Adrenergic control of the cardiovascular system in the turtle Trachemys scripta
1 Department of Zoophysiology, Aarhus University, Building 131, 8000 Aarhus
C, Denmark
2 Department of Biological Sciences, Simon Fraser University, Burnaby,
British Columbia, V5A 1S6, Canada
* Author for correspondence (e-mail: johannes.overgaard{at}biology.au.dk)
Accepted 8 August 2002
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Summary |
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Key words: turtle, Trachemys scripta, adrenergic response, cardiac shunting, cardiovascular, pulmonary resistance, systemic resistance
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Introduction |
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While the overall haemodynamic effects of adrenergic stimulation have been
characterised to some degree in turtles, it remains unknown as to what extent
the changes in cardiac shunt pattern are caused by increased systemic
resistance (Rsys) or decreased Rpul.
Furthermore, the specific role of -adrenergic and ß-adrenergic
receptors underlying the regulation in the pulmonary circulation is largely
unknown. Non-anaesthetised turtles primarily regulate the ratio of the
vascular resistances (Rpul/Rsys), and
thereby cardiac shunt pattern, through a cholinergically mediated constriction
of the pulmonary circulation. However, owing to the lack of vagal tone in
anaesthetised turtles, the present study allowed us to examine how the ratios
of vascular resistances affects shunt patterns when the resistances are
manipulated through adrenergic stimulus or blockade. We measured haemodynamic
responses following bolus injections of norepinephrine and the specific
- and ß-adrenergic agonists phenylephrine and isoproteronol.
Furthermore, we investigated the effects of pharmacological blockade using the
-adrenergic antagonist phentolamine and the ß-adrenergic
antagonist propranolol. Here, we aim to characterise the adrenergic regulation
of the cardiovascular system in turtles and its possible functional
implications.
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Materials and methods |
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Anaesthesia and surgery
Turtles were anaesthetised by an intramuscular injection of sodium
pentobarbital (Nembumal, Sygehusapotekerne, Denmark; 50 mg kg-1)
and normally ceased to exhibit responses to pinching of the legs or tail
within 60 min. The trachea was then exposed by a ventral incision in the neck,
and the turtle was tracheotomised for artificial ventilation. During surgery
and the entire experimental protocol, turtles were maintained ventral side up
and received continuous artificial ventilation with a tidal volume of 20-30 ml
kg-1 at a frequency of 20-30 breaths min-1 using an HI
665 Harvard Apparatus Respirator (Cambridge, MA, USA). Because of the high
ventilation rate, we used a gas mixture of 97% room air and 3% CO2
delivered by a Wösthoff gas-mixing pump (Bochum, Germany) to mimic the
arterial blood PCO2 in vivo (e.g.
Glass et al., 1983; see
Crossley et al., 1999 for arterial blood gas composition of anaesthetised
turtles using a similar experimental design).
To access the central vascular blood vessels, a 5 cm x 5 cm portion of the plastron was removed using a bone saw, and the pectoral muscles were gently loosened from the excised piece. A polyethylene catheter, containing heparinised saline, was occlusively inserted into the left carotid artery and advanced into the right aortic arch. The common pulmonary artery was non-occlusively cannulated using an intravenous catheter (Surflo, Terumo Medical Cooporation, Elkton, MD, USA) inserted upstream into the common pulmonary artery to within 0.5 cm of the heart. This required that the pericardium was opened by a 1 cm incision. After insertion, the intravenous catheter was connected to PE-60 tubing, which, in turn, was connected to a Baxter Edward disposable pressure transducer (model PX600, Irvine, CA, USA). The signals from the pressure transducers were amplified using an in-house-built preamplifier and were calibrated daily against a static column of water. For measurements of systemic and pulmonary blood flows, a 1-1.5 cm section of the left aortic arch (LAo) and the left pulmonary artery (LPA) were freed from connective tissue for placements of transit-time ultrasonic blood-flow probes (2R or 2S probes; Transonic System, Inc., NY, USA). To improve the signal, acoustical gel was infused between the blood vessel and flow probe. The flow probes were connected to a Transonic dual-channel blood-flow meter (T206) for measurements of instantaneous blood-flow rates. Signals from the pressure transducer and the blood-flow meter were recorded with a Biopac MP100 data acquisition system (Biopac Systems, Inc., Goleta, CA, USA) at a sampling frequency of 50 Hz.
Calculation of blood flows, net shunt, stroke volume and resistance
to blood flow in the systemic and pulmonary circulations
This study did not measure blood flow in all systemic and pulmonary
arteries. Several studies on anaesthetised and non-anaesthetised freshwater
turtles have shown that systemic blood flow
(sys) can be adequately
estimated as 2.85
LAo
(Shelton and Burggren, 1976
;
Comeau and Hicks, 1994
;
Wang and Hicks, 1996a
; this
relationship also persists after injection of adrenergic antagonists and
agonists in fully recovered turtles; J. A. W. Stecyk, J. Overgaard, A. P.
Farrell and T. Wang, unpublished data). Likewise, pulmonary blood flow
(
pul) can be calculated as
2
LPA under the assumption
that blood flow in the right pulmonary artery equals that in the left.
fH was calculated from the instantaneous blood-flow trace from the
LAo. Total cardiac output
(
tot) was calculated as
sys+
pul,
and total stroke volume (VStot; pulmonary + systemic) was
calculated as
tot divided
by fH. Pulmonary and systemic resistances (Rpul
and Rsys, respectively) were calculated from mean blood
pressure (P) and mean blood flow
(Rpul=Ppul/
pul
and
Rsys=Psys/
sys)
using the assumption that central venous blood pressures are zero. This
assumption may lead to a small overestimation of vascular resistances, as
pointed out by Badeer and Hicks
(1994
).
Experimental protocol
After ensuring steady-state conditions (stable pressures and flows for a
minimum of 30 min), the turtles were sequentially injected with adrenergic
receptor antagonists and agonists using the protocol described below. The
injections were administered through the systemic catheter, which was
subsequently flushed with saline. Although not studied in detail, injections
of adrenergic agonists in the pulmonary artery yielded similar responses to
those following systemic injections. The total volume injected never surpassed
2 ml, and control injections of 2 ml saline did not cause haemodynamic
changes. Following injection of each drug, we recorded haemodynamic parameters
at a maximal response. This usually occurred after 1-2 min with the agonists
and after 30 min with the antagonists. After injections of agonists, the
haemodynamic variables were allowed to return to baseline values before
continuing the protocol. Following injection of antagonists, we waited for at
least 30 min until a new steady-state was established.
The animals were randomly divided into two groups (body mass of 0.78±0.03 kg and 0.92±0.12 kg for group 1 and 2, respectively) and presented with the following pharmacological protocols (all chemicals were purchased from Sigma-Aldrich, Vallensbæk Strand, Denmark).
Group 1: norepinephrine 5 µg kg-1, phenylephrine 5 µg kg-1, propranolol 3 mg kg-1, norepinephrine 5 µg kg-1, phenylephrine 5 µg kg-1, phentolamine 3 mg kg-1. Group 2: these animals were exposed to the same protocol as group 1 with the exception that the injections of phentolamine and propranolol were reversed. In addition, eight of the twelve animals (four from each group) were injected with a lower dose of norepinephrine (1 µg kg-1), and four animals (two from each group) were injected with isoproteronol (1 µg kg-1). These injections were performed before administration of the first antagonist. After completion of the experimental protocol, all turtles were euthanized by a lethal injection of saturated KCl.
Data analysis and statistics
Recordings of blood flows and pressures were analysed using AcqKnowledge
data analysis software (Biopac Systems, Inc., Goleta, CA, USA, version 3.7.0)
where the mean values for fH,
LAo,
LPA,
Psys, Ppul, Rsys
and Rpul were determined over a 1-2 min period following
each injection. Differences in control values between groups 1 and 2 were
tested using a t-test. In each group, the results obtained following
injections of agonists and antagonists were tested for significant differences
from untreated baseline values using a one-way analysis of variance (ANOVA)
for repeated measures. Significant differences among mean values were
identified using a post hoc StudentNewmanKeuls (SNK)
test. Effects of agonists (phenylephrine and norepinephrine) after injection
of antagonists (propranolol or phentolamine) were compared with the baseline
value that prevailed 30 min after injection of the antagonist. Similarly, the
eight turtles that received two doses of norepinephrine were tested using a
one-way ANOVA for repeated measures and a post hoc SNK test. A paired
t-test was used to assess for significant differences from control
values in the four animals injected with isoproteronol. In all tests, a limit
of P<0.05 was applied to identify significant differences. Owing
to low N values for some comparisons, type 1 errors are possible, and
lack of significant differences should be interpreted cautiously. The data are
presented as means ± S.E.M. and normalised to a 1 kg turtle.
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Results |
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Effect of norepinephrine
The temporal changes in heart rate, blood flows and pressures following
injection of norepinephrine are illustrated in Fig.
1A,
2A for two turtles from each
experimental group. The group data are presented in
Table 1. Data from the eight
turtles (four from each group) that received two doses of norepinephrine were
pooled and are presented in Fig.
3. Both concentrations of norepinephrine had significant
chronotropic and inotropic effects.
tot,
pul, fH and
VStot all increased significantly following
injection of 1 µg kg-1 norepinephrine, and fH also
increased further following injection of 5 µg kg-1
norepinephrine (Fig. 3A).
sys was unchanged following
injection of 1 µg kg-1 norepinephrine but decreased
significantly after injection of 5 µg kg-1 norepinephrine.
Norepinephrine caused significant dose-dependent increases in
Ppul and Psys but did not affect
Rpul, while Rsys increased
significantly from baseline values following injection of 5 µg
kg-1 norepinephrine (Fig.
3D).
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Effect of -adrenergic stimulation and blockade
Injection of the -agonist phenylephrine led to an increase in
tot, although the effect
was only significant in group 2 (Table
1). The increase in
pul and
tot following injection of
phenylephrine was slightly lower than that following norepinephrine, and this
correlated with the lack of a chronotropic effect of phenylephrine, but there
were similar increases in VStot after injection
of either phenylephrine or norepinephrine
(Table 1). As with
norepinephrine, phenylephrine elicited a significant increase in
pul, while
Rpul was not affected. The change in
sys following phenylephrine
was not statistically significant, although Rsys almost
doubled (Table 1; Figs
1A,
2A).
Blockade of the -receptors by phentolamine induced significant
reductions in Rsys, Psys,
Ppul and
pul without altering
fH,
sys and
Rpul (Table
1). The pronounced
-adrenergic systemic vasoconstriction
was abolished by phentolamine. Thus, when phenylephrine or norepinephrine were
injected after phentolamine, there were no significant cardiovascular changes
except for an increase in Psys and
tot following
phenylephrine.
Effect of ß-adrenergic stimulation and blockade
The haemodynamic changes caused by ß-adrenergic receptor stimulation
using isoproteronol are presented in Fig.
4. Isoproteronol produced significant positive chronotropic
effects and significantly reduced Vstot, while there were
no significant changes in
pul or
sys. Although there were no
significant changes in Rsys and Rpul,
isoproteronol caused significant hypotension in both the pulmonary and
systemic circuits.
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Abolishment of ß-adrenergic tone, using propranolol, significantly
reduced fH and tot
but did not affect Vstot. A significant increase in
Rpul resulted in a decrease in
pul and no change in
Ppul. The changes in Rsys and
sys were not statistically
significant. Similarly, when propranolol was applied after phentolamine (group
2), fH decreased significantly, without any further change in
tot and
pul (which had already been
reduced significantly by phentolamine). The increases in
Rsys and Rpul following propranolol
injection did not reach statistical significance. Compared with norepinephrine
injection before ß-adrenergic blockade, norepinephrine injection
following propranolol (group 1) caused an even larger increase in
Rsys, while the systemic hypertension was of similar
magnitude. Phentolamine injection following ß-adrenergic blockade (group
1) caused cardiac collapse, with
tot decreasing to 25% of
the initial control values, and systemic and pulmonary blood pressures
decreasing to 50% of their initial control values
(Table 1).
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Discussion |
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Comparison of haemodynamic variables between anaesthetised and fully
recovered animals
We studied anaesthetised turtles to isolate the adrenergic control of the
cardiovascular system without the confounding effects of the often-profound
cardiovascular changes associated with ventilation in non-anaesthetised
animals. The haemodynamic variables of anaesthetised turtles differ markedly
from that of non-anaesthetised and recovered animals. For example, during
non-ventilatory periods, recovered animals are characterised by a low
fH and a large right-to-left shunt, whereas lung ventilation produces
increases in fH,
pul and
pul/
sys
(White and Ross, 1966
;
Shelton and Burggren, 1976
;
West et al., 1992
;
White et al., 1989
;
Wang and Hicks, 1996a
). The
low fH and
pul
during apnoea appear to stem from a large vagal tone, as injection of atropine
increases both fH and
pul and abolishes their
reduction during breath holding (Berger,
1972
; Burggren,
1975
; Hicks and Wang,
1998
; Hicks, 1998
;
Hicks and Farrell, 2000
).
Injection of a beta-blocker did not affect the changes in fH
associated with intermittent ventilation
(Burggren, 1975
), although
nadolol reduced mid-apnoeic fH
(Hicks and Farrell, 2000
). It
is unknown whether the decreased fH results from blocking the effects
of circulating catecholamines or the adrenergic innervation of the heart.
Hicks (1994
) suggested that
part of the increased
pul
and fH during ventilation can be attributed to increased adrenergic
tone. Indeed, in anaesthetised turtles, afferent stimulation of the vagus
causes tachycardia and increased
pul, which is abolished by
inhibiting adrenaline release from nerve endings with bretylium
(Comeau and Hicks, 1994
).
Hence, it seems that the reciprocal changes in fH and blood flows
associated with breathing are predominantly caused by alterations in vagal
tone, but that changes in adrenergic tone contribute to cardiac rhythm in
non-anaesthetised turtles.
Blood flow and fH of anaesthetised turtles are higher than in
non-anaesthetised, apnoeic turtles because vagal tone on the heart and
pulmonary artery is lost in anaesthetised and ventilated animals
(Crossley et al., 1998). As a
result, blood flow and fH in anaesthetised turtles are quantitatively
more similar to those measured in non-anaesthetised turtles during
ventilation, when vagal tone is reduced. Nevertheless, anaesthetised turtles
maintain an adrenergic tone similar to recovered animals, as the 35% reduction
in fH occurring with propranolol injection in the present study
(Table 1) agrees well with the
16-35% reduction in fH after nadolol injection in non-anaesthetised
turtles (Hicks and Farrell,
2000
).
- and ß-adrenergic responses on the heart and
vasculature
This is the first study to simultaneously examine - and
ß-adrenergic regulation of the heart as well as the pulmonary and
systemic circulations in turtles. Previous studies have shown that systemic
injection of catecholamines leads to an increased heart rate that can be
blocked or greatly attenuated by injection of ß-receptor antagonists
(Burggren, 1975
;
Hicks and Farrell, 2000
). In
our study, propranolol caused a large reduction in fH but did not
completely abolish the chronotropic effect of norepinephrine
(Fig. 1;
Table 1). This is likely to
result from competitive binding between propranolol and norepinephrine on the
cardiac ß-adrenergic receptors, as phentolamine and phenylephrine did
not affect fH, whereas specific stimulation of ß-adrenergic
receptors using isoproteronol elicited marked tachycardia
(Fig. 4). These observations
are consistent with studies on isolated ventricular strips from
Trachemys, where no chronotropic effects could be demonstrated
following
-adrenergic stimulation
(Van Harn et al., 1973
).
In this study, we used bolus injections of adrenergic agonists and antagonists to evaluate the adrenergic regulation of the heart and vascular tones. This experimental design does not allow for a differentiation between the effects of circulating catecholamines relative to the effects of catecholamine release from nerve endings.
In our study, high doses of norepinephrine caused a marked increase in
Rsys (Table
1). This response was mimicked by phenylephrine and could be
blocked by phentolamine, demonstrating that the systemic vascular constriction
following norepinephrine injection is caused by -adrenergic receptors
(Table 1;
Fig. 2). Phentolamine halved
Rsys, pointing to a substantial
-adrenergic tone on
the systemic circulation in anaesthetised turtles
(Table 1). This is also the
case in fully recovered turtles, where phentolamine reduced
Rsys from 0.08 kPa ml-1 min kg to 0.06 kPa
ml-1 min kg (A. W. Stecyk, J. Overgaard, T. Wang and A. P. Farrell,
unpublished data). Thus, as in virtually all other vertebrates examined so
far, stimulation of the
-adrenergic receptors in the systemic vascular
beds is associated with constriction
(Nilsson, 1983
). Conversely,
stimulation of ß-adrenergic receptors with isoproteronol was associated
with relaxation of the systemic vascular beds
(Fig. 4), and blockade of
ß-adrenergic receptors increased Rsys by a factor of
1.4 (Table 1;
Fig. 1). Similar changes have
been observed in fully recovered turtles, where ß-adrenergic blockade
using nadolol led to a threefold increase in Rsys from
0.05 kPa ml-1 min kg to 0.15 kPa ml-1 min kg
(Hicks and Farrell, 2000
).
Comeau and Hicks (1994)
reported a small decrease in Rpul of anaesthetised turtles
following catecholamine injection, whereas other studies were unable to detect
reductions in Rpul
(Luckhardt and Carlson, 1921
;
Berger, 1972
;
Milsom et al., 1977
). In our
study, both norepinephrine and phenylephrine elicited a small, statistically
non-significant reduction in Rpul
(Table 1;
Fig. 1). A potentially minor
dilatory role for
-adrenergic receptors was further suggested by the
increase in Rpul (albeit not statistically significant)
following phentolamine injection (Table
1). Thus, the pulmonary circulation is much less responsive to
-adrenergic stimulation than is the systemic circulation, where
Rsys doubled after injection of phenylephrine. Burggren
(1977
) earlier reported a
15-20% reduction in the resistance of the isolated distal pulmonary artery
upon injection of epinephrine. In the lizard Trachydosaurus rugosus,
stimulation of ß-receptors dilates the pulmonary vasculature, while
stimulation of
-receptors appears to cause a constriction
(Berger, 1973
). In the snake
Elaphe obsoleta, there is also evidence for ß-adrenergic
relaxation of the pulmonary artery (Donald
et al., 1990
). The role of ß-receptors in the pulmonary
circulation is less clear in turtles. Thus, while propranolol caused a
significant increase in Rpul, suggesting a tonically
active ß-adrenergic mediated relaxation
(Table 1; Fig. 1), injection of
isoproteronol did not reduce Rpul
(Fig. 4), perhaps because this
vasoactive mechanism was already fully activated.
Our study demonstrates marked differences in the vascular response to
adrenergic stimulation between the pulmonary and systemic circulations. The
pulmonary circulation is much less responsive to catecholamines, and
-adrenergic receptors could even mediate opposite changes in vascular
tone. Other studies also show that vasoactivity in the systemic and pulmonary
circulations of turtles differs in other respects. Thus, hypoxia causes
vasodilation in the systemic circulation as opposed to vasoconstriction in the
pulmonary circulation (Crossley et al.,
1998
). NO exerts a substantial role in maintaining systemic
vascular tone but does not seem important in the pulmonary circulation
(Crossley et al., 2000
).
Conversely, pulmonary resistance is under strong cholinergic control
(Berger, 1972
;
Burggren, 1977
;
Milsom et al., 1977
;
Hicks and Comeau, 1994
),
whereas the cholinergic tone on the systemic circulation is either low or
absent (Kirby and Burnstock,
1969
; Berger and Burnstock,
1979
; Comeau and Hicks,
1994
). Indeed, more studies are needed to better define the basis
of these differences in vasoactivity.
The present study is revealing in terms of a potential role of venous
venoconstriction on cardiac function. For example, despite the slight decrease
in sys and the marked
increase in Rsys with both phenylephrine and
norepinephrine, there was an increase in
tot and
Vstot. The increase in Vstot could be
a result of an
-adrenergically mediated venoconstriction. Conversely,
the apparent negative inotropic effect of isoproteronol on the heart (i.e. the
decrease in Vstot) might be best explained by a
ß-adrenergically mediated venodilation reducing venous return to the
heart. These venous effects of adrenergic stimulation need not be manifest in
changes in overall vascular resistance but warrant further attention because
of their potential effects on Vstot and
tot. Thus, although it
seems that arterial vascular resistances determine the relationship between
pulmonary and systemic blood flows, it is likely that the magnitude of changes
in total blood flow is determined, in part, by the degree of venous
vasoactivity.
Functional implications of adrenergic regulation of cardiac
shunts
Our study is the first to comprehensively evaluate effects on adrenergic
stimulation on cardiac shunt patterns. Fig.
5 depicts the relationship between blood-flow distribution,
expressed as
pul/
sys,
and the ratio of the vascular resistances in the pulmonary and systemic
circulations (Rpul/Rsys). A similar
relationship illustrated that the distribution of blood flows between the
systemic and pulmonary circuits in turtles correlates closely with the ratio
of pulmonary and systemic vascular resistances
(Hicks et al., 1996
;
Crossley et al., 1998
). We were
able to show that an even more profound range of cardiac shunting can be
produced with adrenergic drug injections that act primarily on the systemic
circulation. Consequently, anaesthetised turtles exhibit large net
left-to-right shunts
(
pul/
sys
of >1) when Rpul is lower than Rsys
(Rpul/Rsys of <1), while a net
right-to-left shunt
(
pul/
sys
of <1) exists when Rpul is higher than
Rsys (Rpul/Rsys of
>1). This relationship implies that systemic outflow resistance, regulated
through
-adrenergic systemic vasoconstriction at the arterial level (as
shown by the fourfold changes in Rsys between
-adrenergic stimulation and blockade), is the primary determinant of
distribution of
tot to the
blood flows between the two circuits in these anaesthetised turtles. In
non-anaesthetised turtles, changes in the shunt pattern are effected primarily
by cholinergically mediated constrictions of the pulmonary circulation. Thus,
by focusing on adrenergic control, our work has provided evidence that
modulation of the systemic vascular resistance produces the same types of
cardiac shunts in turtles as does modulation of pulmonary resistance.
Consequently, for turtles, it appears that up to 97% of the observed
variability in the cardiac shunting (Fig.
5) can be explained by the ratio of the resistances in the two
circulations.
|
It remains unanswered whether the profound changes in cardiac shunting
produced here by adrenergic mechanisms play a role in non-anaesthetised
turtles. Increased adrenergic tone is often associated with exercise and
stressful conditions such as hypoxia, where sympathetic stimulation safeguards
systemic oxygen delivery through increased fH and cardiac output. In
addition, reduced cardiac right-to-left shunting through increased adrenergic
tone and decreased vagal tone increases oxygen delivery (Wang and Hicks,
1996b,
2002
). Our study is consistent
with this view. However, because anaesthetised turtles have no vagal tone,
adrenergic stimulation serves to increase the net left-to-right shunt rather
than abolishing the net right-to-left shunt that would occur in vivo.
Furthermore, the changes in shunt pattern are primarily accomplished through
increased Rsys and are associated with reductions in
sys. Therefore, adrenergic
stimulation of anaesthetised animals is unlikely to improve systemic oxygen
delivery. It is probable, however, that oxygen delivery in fully recovered
animals would benefit from increased sympathetic tone, as resting and
undisturbed animals are characterised by net right-to-left shunts and low
arterial oxygen levels (see tables
1, 2 in
Wang and Hicks, 1996a
).
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Acknowledgments |
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References |
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