absolute perfusion of the brain or the
myocardium (Stecyk et al.,
2004), which differs from previous studies on anaesthetised
turtles (Davies, 1989;
Davies, 1991;
Bickler, 1992;
Hylland et al., 1994;
Hylland et al., 1996).
|
; Hicks and Farrell,
2000b) (Fig. 4).
The parasympathetic tones, however, are not larger than in normoxic animals.
Similarly, while inhibition of cardiac ß-receptors also slows the heart
in both normoxic and anoxic turtles, the anoxic bradycardia cannot be
explained by a reduced sympathetic tone. The density of ventricular
ß-receptors, nevertheless, is reduced during anoxia, but the marked rise
in circulating levels of catecholamines may obliterate the effects of this
downregulation (Wasser and Jackson,
1991; Keiver et al.,
1992; Hicks and Farrell,
2000b). The autonomic modulation of the heart was even less
pronounced at low temperature (Hicks and
Farrell, 2000b), and the most pronounced contribution to the
anoxic bradycardia, therefore, appears to be a reduction in pacemaker
activity.
A direct inhibition of the pacemaker by anoxia is strongly indicated from
the marked reduction in the intrinsic heart rate during anoxia
(Hicks and Farrell, 2000b). As
shown in Fig. 4, heart rate
after the combination of parasympathetic and sympathetic blockade is markedly
lower in anoxic turtles. This indicates a decline in pacemaker activity.
Clearly, the mechanism underlying this reduction in pacemaker activity would
be interesting to characterise. The direct inotropic effects of anoxia on the
pacemaker have been revealed from recording of heart rates of isolated and
in vitro or in situ perfused hearts where all nerves
innervating the heart have been severed. While all such studies concur that
anoxia slows heart rate, the variability of the response varies considerably
among studies and ranges from having small effects (e.g.
Farrell et al., 1994;
Bailey and Driedzic, 1995), to
reducing heart rate by more than 25%
(Reeves, 1963;
Wasser et al., 1990b) to
reducing heart rate by approximately 75%
(Wasser et al., 1997). Some
of this variability may be caused by damage to the pacemaker region within the
sinus venosus when the hearts are isolated and/or excised for perfusion, but
it is also likely that differences in filling pressures and outflow pressures,
as well as acid–base status and ionic composition of the perfusate,
explain a large part of the variability. Contractions of stimulated isolated
ventricular strips, for instance, became unstable and irregular during high
extracellular potassium, indicating a loss of excitability
(Overgaard et al., 2005).
Furthermore, isolated but spontaneously contracting ventricular strips reduce
the rate of contraction by approximately 50% when exposed to anoxia, but the
slowing of the contractions is greatly alleviated if the Ca2+
concentration is increased from 1 to 10 mmol l–1
(Wasser et al., 1990b).
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;
Wasser et al., 1997). |
Cardiac performance of the anoxic turtle heart: intra- and extracellular effects |
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TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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; Jackson,
2002). Here the origin for these changes is summarised in
Fig. 2 and the progressive
development of change versus time is shown in
Fig. 5. Although metabolic
depression is associated with a decreased membrane permeability and lower
nervous activity (cf. Hochachka et al.,
1996; Jackson,
2002), ion homeostasis is disturbed and leads to a gradual rise in
extracellular potassium (Fig.
5), causing a progressive depolarisation
(Jackson and Ultsch, 1982;
Reese et al., 2002;
Nielsen and Gesser, 2001). The
continued anaerobic metabolism acidifies the extracellular compartment by more
than one pH unit (Fig. 5), and
the intracellular pH of most organs, including the heart, also decreases
(Ultsch and Jackson, 1982;
Herbert and Jackson, 1985a;
Herbert and Jackson, 1985b;
Wasser et al., 1990a;
Ultsch, 2006). Some of the
acidosis is buffered by magnesium and calcium carbonate in the shell, which
causes a progressive rise in extracellular Ca2+ and Mg2+
concentrations (Figs 2,
5)
(Jackson and Heisler, 1982).
All in all, the extracellular disturbance during long-term anoxia includes
increased concentrations of H+, Ca2+, Mg2+
and K+, increased levels of circulating catecholamines, as well as
reductions in cellular energy state (Figs
2 and
5).
Several studies have investigated how the many changes in the intra- and
extracellular fluids affect cardiac performance during anoxia; some
characterised isolated effects, while others investigated simultaneous
combinations of the intra- and extracellular perturbations. These studies
reveal several clear trends, but it is also obvious that some of the effects
vary and depend on the conditions under which they are examined. Studies on
perfused hearts have the clear advantage that the hearts generate real work
and therefore mimic the in vivo conditions closely. However, if
cardiac function is compromised severely, it is more difficult to control the
extracellular conditions of the myocardium as reduced cardiac output slows
replacement of the buffer to which the heart is exposed. This problem does not
exist for ventricular or atrial preparations that are typically bathed in a
large volume of homogeneous buffer. In most studies, however, these
preparations do not perform external work, and isometric force development
must therefore be measured as a proxy for the functional capacity of the
heart. Isometrically contracting cardiac preparations do, nevertheless,
increase ATP consumption considerably while contracting, and the energetic
turnover of cardiac strips and perfused hearts may be quite similar (cf.
Farrell et al., 1994;
Overgaard and Gesser,
2004).
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Anoxia and energy state |
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TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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GATP), ATP concentrations in the turtle
heart are relatively well defended and only decreased by 10–20% during
short anoxic exposures (Wasser et al.,
1990a; Jackson et al.,
1995; Hartmund and Gesser,
1996; Overgaard and Gesser,
2004). A decreased energy state is, therefore, more evident from
the reduction in the PCr/Cr2 ratio, which is a more sensitive
estimate of the energy state (cf. Meyer,
1988). In comparison with both mammals and other ectothermic
vertebrates, the anoxic turtle heart maintains cellular energy state very well
(Wasser, 1996;
Hartmund and Gesser, 1996).
The red-eared slider, for example, was considerably better at maintaining
cellular energy state than eel, rainbow trout or cod in electrically paced
ventricular strips exposed to either 30 min or 70 min of anoxia
(Hartmund and Gesser, 1996;
Overgaard and Gesser, 2004).
The ability to maintain a high energy state is likely to be important for the
preserved anoxic performance of turtle hearts, as the relation of twitch force
to cellular energy state seems to be similar between species
(Hartmund and Gesser, 1996).
Given the ability of the turtle heart to limit the basic cellular energy
expenditure during anoxia (i.e. that not relating to contraction), it
maintains contractile function at an overall low energetic cost
(Overgaard and Gesser, 2004).
The apparent reduction in the cost of force production is, however, primarily
a consequence of a reduced basal metabolism, as studies have showed that the
direct energetic cost of contraction was equal in hypoxia and normoxia
(Reeves, 1963;
Arthur et al., 1997).
Even though turtles perform comparatively well during anoxia, cardiac
performance is still reduced by 20–50% of the normoxic level
(Fig. 1). This reduction is
likely due to the combination of intracellular acidosis, lowered
phosphorylation potential and increased levels of free phosphate
(Pi) (e.g. Allen et al.,
1985; Godt and Nosek,
1989; Hartmund and Gesser,
1996). High levels of inorganic phosphates generally depressed
force developed by actin–myosin bridges
(Cooke and Pate, 1985) and
reduced Ca2+ sensitivity of the myofilaments
(Bers, 1991;
Driedzic and Gesser, 1994;
Fukuda et al., 2001), which
would be accentuated by the concomitant intracellular acidification. In
turtles, however, the effect of free phosphate may be relatively small
(Jensen and Gesser, 1999).
Furthermore, decreases in energy state in turtles only elicit a minor release
of free phosphate as the phosphocreatine stores of turtle hearts are
relatively small compared to those of other ectothermic vertebrates
(Christensen et al., 1994).
Finally, turtles show an excellent defense of the cellular Ca2+
homeostasis during anoxia (Wasser,
1996; Wasser and Heisler,
1997) and also have an ability to attenuate formation of rigor
complexes, as seen from the very limited increase in resting tension of anoxic
ventricular strips from turtle hearts where glycolysis has been blocked
(Hartmund and Gesser,
1996).
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Metabolic capacities during anoxia and normoxia |
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TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
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). Myocardial
energy liberation is almost exclusively mitochondrial when sufficient oxygen
is available, whereas glycolysis becomes dominant during oxygen lack
(Reeves, 1963;
Arthur et al., 1997;
Overgaard and Gesser, 2004)
(Fig. 2). In accordance with
this, there is a positive correlation between the cardiac anoxia tolerance in
different species and their ratio of pyruvate kinase to cytochrome oxidase
activities (Gesser and Poupa,
1974). In a separate study, the turtle heart had the highest PK/CO
activity ratio among 13 vertebrates studied under identical experimental
conditions (Christensen et al.,
1994). A high ratio is not a general reptilian trait, and
Python, for example, has a much lower ratio between pyruvate kinase
and cytchrome oxidase activities (Zaar et
al., 2007). The hearts of Crucian carp and hagfish, both of which
are very hypoxia tolerant, also have high ratios
(Christensen et al., 1994).
Furthermore, turtle, hagfish and Crucian carp have high cardiac creatine
kinase activities relative to that of cytochrome oxidase
(Christensen et al., 1994).
While the functional importance of this observation remains somewhat elusive,
it may relate to the temporal buffering of ATP and the facilitated transport
of ATP and ADP within the cell provided by creatine kinase
(Meyer et al., 1984;
Saks et al., 2001;
Birkedal and Gesser, 2003).
The role of creatine kinase seems to be of particular importance during
long-lasting hypoxia to counteract local reduction in energy state at the
ATPase sites as well as formation of rigor complexes
(Veksler et al., 1997).
As suggested by studies of the enzyme complement
(Christensen et al., 1994),
the turtle heart has a glycolytic capacity, which is comparatively high
relative to the aerobic capacity. However, the glycolytic capacity in absolute
terms is not extraordinarily high and it is, furthermore, questionable if the
turtle heart uses this capacity to its full extent during anoxia. As already
mentioned, both cardiac work and metabolic rate are reduced by approximately
one order of magnitude. As this is similar to the magnitude of the reduction
in ATP production when changing from aerobic to anaerobic metabolism
(Fig. 2), it seems that
freshwater turtles have no immediate need for an extraordinary glycolytic
capacity to support ATP production. Even so, the proportionally high
glycolytic capacity of turtles compared to other ectothermic vertebrates may
reflect an excess capacity for ATP production during these adverse conditions,
and it may also help to maintain a relatively high energetic state locally in
the cell.
Acidosis
Acidosis can depress glycolytic activity, impair the
excitation–contraction (E–C) coupling and exert negative effects
directly at the contractile apparatus
(Steenbergen et al., 1977;
Orchard and Kentish, 1990;
Bers, 1991;
Bers, 2002). Thus, acidosis
markedly depresses twitch force in most fish species, while the effects on
many air-breathing ectotherms are less pronounced and may depend on whether
the acidosis is metabolic or respiratory in origin
(Driedzic and Gesser, 1994;
Gesser and Poupa, 1983). As
seen in Table 1 and
Fig. 6, the effects of acidosis
are generally small in freshwater turtles, ranging from a 35% depression to an
unchanged force production in some studies. Overgaard et al.
(Overgaard et al., 2005) found
no effect of lactic acidosis at 25°C, while a similar reduction in pH
significantly reduced twitch force at 5°C. Thus, it is possible that
acidosis impairs contractility more during overwintering than at higher
temperatures. More importantly, acidosis typically occurs together with anoxia
during anoxic submergence. Under such conditions, the extracellular lactic
acidosis will exacerbate the intracellular acidosis caused by anaerobic
metabolism. Severe acidosis may partially inhibit glycolysis and thereby cause
reductions in cellular energy state. Indeed, when acidosis and anoxia occur
simultaneously, they depress contractility, intracellular pH and energy state
in a synergistic manner so that function is typically depressed to around
25–30% of control values (Table
1) (Shi and Jackson,
1997; Shi et al.,
1999; Wasser et al.,
1990a; Jackson et al.,
1995; Bobb and Jackson,
2005). This force depression can, however, be moderated slightly
when the extracellular Ca2+ concentration is elevated to mimic the
in vivo conditions (Yee and
Jackson, 1984; Shi et al.,
1999; Wasser et al.,
1990a).
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Hyperkalemia
Several recent studies show that the high extracellular concentrations of
potassium occurring in vivo after extended periods of anoxic
hibernation severely depress twitch force
(Nielsen and Gesser, 2001;
Kalinin and Gesser, 2002;
Overgaard et al., 2005;
Gesser, 2006)
(Table 1 and
Fig. 6). Elevated
[K+]o depolarises the membrane potential and shortens
the ventricular action potential, which reduces Ca2+ influx and
contractility (Paterson et al.,
1993; Nielsen and Gesser,
2001). In turtles an elevation of [K+]o from
2.5 to 10 mmol l–1 causes a 50–95% reduction of twitch
force of ventricular strips (Table
1), and it also results in unstable contractions and a lowering of
the maximal frequency at which regular contractions can be produced
(Nielsen and Gesser, 2001;
Kalinin and Gesser, 2002;
Overgaard et al., 2005;
Gesser, 2006). Thus, it seems
that hyperkalemia also compromises excitability of the cardiac tissue and, as
mentioned above, it is possible that this contributes to the lowering of the
heart rate during anoxia (Nielsen and
Gesser, 2001; Overgaard et
al., 2005). The reduced excitability is most likely linked to a
depolarisation and inactivation of the Na+ channels responsible for
generating the action potential (Kern et
al., 1978; Volkmann,
1983). The negative inotropic effects of hyperkalemia are more
pronounced at low temperature and also larger in cold-acclimated turtles than
in warm-acclimated turtles, which indicates that the increases in
extracellular potassium may severely limit cardiac performance during anoxia
in overwintering turtles (Overgaard et
al., 2005). In fact, hyperkalemia seems to be far the most potent
depressor of contractile force in cold anoxic turtles, and it is possible that
the progressive increase in potassium levels may ultimately compromise
sustained cardiac activity in overwintering turtles. It should, however, be
noted that T. scripta seems to be considerably less responsive to
hyperkalemia than C. picta. Thus in T. scripta, the effect
of hyperkalemia is smaller and can be almost completely removed by a high
adrenergic tone, while C. picta can only recover a small part
(Table 1,
Fig. 6)
(Nielsen and Gesser, 2001;
Overgaard et al., 2005;
Gesser, 2006).
Adrenaline, Ca2+ and Mg2+
The progressive buffering of acidosis by the carapace during long-term
anoxia leads to increased levels of free Ca2+ and Mg2+.
Increased Ca2+ levels in the extracellular fluid generally increase
cardiac contractility in turtle, in which the sarcoplasmatic reticulum is
known to play a minor role for cardiac calcium transport (Galli et al.,
2006a,b).
In contrast, elevated Mg2+ may decrease the inward Ca2+
current and thereby impair cardiac performance
(Hall and Fry, 1992). Although
a considerable amount of the Ca2+ released from the shell forms
complexes with plasma lactate, the level of free Ca2+ also
increases quickly in the cold anoxic turtle
(Jackson and Heisler, 1982)
(Fig. 6). Such an increase may
directly improve twitch force at high temperature (20°C), while the effect
was absent at low temperature (5°C)
(Overgaard et al., 2005)
(Table 1). Similarly, the
isolated effects of increased Mg2+ do not exert strong inotropic
effects (Gesser, 2006), and it
may be that these changes are more important when they occur together with
other changes in the extracellular environment associated with long-term
anoxia.
Anoxia is associated with a large increase in circulating catecholamine
levels (Wasser and Jackson,
1991; Keiver et al.,
1992). Adrenergic stimulation increases Ca2+ currents
through L-type Ca2+-channels in the sarcolemma and thereby exerts a
positive inotropic effect (Bers,
1991; Bers, 2002).
Indeed, adrenergic stimulation increases the duration of the action potential
in turtles, although this was only significant when the action potential had
previously been compromised by hyperkalemia
(Nielsen and Gesser, 2001),
and adrenaline increases twitch force in ventricular strips from
Trachemys (Ball and Hicks,
1996; Nielsen and Gesser,
2001; Overgaard et al.,
2005; Galli et al.,
2006a). These effects are consistent with the rise in stroke
volume, which occur upon adrenergic stimulation in vivo
(Overgaard et al., 2002;
Hicks and Wang, 1998). For
both adrenergic stimulation and hypercalcaemia, the potential positive effects
may be more prominent in alleviating other negative inotropic agents tending
to reduce sarcolemmal Ca2+ influx. Indeed, hypercalcemia and
adrenaline, in particular, have been shown to alleviate negative inotropic
effects of hyperkalemia, acidosis and anoxia
(Jackson, 1987;
Nielsen and Gesser, 2001; Yee
and Jackson, 1982; Overgaard et al.,
2005; Gesser,
2006).
|
Contractile performance in the cold anoxic turtle |
|---|
|
TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
|---|
;
Wasser et al., 1990b;
Jackson, 1995; Shi and Jackson,
1997; Shi et al.,
1999; Nielsen and Gesser,
2001; Overgaard et al.,
2005; Gesser,
2006), while adrenergic stimulation and hypercalcemia may salvage
contractility during hyperkalemia, acidosis or anoxia
(Gesser and Jørgensen,
1982; Yee et al., 1984; Shi et
al., 1999; Nielsen and Gesser,
2001; Overgaard et al.,
2005). In a recent study, we investigated the combined and
isolated effects of the major extracellular disturbances encountered by the
anoxic turtle heart. The results are summarized in
Fig. 6, showing that
hyperkalemia, in particular, but also acidosis and anoxia, depress twitch
force. When these three treatments are combined, less than 5% of twitch force
remains. Addition of adrenaline and high [Ca2+]o did,
however, recover force to approximately 20% of control force. This observation
supports the contention that increased Ca2+ and catecholamines
ensure cardiac performance during long-term anoxic submergence
(Jackson, 1987;
Shi et al., 1999;
Jackson, 2000). While the
reductions of contractility during cold anoxia are indeed dramatic, it should
be remembered that cardiac power output also decreases dramatically during
anoxic submergence, so that 20% of the contractility may suffice to ensure
cardiac pumping (Herbert and Jackson,
1985a; Jackson,
1987; Wasser,
1996; Hicks and Farrell,
2000a; Stecyk et al.,
2004). Of all the parameters examined, it seems that hyperkalemia
is most detrimental in terms of cardiac performance. During long-term anoxic
submergence, [K+]o actually increases above 10 mmol
l–1 in painted turtles
(Ultsch and Jackson, 1982;
Ultsch et al., 1999), and it
is possible that the progressive hyperkalemia and the ensuing depolarisation
are ultimately important for determining the limit for anoxic survival. |
Conclusion |
|---|
|
TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
|---|
|
Acknowledgments |
|---|
|
References |
|---|
|
TOPSummaryThe anoxia tolerant turtleComparative hypoxia tolerance of...Energetic and cardiac...In vivo cardiovascular...Cardiac performance of the...Anoxia and energy stateMetabolic capacities during...Contractile performance in the...ConclusionReferences |
|---|
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36 mol ATP are produced mol–1 glucose and waste
products in the form of CO2 and water are lost to the blood; Top
right: in the normoxic cell, energy is predominantly used for protein
synthesis, contractile work and ion-motive pumps such as the
Na+/K+ ATPase and the Ca2+ATPase that are
both important for contractile performance and Ca2+ transport.
Thus, the Na+ gradient established by the
Na+/K+ ATPase pump is used for the extrusion of
Ca2+ through the Na+/Ca2+ exchanger during
relaxation. The energetic state is high with a high ATP/ADP ratio and low
levels of free phosphate. Bottom left: Anaerobic respiration only produces 3
mol ATP mol–1 glucose, and the waste product lactic acid
accumulates intra- and extracellularly causing intra- and extracellular
acidification. The turtle shell buffers a considerable part of the lactic
acidosis whereby calcium- and magnesium ions are released. During anoxia,
energy state, i.e. the ATP/ADP ratio, decreases and the level of free
phosphate increases. Anoxia is associated with a general metabolic depression
due to translational arrest, spike and channel arrest. Moreover, mechanical
work is reduced. Despite channel and spike arrest, long-term anoxia in turtles
is associated with a progressive leak of K+, which accumulates in
the extracellular space and cause a depolarisation.
