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Department of Ecology and Evolutionary Biology, University of California, Irvine, California 92697-2525
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated the effects
of vagal reductions in O2 delivery on oxygen consumption
(
O2) in the anesthetized freshwater turtle Trachemys scripta. Specifically, these experiments
tested the hypothesis that reductions in arterial oxygen partial
pressure (PO2) and/or systemic oxygen transport
(SOT) trigger a metabolic downregulation. During electric stimulation
of the efferent branch of the sectioned right vagus nerve (RVEF),
systemic cardiac output decreased 60-70%, systemic
PO2 fell by ~30%, and SOT decreased by
60-70%. During RVEF simulation, O2
dropped ~35%. During control conditions, injection of the metabolic
uncoupler 2,4-dinitrophenol (DNP) more than doubled
O2, reflecting an increase in ATP
turnover. RVEF stimulation after DNP injection produced similar
cardiovascular and blood gas changes as before DNP, but
O2 was higher than the
O2 measured in untreated control
animals, indicating that oxygen availability during RVEF stimulation is
still sufficient to support O2 rates
that are even higher than resting rates. We conclude that vagal
stimulation triggers metabolic downregulation, primarily through the
effects on oxygen transport, although the factor(s) that trigger the
hypometabolism remain unknown. The PO2 may
still be an important messenger in metabolic control, but our results
suggest that changes in SOT to the metabolically active tissues, rather
than changes in PO2 per se, play an important role in triggering hypometabolism in the freshwater turtle.
oxygen consumption; metabolic rate; vagal control; 2,4-dinitrophenol
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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MOST VERTEBRATES HAVE the ability to reduce metabolic rate in response to reduction in oxygen availability (36). In endothermic vertebrates (i.e., mammals and birds) this metabolic downregulation can be achieved by reducing metabolic heat production resulting in a decrease in oxygen demands (2, 14, 36). In addition, endothermic and ectothermic vertebrates also alter thermoregulatory behavior in heterothermal environments to downregulate body temperature and reduce O2 demands (36). Although ectothermic animals lack mammalian-like physiological regulatory mechanisms for thermoregulation and rely on altered thermoregulatory behavior for thermoregulatory control in response to lower O2 levels, they still have the ability to downregulate cellular metabolism and heat production in response to anoxia (3, 11, 21, 28, 37). This metabolic downregulation (the hypometabolic state) is a regulated response that involves changes in active membrane transport and membrane permeability and downregulation of various synthetic pathways, such as protein synthesis (4, 22, 25, 26).
Many reptiles and amphibians exhibit intermittent breathing patterns with brief periods of ventilation interspersed among periods of apnea of variable duration. In turtles, large right-to-left (R-L) intracardiac shunts often develop during apnea, which causes internal hypoxia (17, 33, 34). This R-L shunt can occur rapidly (s), reducing arterial oxygen levels, increasing arterial partial pressure of carbon dioxide (PCO2) levels and decreasing pH, as a consequence of recirculated metabolically produced CO2. In a recent study by Hicks and Wang (20), it was hypothesized that the development of an R-L shunt with its ensuing reductions in arterial PO2 would induce hypometabolism. They demonstrated that progressive hypoxia induces hypometabolism in the anesthetized turtle Trachemys scripta. These authors suggest that the hypometabolic state may be an important means of oxygen conservation resulting in prolonged aerobic dive times in freshwater turtles.
In T. scripta, the rapid onset of a R-L shunt is under vagal control (19). Therefore, the aim of the present study was to test the hypothesis that vagally induced R-L shunts with the subsequent reductions in arterial oxygen partial pressure (PO2) and/or systemic oxygen transport (SOT) trigger a metabolic downregulation.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
The study was performed on freshwater red-eared sliders, T. scripta (body mass, 1.0-2.2 kg; mean 1.55 kg; n = 18), obtained from Lemberger (Oshkosh, WI). Animals were housed at room temperature (24-26°C) in a 0.8 × 1.5-m plastic tank containing fresh water and free access to dry and heated areas, allowing for behavioral thermoregulation. Animals were fasted for at least 1 wk before the experiments.Animal Preparation
On the day of experimentation, turtles were anesthetized with an intramuscular injection of 50 mg/kg pentobarbital sodium (Veterinary Laboratories). In cases where the pedal withdrawal response did not disappear within 60 min, an additional dose of pentobarbital (25 mg/kg) was injected to abolish the withdrawal response. Animals were placed in a supine position, tracheostomized, and ventilated with room air (3-4 breaths/min) at a tidal volume of 30-40 ml/kg (SAR-830 ventilator, CWE).An occlusive saline-filled PE-50 or PE-10 polyethylene catheter was inserted in the left femoral artery and advanced toward the heart ~2-3 cm. The catheter was used for blood sampling and infusion of drugs. In seven of the animals (group 3), an additional occlusive saline-filled PE-50 polyethylene catheter was inserted in the left femoral vein for infusion of plasma, saline, and drugs.
To access the central blood vessels, a 3 × 3-cm portion of the ventral plastron was removed with a bone saw. The pectoral muscles were gently loosened from the excised piece, and bleeding from small superficial vessels was stopped by cauterization. For measurements of pulmonary blood flow (Qpul), a 1-cm section of the left pulmonary artery (LPA) was freed from connective tissue for placement of a 2S transit-time ultrasonic blood flow probe (Transonic Systems, Ithaca, NY). The total Qpul was calculated as 2 × LPA flow. For measurements of systemic blood flow (Qsys), a flow probe was placed on the left aortic arch (LAo), a flow probe was placed on the far right branch (RRAo) of the right aortic arch, and finally, a flow probe was placed around both the right subclavian (RSC) and right common carotid (Rcc). The total Qsys was calculated as the sum of LAo, RRAo, and 2 × (RSC + Rcc) flows.
The left cervical vagus was isolated by separating the muscles located laterally to the trachea. The nerve was carefully dissected free from the carotid artery. Two loops of silk suture (3-0) were tied around the vagus, and the nerve was sectioned between the loops so that either the afferent (RVAF) or the efferent (RVEF) part of the vagus nerve could be independently manipulated onto a stimulating electrode during the experiments.
After instrumentation the turtles were left unmanipulated for ~60 min before any measurements were conducted.
Measurements
All measurements were conducted on anesthetized animals at an ambient temperature of 25 ± 2°C.Rate of oxygen consumption (O2) and
carbon dioxide production (CO2) were
computed by measuring static samples of inflow-outflow gas
concentration multiplied with the lung ventilation over a given period
of time. Inflow gas concentrations were sampled from ambient air, and
outflow gas concentrations were sampled from a mixing chamber attached
to the excurrent line of the ventilator. O2 and
CO2 concentrations were measured with an oxygen analyzer (S-3A, Applied Electrochemistry, Sunnyvale, CA) and a CO2
medical gas analyzer (LB-2, Beckman, Fullerton, CA),
respectively. Ventilation was calibrated at the end of each
experiment by volumetric measurement of the outflow from the excurrent
line of the ventilator over a given period of time.
Blood samples (450 µl/sample) were collected via the femoral catheter and analyzed for PO2, PCO2, and pH using a Radiometer (Copenhagen, Denmark) O2 electrode (E5047), CO2 electrode (E5037), and a capillary pH electrode (G299A), respectively. All electrodes were maintained at 25°C in a BMS Mk2 electrode assembly. Hematocrit (Hct) was measured using a standard capillary tube method. Total amount of O2 content (O2ct) was estimated using the partial pressure of oxygen (PO2), Hct, and pH values and from known values of the Bohr effect and Hill's n, reported in previous studies in T. scripta (6, 27). Blood plasma lactate content was analyzed by adding 300 µl of blood to an Eppendorf tube containing 1,200 µl of a 6% perchloric acid solution kept on ice. Plasma lactate was measured enzymatically with a Sigma kit (no. 826-UV).
Signals from the O2, CO2, and Transonic meters were continuously collected onto a computer using a commercial data acquisition system (AcqKnowledge MP 100, Goleta, CA). Beat-to-beat heart rate (HR) was derived from the LAo flow signal.
Experimental Protocol
Dose/response.
The animals were divided into three different experimental groups.
Group 1 (n = 5) was used to find the optimal
dose/response for the metabolic uncoupler 2,4-dinitrophenol (DNP) and
O2. Values of Qpul, Qsys, HR,
O2, and
CO2 were recorded at rest and 3 min
after the onset of a RVEF stimulation (4 Hz, 8 V, 2-30 µA, and
200 ms duration). Stimulation current was adjusted to produce a
60-70% reduction in HR. After a recovery period of 30 min,
animals were intra-arterially injected with a dose of 5 mg/kg DNP (10 mg DNP and 5 mg NaHCO3/ml H2O), and control and
RVEF stimulation recordings were repeated, starting 15 min after DNP
injection. The same procedures were repeated for accumulative doses of
5 mg/kg DNP every 30 min to a total of 30 mg/kg injected DNP.
Vagal stimulation.
In group 2 (n = 6), control values of Qpul,
Qsys, HR, O2, and
CO2 were recorded at rest, 3 min after
the onset of RVAF stimulation (4 Hz, 8 V, 50-80 µA, and 200 ms
duration), 3 min after the onset of RVEF stimulation (4 Hz, 8 V,
2-30 µA, and 200 ms duration), and 30 min after RVAF
stimulation. Stimulation currents were adjusted to produce a visually
detectable change in Qpul (RVAF) and a 60-70% reduction in HR
(RVEF) [according to Hicks and Comeau (19)].
O2 were recorded 25 min after each
injection and after repeated RVAF and RVEF stimulations, following the
same protocol as preinjections.
A 450-µl blood sample was withdrawn during the period of each one of
the abovementioned data recordings for analysis of blood gases, pH,
Hct, and lactate. In addition, recordings of cardiovascular and
O2 "control" values were made just
prior to each RVEF stimulation.
Reduced Hct.
This part of the study was performed in an attempt to mimic the
60-70% reduction in SOT seen during the RVEF stimulations (for
further information see RESULTS and
DISCUSSION). In group 3 (n = 7),
an initial blood sample was taken and Hct was measured. Control values
of Qpul, Qsys, HR, O2, and
CO2 were recorded at rest and 3 min
after the onset of RVEF stimulation (4 Hz, 8 V, 2-30 µA, and 200 ms duration). After the vagal stimulation, 10 ml of blood was withdrawn
from the arterial catheter and 10 ml of saline was infused
simultaneously through the venous catheter. The blood was centrifuged,
and the plasma was recovered and mixed with saline to a total volume of
20 ml. Hct was measured 10 min after withdrawal/infusion.
Withdrawals/infusions of 20 ml blood/plasma and saline mixtures
followed by Hct measurements were repeated until Hct was reduced to
30-40% of the control value. O2
was recorded before and 10 min after an injection of DNP (10 mg/kg). Thirty minutes after the DNP injection, an additional RVEF stimulation was conducted, and O2 was measured 3 min
after the onset of the stimulation.
Data Analysis and Statistics
All recordings of blood flows, HR,O2, and
CO2 were analyzed using AcqKnowledge
data analysis software (version 3.2.3; Biopac). For control
measurements, 30 min after DNP injection and 30 min after
NaHCO3 injection, mean values of Qsys, Qpul, HR,
O2, and
CO2 were created. For each vagal
stimulation, mean values of Qsys , Qpul, HR,
O2, and
CO2 were determined for a 1-min period
starting 3 min after the onset of stimulation. Blood samples for
analysis of PO2, PCO2,
pH, Hct, lactate, and calculation of O2ct were withdrawn 3 min after the onset of vagal stimulation. All data are presented as
mean values ± SE for n animals.
Evaluation of statistically significant differences (P 
0.05) in the observations was made using the Wilcoxon signed-ranks test. A sequentially rejective Bonferroni test (23) was
used to reduce, as far as possible, the possibility of discarding any true null hypothesis.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Group 1
Accumulative doses of 5 mg/kg DNP (5-30 mg/kg) were used to establish a dose-response curve for the effect of DNP onO2 during rest and RVEF stimulation. DNP
induced significant (P 0.05) increases in resting
O2 at all doses used, with a maximum increase in O2 after 15 mg/kg (Fig.
1). At rest and after each of the DNP
doses, O2 was significantly depressed
(~25-40%) during RVEF stimulation. In addition, the
O2 recorded during RVEF stimulation was
significantly higher after 10-30 mg/kg compared with control values of O2 recorded at rest. A DNP
dose of 10 mg/kg was chosen for all experiments in group 2.
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Group 2
RVAF stimulation before injection of DNP produced a significant increase in Qpul and HR (~30 and 6%, respectively) (Fig. 2) but did not changeO2 or any of the blood parameters
measured (Table 1). RVEF stimulation in
untreated animals produced significant reductions in Qpul,
Qsys, and HR (60-70%) (Figs. 2 and 3), and a 60-70%
decrease in SOT (Fig. 3) accompanied by
significant decreases in O2,
PO2, CO2, and
PCO2 (Table 1 and Fig. 3). Injection of DNP
induced a drop in total cardiac output (Qtot = Qpul + Qsys) caused by a
drop in Qpul during rest (Fig. 2).
O2, CO2,
and PCO2 were significantly increased and
PO2 was significantly decreased during
resting conditions after DNP injection. DNP also induced a drop in pH
and an increase in plasma lactate levels, changes that were
further expressed in the two after vagal stimulations (Table 1 and Fig.
3). In addition, post-DNP RVAF stimulation produced increases in Qtot,
Qpul, CO2, and
PCO2 (Fig. 2 and Table 1). Post-DNP RVEF
stimulation induced significant decreases in
O2, PO2,
CO2, PCO2, and
SOT (Table 1 and Fig. 3). In comparison of pre-DNP RVEF stimulation and
post-DNP RVEF stimulation, there were no differences in any of the
flows measured, but O2 was significantly
higher after DNP injection. O2 was
significantly higher during RVEF stimulation after DNP injection than
in resting controls (Figs. 2 and 3, Table 1). No changes in plasma
lactate levels could be correlated to the stimulations per se, but a
gradual two- to threefold increase was observed after the DNP injection (Table 1). Finally, injection of NaHCO3 (used as control of
DNP vehicle) had no effects on any of the cardiovascular or blood parameters measured (Table 1). O2ct did not significantly
change during the experiment (Fig. 3).
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Group 3
A 60-70% reduction of Hct produced a significant decrease inO2, without any significant changes in
Qsys or Qpul (Fig. 4). O2 after Hct reduction was not
significantly different from the O2
measured during the control RVEF stimulation. Injection of DNP reversed
the O2 to control values. The RVEF
stimulation after DNP produced decreases of ~50% in
O2 and 60-70% in Qsys and Qpul.
The CO2 values in this group followed
those of O2, and HR was not
significantly different from groups 1 and 2 (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study shows that vagal nerve stimulation triggers a decrease
in O2 in anesthetized turtles. This
hypometabolic response is correlated with the reductions in arterial
PO2 and SOT and was not associated with
significant increases in plasma lactate. In all animals, injections of
DNP during vagal nerve stimulation increased
O2 to levels greater than those measured
during control periods. We conclude that the reduction in
O2 associated with vagal nerve
stimulation and the following reduction in SOT most likely reflect
downregulation of ATP turnover rates.
Comparison with Data on Conscious Turtles
The gas exchange, cardiovascular, acid-base and blood gas data measured in our in situ preparation (Table 1) were in close agreement with values measured in previous studies in turtles. TheO2 reported from previous studies on
metabolism in turtles ranges from 0.4 to 1.4 ml/min (5, 24,
33). Although pulmonary and systemic blood flows in our study
were high compared with previously reported data, both were still
within the range of blood flows previously measured in T. scripta [(28-75 ml/min); Refs. 7,
8, 16, 32, 33]. Finally, our
measured values for arterial PO2, pH, and
plasma lactate were similar to the values reported in anesthetized and
conscious resting turtles at a similar body temperature (8, 20,
34).
Hypometabolism Induced by Vagal Stimulation
In the following discussion,O2
will be used as an indicator of metabolic rate. This study demonstrates
that RVEF stimulation produces a decrease in
O2 of ~35%, reflecting a reduction in aerobic metabolic rate to the same extent (Table 1). Associated with
RVEF stimulation were reductions in both HR and cardiac output, which
decreased by as much as 70% (Fig. 2). This vagally induced reduction in cardiac output clearly contributes to the reduction in the
overall O2, and the obvious question
arises: How much of the overall reduction in
O2 can be accounted for by the
reduction in cardiac work? Although we did not directly measure
the O2 of the heart, the contribution of
the O2 of the heart to the total
O2 can be estimated from previous
studies on heart metabolism in the turtle (1, 5, 9, 10,
12) and extrapolated to the conditions during our experiments.
From this extrapolation, we estimate that the
O2 of the heart is <10% of the total
O2. Thus, if the
O2 of the heart is <10% of total
O2, the reduction in the work of the
heart, theoretically, cannot be responsible for more than 20% of the
O2 reduction measured during RVEF. The
remaining 80% of the metabolic decrease must therefore be attributed
to a general decrease in metabolic rate, i.e., the onset of a
hypometabolic state.
Delivery vs. Controlled Response: DNP
The reduction inO2 during RVEF
stimulation may be caused by either an inability of the cardiopulmonary
system to supply a sufficient amount of oxygen to the tissues or a
downregulation of metabolism, i.e., reduction in ATP demand. To
distinguish between these two possibilities, we used injections of the
metabolic uncoupler DNP. We found that the reduction in
O2, associated with RVEF and reduced
SOT, reversed after DNP injection. This result indicates that during
RVEF stimulation, the lower SOT was still sufficient to support
tissue respiration, because O2
after DNP exceeded even the O2 measured
in untreated control animals (Table 1 and Fig. 3). Pharmacological
stimulation of O2 during periods of
tissue hypoxia have been previously reported for isolated cells and
whole animals. In the aquatic turtle Chrysemys scripta,
isolated hepatocytes exhibit rapid metabolic depression during anoxia, which is reversed by treatment with DNP (4). In the
freshwater turtle T. scripta, hypoxia-induced hypometabolism
is reversed by a single injection of DNP (20). Finally, in
rats, an intravenous injection of DNP (17 mg/kg) reversed the hypoxic
induced reduction in O2
(30).
Reduced Hct
The approach of mimicking the reduced SOT seen during RVEF stimulation by reducing Hct further supports the hypothesis that SOT is at least one of the components that triggers the hypometabolic state. A 60-70% reduction in SOT caused by reducing the Hct results in a decrease inO2 comparable to the
60-70% reduction in SOT caused by reduced Qsys (Figs. 3 and 4).
When DNP was injected in animals with reduced Hct, the
O2 increased to a level not significantly different from control values, without any detectable change in SOT (Fig. 4). In addition, RVEF stimulation after DNP injection produced a decrease in O2
similar to that during the RVEF stimulation under control conditions
(Fig. 4).
We conclude that the reduction in O2
during vagal nerve stimulation reflects a downregulation of ATP
turnover rate. This conclusion is based on the observations that
1) plasma lactate did not significantly increase during
periods of vagal reductions in SOT, indicating that net ATP
production derived from anaerobic glycolysis was not increased; and
2) O2 could be
pharmacologically stimulated by injection of DNP during periods of
reduced SOT, suggesting that oxygen delivery alone did not limit
aerobic metabolism. Similar conclusions have been previously reached
with comparable data in both ectotherms and endothermic vertebrates
(20, 30). In endothermic vertebrates (mammals), the
reduction of metabolism during periods of hypoxia has been suggested to
result from inhibition of the pathways involved in thermogenesis
(13). However, as previously suggested
(20), significant thermogenic processes are absent in
ectotherms, and, therefore, the reduction in
O2 at the organismal level may result
from mechanisms that are similar to those that depress metabolism
during anoxia.
Role of the R-L Shunt in Control of the Hypometabolic State
In freshwater turtles, diving is often associated with bradycardia, decreased Qpul, and the development of a large R-L intracardiac shunt (17, 32-35). A recent study by Hicks and Wang (20) in the anesthetized turtle demonstrated that severe hypoxia (FIO2 = 0.05), which reduced arterial oxygen levels to values observed during diving, induced a 30% reduction inO2. Consequently, Hicks and
Wang (20) hypothesized that the development of an R-L
shunt may trigger the rapid onset of a hypometabolic state in the
tissues and therefore contribute to the prolongation of aerobic dive times.
In the present study, we could not see from the flow data alone evidence for the development of a large net R-L intracardiac shunting during RVEF stimulation. However, in turtles, the net blood flows are not necessarily precise indicators of R-L shunt (17, 18). Intracardiac shunts can be defined as either anatomic or effective (18). An anatomic shunt is defined as a shift of net blood flow from the pulmonary to the systemic circulation or vice versa. The effective shunt is the relative amount of systemic blood that mixes with pulmonary blood and is detected by measurements of blood oxygen levels (18). An effective R-L shunt (i.e., reduction in arterial PO2) has been demonstrated to occur during RVEF stimulation in the turtle (19). An effective R-L shunt most likely occurs in our experiments, because arterial PO2 drops during RVEF stimulation. During RVEF stimulation, arterial O2ct did not change but arterial PO2 was significantly reduced (Table 1), suggesting that PO2 may be the mediator for the metabolic downregulation. However, this is unlikely in the present study, because the PO2 changes measured were only 25-30% of the changes reported by Hicks and Wang (20) to produce hypometabolism. Whether the changes in PO2 are the consequences of an R-L shunt cannot be confirmed by our data.
The present study supports the hypothesis that reduction in oxygen transport induced by vagal stimulation triggers a downregulation of metabolism, which reflects a reduction in ATP turnover in the tissues of the freshwater turtle. Reduced arterial PO2 is a possible mediator but is not necessary for the metabolic downregulation. Another, perhaps more likely, candidate is the combination of Qsys and arterial O2ct, the SOT. In the study by Hicks and Wang (20), hypoxia induced a decrease in O2ct without any changes in blood flow, resulting in a reduced SOT and an induction of a hypometabolic state. This agrees with our findings, where SOT was reduced by the decrease in Qsys and by the reduction in Hct. Obviously, further investigations are needed to extend these findings to in vivo studies on diving turtles.
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ACKNOWLEDGEMENTS |
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We are greatly indebted to Dr. D. Crossley and L. Hartzler for all help and constructive criticism during this project. We also thank Dr. S. Hillman for good suggestions on parts of the experiments.
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FOOTNOTES |
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This work was supported by National Science Foundation Grant IBN-9982671 and Swedish Foundation for International Cooperation in Research and Higher Education Grant Dnr 99/459.
Address for reprint requests and other correspondence: B. Platzack, Dept. of Ecol. Evol. Biol., Univ. of California, Irvine, Irvine, CA 92697-2525 (E-mail: platzack{at}uci.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 November 2000; accepted in final form 12 June 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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) and turtles stimulated in the efferent branch of the
right vagus nerve (RVEF; 
). *Significant differences
(P < 0.05) compared with controls at the same dose of
DNP; **significant differences (P < 0.05) compared
with uninjected, unstimulated control. Vertical bars show SE.
