Delayed depolarization of the cog-wheel valve and pulmonary-to-systemic shunting in alligators
1 Department of Biological Sciences, 2500 University Drive NW, University of
Calgary, Calgary, Alberta, Canada T2N 1N4
2 Department of Zoology, University of British Columbia, Vancouver, British
Columbia, Canada V6T 1Z4
Present address: Ocean Sciences Centre, Memorial University of Newfoundland,
St John's, Newfoundland, Canada A1C 5S7
Present address: Distinguished Scholar, Peter Walls Institute for Advanced
Studies, The University Centre, University of British Columbia, Vancouver,
British Columbia, Canada V6T 1Z4
* e-mail: syme{at}ucalgary.ca
Accepted 11 April 2002
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Summary |
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Key words: alligator, Alligator mississippiensis, blood pressure, cardiac muscle, heart, shunt, left aorta, pulmonary artery, right ventricle, electrocardiogram, cog-wheel valve, conduction velocity, nodal delay
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Introduction |
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Crocodilians also possess a well-developed and muscular cog-wheel valve
located in the subpulmonary conus just outside the RV
(Fig. 1) (Greenfield and Morrow, 1961;
Webb, 1979
;
Farrell et al., 1998
). This
valve consists of connective tissue nodules that fit together to partially or
completely occlude the conus; it is surrounded by a mass of cardiac muscle
(van Mierop and Kutsche,
1985
). Contraction of this muscle causes closure of the valve and
increased pulmonary input resistance and would account for the phasic and
complex alterations in RV pressure that occur with each cardiac cycle and
cause P
S shunting (Greenfield and
Morrow, 1961
; White,
1969
,
1970
;
Grigg and Johansen, 1987
;
Axelsson et al., 1989
,
1996
;
Shelton and Jones, 1991
;
Jones and Shelton, 1993
;
Jones, 1996
).
In crocodilians, the merits of PS shunting and the mechanism(s) by
which shunts are controlled are not well understood (for reviews, see
Jones, 1996
;
Burggren, 1987
). Franklin and
Axelsson (2000
), using an
isolated heart model in which the pulmonary outflow tract had been removed,
showed that ß-adrenergic stimulation reduces resistance in the
subpulmonary conus, reduces RV pressure development and thus inhibits P
S
shunting in the crocodile. In addition, Axelsson and Franklin
(2001
) show that the calibre of
the foramen of Panizza in the aortic outflow tract is variable and subject to
adrenergic constriction, which will have consequences for flow patterns in the
left and right aortas during shunting. However, sustained adrenergic tonus
cannot account for the aforementioned phasic and complex changes in RV
pressure seen in crocodilians late in the cardiac cycle. Thus, there must also
be large and phasic changes in resistance in the pulmonary outflow tract with
each heart beat. Franklin and Axelsson
(2000
) and Axelsson and
Franklin (2001
) make no claim
that an adrenergically mediated mechanism causes phasic changes in resistance
within each cardiac cycle; indeed, such changes occurred with a time course of
minutes in their experiments. Hence, some other mechanism(s) must also be
responsible for regulating this valve and shunting in crocodilians.
The phasic changes in resistance suggest phasic activity of the cog-wheel
valve during each cardiac cycle and strongly suggest that depolarization of
the muscle mass surrounding the valve is linked to RV contraction. White and
Brady (unpublished observation cited in
White, 1968) noted a 350 ms
delay between depolarization `near the pulmonary artery' and the adjacent
ventricle in alligators, and proposed that this may be the source of the
phasic increase in resistance between the RV and pulmonary artery (PA).
Further, Burggren's (1978
) work
on turtle hearts implies a 200-300 ms delay mechanism linking depolarization
in the main ventricle to that in the bulbus surrounding the PA. There are no
published reports that describe a link between depolarization of the RV and of
the cog-wheel valve muscle in crocodilians nor the phasic relationships
between valve depolarization and the central pressure gradients causing
P
S shunting. In this paper, we present evidence that cog-wheel valve
activity is synchronized with RV depolarization through a nodal delay
mechanism and that the phasic relationships that exist between RV contraction
and valve activity are a key mechanism allowing crocodilians to regulate
shunting on a beat-by-beat basis.
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Materials and methods |
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Anaesthesia and instrumentation
Animals were initially sedated by injecting 25 mg kg-1 Ketamine
HCl (Ketalean, Bimeda-MTC, Cambridge, Ontario, Canada) into the tail
musculature, and then placing a mask containing a Halothane-wetted cloth over
their nostrils (MTC Pharmaceuticals, Cambridge, Ontario, Canada). When the
animals had been sufficiently sedated, they were weighed and placed supine on
a surgical table. They were then intubated and ventilated with a small-animal
ventilator, modified for use on alligators, and brought to surgical
anaesthesia with 3-4 % Halothane in 1:1 N2O:O2. A
catheter was placed in the right femoral vein, and infusion of Ketamine (5-15
mg-1 kg-1 h-1) was initiated. Halothane and
N2O anaesthesia were suspended at this point, but forced
ventilation with 100 % oxygen was continued. A heating pad was used to
maintain core body temperature at 30 °C throughout the experiments
(monitored using a rectal probe).
Xylocaine (2 % lidocaine HCl, Astra Pharma Inc., Mississauga, Ontario, Canada) was then injected subcutaneously along the ventral midline, and an incision was made through the skin and ribs to expose the heart and central vasculature. The heart was exposed by slitting the pericardial sac along the rostro-caudal midline. Silk sutures were tied to the cut edges of the pericardium and secured to a ring stand placed above the heart. This formed a bath around the heart that was filled with mineral oil to prevent desiccation and to reduce the bulk flow of current around the heart. A non-occlusive pressure catheter (Bolab medical vinyl tubing, Lake Havasu City, Arizona, USA), pre-treated with an anticoagulating agent (TD-MAC, Polysciences Inc., Warrington, Pennsylvania, USA), was inserted into the right subclavian artery. The tip of a 16-gauge hypodermic needle was fixed to a second pressure catheter and inserted into the pulmonary artery. A third catheter, similarly fashioned, was inserted directly into the right ventricle through the ventricular wall. Catheters were filled with degassed, heparinized (40 i.u. ml-1), 0.9 % NaCl saline, cleared of bubbles and connected to Deltran II pressure transducers (Utah Medical Products, Midvale, Utah, USA). These transducers were routinely calibrated against a mercury column during experiments.
Bipolar ECG electrodes (1 mm tip spacing) were made from 44-gauge copper magnet wire and chemically sharpened. One was inserted into the main RV muscle mass, and the other was inserted into the centre of the mass of muscle surrounding the cog-wheel valve. ECG electrodes were connected to Gould isolated preamplifiers (model 11-5407-58) and Gould universal amplifiers (model 13-4615-58) with a 3 Hz to 1 kHz band-pass. The ECG data were digitally filtered offline using a high-pass finite impulse response (FIR) filter (10-30 Hz cut-off) to remove movement artifacts. All pressure and ECG data were collected on a computer using LabTech Notebook Pro v9 software (Labtech, Andover, Massachusetts, USA).
ECG recordings
Propagation of the ECG across the RV and into the muscle surrounding the
cog-wheel valve was recorded by positioning one electrode in the cog-wheel
muscle (located approximately 1 cm from the base of the RV) and a second
electrode at different locations on the RV (11-15 different locations in each
of three animals). Conduction velocity across the RV was calculated as the
slope of the regression relating the distance between electrodes and
conduction time. The intercept of this relationship was the conduction delay
that occurred at the junction of the RV and cog-wheel valve muscle (nodal
delay).
Experimental manipulations
After recording the RV conduction velocity and delay, the effects of
parasympathetic and cholinergic stimulation on central pressures, ECGs and
cog-wheel valve function were studied. ECG electrodes were placed in the
middle of the RV and in the muscle mass surrounding the cog-wheel valve.
Pressures from two of the three catheters (RV, subclavian, PA) and both ECGs
were measured under `control' conditions (no manipulations), when cog-wheel
valve contraction and heart rate were modified by direct application of
acetylcholine (ACh) to the muscle surrounding the cog-wheel valve or to the RV
muscle (see Table 1 for
details), during vagal stimulation or after cog-wheel valve function had been
temporarily weakened by injecting Xylocaine or the valve had been killed by
injection of 95 % ethanol into the cog-wheel valve muscle. Vagal stimulation
was successful in two of the three animals in which it was attempted; we
report results from only the two successful experiments. In these animals, a
cuff electrode (custom-made) was placed around the isolated left vagus nerve,
and the stimulation frequency was set at 10, 20 or 50 Hz (50 µs pulse
duration and 5-7 V amplitude). Changes in pressure profiles, heart rate, the
conduction delay between the RV and cog-wheel ECGs, the phase of the cog-wheel
ECG (see below) and the integrated cog-wheel ECG (see below) were measured
after these manipulations. These experimental recordings were bracketed by
control recordings, although it was not possible to bracket experiments in
which the cog-wheel muscle was killed with ethanol.
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Phase was defined as the percentage ratio of the conduction delay to the duration of a cardiac cycle (i.e. the percentage of a cardiac cycle that elapsed between the RV ECG and the cog-wheel ECG). The integrated cog-wheel ECG was used as a measure of the strength of the cog-wheel depolarization or the muscle's activity; the filtered cog-wheel ECGs were rectified, and the voltage/time integral was subsequently measured over the period of the ECG. All calculations were made using AcqKnowledge software (v3.01 BIOPAC Systems, Inc., Santa Barbara, California, USA). At the conclusion of each experiment, the animals were killed with an intracardiac overdose of pentobarbital, and the hearts and central vessels were dissected to confirm the appropriate placement of all pressure catheters.
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Results |
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Timing of the cog-wheel valve ECG
The delay between the RV ECG and the ECG in the cog-wheel valve muscle
decreased as the electrode in the RV was moved towards the base of the heart
(i.e. closer to the cog-wheel valve) (Fig.
4), suggesting that the RV ECG spread across the RV surface from
the apex towards the base. The slope of the relationship between electrode
separation and conduction delay is the conduction velocity across the RV and
averaged 91±23 cm s-1
(Fig. 4). The intercept of this
relationship is the nodal delay that occurred at the junction of the RV and
cog-wheel muscle and averaged 248±28 ms in the three animals studied
(Fig. 4). This delay was only
slightly shorter than the total conduction delay measured from the centre of
the RV to the cog-wheel valve muscle (267±21 ms, N=9), which
includes both the time for the action potential to sweep over the RV and the
delay associated with its passage across the RV/cog-wheel junction. Thus,
approximately 90 % of the total conduction delay was due to a nodal delay at
the RV/cog-wheel junction. The mean phase of the cog-wheel muscle ECG was
13.2±1.89 % of a cardiac cycle. There was a highly significant
relationship between phase and heart rate
(Fig. 5A) and between phase and
absolute delay (Fig. 5B). There
was no relationship between the absolute ECG delay and heart rate
(Fig. 5A).
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Because of the slow heart rates exhibited by these animals (28.6±2.2 beats min-1), it was possible to confirm visually that contraction of the muscle surrounding the cog-wheel valve coincided with the cog-wheel muscle ECG. Further evidence that the cog-wheel muscle ECG coincided with valve contraction comes from the changes in RV and PA pressures that followed the cog-wheel muscle ECG (see above). We did not detect a deflection in the cog-wheel ECG that might signify termination of the action potential (equivalent to a ventricular `T' wave). However, relaxation of the cog-wheel valve muscle preceded relaxation of the ventricle by a period great enough that it could easily be observed; the duration of the cog-wheel contraction was considerably shorter than that of the ventricle.
Manipulation of valve function
Conduction delay was quite constant for a given heart working at a
particular heart rate. However, it changed when the heart was vagally
stimulated or when ACh was applied to the cog-wheel valve muscle. In the two
animals in which vagal nerve stimulation was successful, heart rate,
conduction delay and cog-wheel phase all decreased substantially
(Table 1). There was also a
decrease in the integrated cog-wheel ECG
(Table 1), signifying a
weakening of cog-wheel muscle contraction. From our limited data, it appeared
that the lower stimulation frequencies (10 and 20 Hz) were more effective than
the high stimulation frequency (50 Hz) at eliciting these effects, although no
clear pattern between vagal stimulation frequency and cog-wheel ECG delay
emerged.
All four animals which had ACh applied topically to the cog-wheel valve muscle showed a decrease in heart rate and a considerable weakening of the integrated cog-wheel ECG (Table 1). The effect on the conduction delay was variable, ranging from an increase of almost 60 % to a decrease of 40 % to complete blockade of cog-wheel muscle contraction. Together with the reduction in the integrated cog-wheel ECG was a reduction in the secondary rise of pressure in the RV (Figs 2B,D, 3C). All these effects were reversible as the ACh washed out.
The effects of application of Xylocaine to the cog-wheel muscle were variable in the two instances it was attempted (Table 1). In one case, the cog-wheel muscle was inactivated and in the other case there was an increase in conduction delay but no effect on the integrated cog-wheel ECG.
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Discussion |
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Although we believe that synchronization of RV depolarization with valve
contraction is the primary mechanism that initiates/controls shunting, a
number of secondary mechanisms by which PS shunting may be influenced
have also been proposed. These include: (i) alterations in RV contractility,
(ii) alterations in pulmonary resistance, including those associated with
ventilation, (iii) changes in systemic vascular resistance, and (iv) changes
in right ventricular end-diastolic volume (via a Starling effect)
and, thus, changes in RV pressure development
(Shelton and Jones, 1991
;
Axelsson and Franklin, 1997
;
Hicks, 1998
).
More recently, Franklin and Axelsson
(2000) report that shunting may
be influenced through ß-adrenergic control of resistance in the
subpulmonary conus, which contains the cog-wheel valve. Injection of the
competitive ß-adrenergic antagonist sotalol into the right side of the
heart increased resistance in the pulmonary outflow tract and induced shunting
in isolated, perfused hearts of the estuarine crocodile Crocodylus
porosus. The subsequent addition of a saturating concentration of
adrenaline caused the shunt to be abolished. While such observations support
the idea that ß-adrenergic stimulation can affect the shunt, the
mechanism they propose (direct, adrenergic stimulation of the cog-wheel muscle
causing valve relaxation) is seemingly at odds with the normal response of
cardiac muscle to adrenergic stimulation. If the cog-wheel muscle mass is of
the cardiac type, which it appears to be, adrenergic stimulation would be
expected to cause valve closure and thus promote P
S shunting, and
removal of ß-adrenergic stimulation by sotalol treatment would diminish
the force of cog-wheel valve contraction and inhibit shunting; this is exactly
opposite to what was observed. This leads us to the conclusion that either the
cog-wheel muscle's response to adrenergic stimulation is very unusual
(relaxation) or perhaps that the fibre orientation in the valve is such that
contraction leads to valve opening (M. Axelsson, personal communication).
Interestingly, adrenergic stimulation of the aortic outflow tract in
crocodiles leads to vasoconstriction
(Axelsson and Franklin, 2001),
presumably through an
-adrenergic response. If the pulmonary outflow
tract behaves similarly (which we do not know at this point), then adrenergic
stimulation would promote shunting. This would not be consistent with the
effects of adrenergic stimulation on shunting noted by Franklin and Axelsson
(2000
) nor with its effects in
animals; adrenergic stimulation in alligators increases systemic blood
pressure (Shelton and Jones,
1991
) to levels that may exceed the pressure that can be developed
by the RV, and disturbing instrumented alligators increases pulmonary blood
flow and always terminates shunting (D. A. S., K. G. and D. R. J., unpublished
observations). However, a ß-adrenergic mechanism that promoted
vasodilation in the pulmonary outflow tract would be in accord with a loss of
the shunt under adrenergic tone. Sustained, ß-adrenergic dilation of the
pulmonary outflow tract could decrease the ability of the animal to shunt by
two mechanisms. First, dilation of the pulmonary outflow tract may
significantly increase blood flow into the PA during early systole, leaving
only a small volume of blood in the RV. This may prevent the RV from
developing the pressure required to initiate a P
S shunt. Second,
dilation in close proximity to the cog-wheel valve may expand the subpulmonary
conus to such a degree that the cog-wheel valve could not effectively occlude
the pulmonary outflow tract. It will be most interesting to learn what the
effects of adrenergic stimulation on the pulmonary outflow tract are and what
the anatomy of the cog-wheel valve musculature is in relation to its behaviour
under adrenergic stimulation.
Cog-wheel valve contraction and shunting
In our anaesthetized alligators, there appeared to be a substantial
resistance in the pulmonary outflow tract that was independent of cog-wheel
valve contraction (but see Axelsson et al.
(1996) for an example in
crocodiles where there is very little resistance). This resistance caused a
large pressure drop between the RV and PA during early systole, before the
cog-wheel ECG (Figs 2A,C,
3A) (see also
Shelton and Jones, 1991
;
Grigg and Johansen, 1987
), and
it did not disappear when the cog-wheel muscle was inactivated (Figs
2B,D,
3C). The catheter used to
measured PA pressure was placed just distal to the cog-wheel valve, and the
majority of the resistance we measured would therefore have resided within or
very close to the valve. However, despite the substantial pulmonary resistance
when the cog-wheel muscle was not active, RV pressures never attained levels
required for shunting (Fig. 2)
and, as far as we are aware, the shunt is always accompanied by a biphasic RV
pressure profile showing the dramatic secondary rise in pressure associated
with phasic, cog-wheel valve contraction. The resistance appears to lessen as
pulmonary and RV pressures rise (Jones and
Shelton, 1993
; D. A. S., K. G. and D. R. J., unpublished
observations), which would be consistent with the cartilaginous nodules of the
cog-wheel valve being `blown open' at higher pressures.
Inhibition of cog-wheel valve contraction, whether by ethanol, ACh, vagal
stimulation or Xylocaine, caused RV pressure to track the lower PA pressure
throughout systole, and there was no possibility of a shunt. Similar pressure
profiles in the RV and pulmonary outflow tract, reflecting activity and
inactivity of the cog-wheel valve, have also been observed during chronic
recordings from the RV and PA of unanaesthetized, estuarine crocodiles
(Axelsson and Franklin, 1997).
Thus, while we agree with Franklin and Axelsson
(2000
) that shunting in
crocodilians is influenced by the relative resistances in the lung
versus systemic circulations and that the major control site of this
resistance is the subpulmonary conus, it does not appear that maintained tonus
in the subpulmonary conus induced by adrenergic withdrawal is adequate in
itself to elicit shunting; active contraction of the valve following muscle
depolarization is required. In support of this, we provide direct evidence
correlating valve contraction and closure (the cog-wheel valve ECG) with the
secondary rise in RV pressure that always precedes shunting (Figs
2,
3).
Cog-wheel ECG
In our study, the wave of depolarization spread across the RV from the apex
towards the base with a conduction velocity of 91 cm s-1. This
conduction pattern is similar to that observed by Christian and Grigg
(1999) in crocodiles; however,
the conduction velocity they report (65 cm s-1) is much slower.
Differences in temperature or species may contribute to this discrepancy;
Christian and Grigg (1999
) do
not report the temperature used in their experiments. The cog-wheel valve
muscle, located at the base of the RV, appeared to be activated by a
depolarization that originated in the RV, and in each animal the two events
were synchronized by a relatively consistent delay. Approximately 90 % of the
delay between the RV ECG and the cog-wheel valve ECG appeared to reside at the
junction between the two muscle masses
(Fig. 5). These data imply that
a mechanism akin to AV nodal delay exists in the alligator heart.
The existence of such a node and the physiological mechanism responsible
for the delay have not previously been described in the alligator heart.
Burggren (1978) noted a similar
phenomenon in turtles, where a delay of 200-300 ms existed between
depolarization of the ventricle and the bulbus cordis surrounding the PA. He
attributed the delay to a slow conduction velocity (2 cm s-1 or
one-fifth to one-tenth of that of the ventricle) in the transition zone
between the cavum venosum of the ventricle and the bulbus cordis. When
watching the contraction of the cog-wheel muscle in alligators, it appeared
that the entire muscle mass contracted synchronously and, hence, it is
unlikely that the delay we report was due to very slow propagation across the
cog-wheel muscle mass itself. However, we did not measure conduction
velocities across the small cog-wheel muscle to confirm this. White
(1968
) alludes to an
unpublished observation of a 350 ms delay in alligators at 25 °C. In our
alligators, the conduction delay averaged 248 ms at 30 °C. Pressure
recordings indicate that this is long enough to allow some PA flow during
early systole (a rise in PA pressure), but short enough to obstruct the PA
before the full stroke volume is delivered to the lungs. Sufficient blood then
remains in the RV to cause a substantial secondary rise in RV pressure during
the latter half of systole and, thus, P
S shunting (Figs
2,
3).
The absolute conduction delay was not dependent on heart rate, but the phase was (Fig. 4A). Thus, changes in phase appear to be more indicative of changes in heart rate (diastolic interval) than of changes in ECG delay. It may be that the absolute delay is maintained within a relatively constant range because the timing of cog-wheel valve closure relative to the onset of RV systole would be critical in controlling shunting, rather than the phase per se. The significant relationship between phase and ECG delay (Fig. 4B) may simply reflect the constancy of heart rates in these animals, such that any change in delay would translate directly into a change in phase.
Changing the delay of the cog-wheel ECG or the ECG magnitude (strength of
cog-wheel contraction) may be mechanisms by which the degree of shunting can
be controlled. The existence of specialized fibres whose conduction velocity
is under autonomic control is well established in reptilian hearts
(Burggren, 1978;
Christian and Grigg, 1999
; and
references therein). If the cog-wheel ECG occurred very late in ventricular
systole, most of the RV output would be sent to the lungs, and a shunt would
not occur. Alternatively, if the timing of cog-wheel valve contraction were
shifted earlier in systole, more of the cardiac output could be shunted back
to the systemic circulation.
Vagal stimulation in alligators resulted in a marked decrease in the
absolute delay and phase of the cog-wheel ECG
(Table 1). Further, Malvin et
al. (1995) found that efferent
vagal stimulation in alligators promoted pulmonary vasoconstriction. Both
these responses would favour P
S shunting. However, the integrated
cog-wheel ECG was decreased under vagal stimulation
(Table 1), which presumably
reflects an inhibition of valve function and a decreased capacity to shunt. In
turtle hearts, peripheral stimulation of the cut vagus or application of ACh
causes the ventricular depolarization pattern to shift transiently from that
seen during apnoea to that observed during breathing, and the absolute
magnitude of the conduction delay is longer during breathing than during
apnoea (Burggren, 1978
). Both
these changes would favour blood flow to the lungs (inhibit shunting), the
latter by the mechanism we propose. In our experiments, the effect of ACh on
the conduction delay was variable (Table
1) and at present does not support a role for a direct effect of
ACh on the timing of valve closure and shunting. However ACh, like vagal
stimulation, did appear to weaken the cog-wheel ECG, and this may inhibit
shunting. Shelton and Jones
(1991
) did not see any effect
of ACh administration on the relative timing of events in the left and right
ventricles. In contrast, White
(1970
) noted that atropine
injection reversed both the diving-induced bradycardia and the large
RVPA pressure gradient in alligators, suggesting that the shunt may
also be cholinergically influenced.
Concluding remarks
The cog-wheel valve in alligators is surrounded by a muscle mass that is
somewhat isolated from the RV. This muscle produces a distinct ECG signal that
is temporally separated by approximately 250 ms from the RV ECG measured at
the base of the heart. The cog-wheel ECG signals the onset of valve closure
and obstruction of the pulmonary outflow tract, resulting in a phasic,
secondary rise in RV pressure and a fall in PA pressure, and sets up the
haemodynamic conditions required for PS shunting. The extent of the
delay could have a major influence on RV pressure and the degree of shunting.
Vagal and cholinergic stimulation had significant but varied effects on the
cog-wheel ECG. Both appeared to weaken cog-wheel valve contraction, which may
inhibit shunting. Vagal stimulation decreased the delay between the RV and
cog-wheel ECGs, which could promote shunting. Although these latter results do
not provide a clear picture of how autonomic nervous tone would control the
extent of P
S shunting, they do, in combination with the results of
Franklin and Axelsson (2000
)
and Axelsson and Franklin
(2001
), provide strong evidence
that nervous and/or humoral mechanisms acting on the subpulmonary conus and
valve can markedly influence the magnitude of P
S shunting in
crocodilians.
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Acknowledgments |
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References |
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