Department of Pharmacology and Toxicology, Cardiovascular
Research Institute Maastricht, Universiteit Maastricht, Maastricht,
6200 MD, The Netherlands
Control of blood pressure and of
blood flow is essential for maintenance of homeostasis. The hemodynamic
state is adjusted by intrinsic, neural, and hormonal mechanisms to
optimize adaptation to internal and environmental challenges. In the
last decade, many studies showed that modification of the mouse genome
may alter the capacity of cardiovascular control systems to respond to
homeostatic challenges or even bring about a permanent
pathophysiological state. This review discusses the progress that has
been made in understanding of autonomic cardiovascular control
mechanisms from studies in genetically modified mice. First, from a
physiological perspective, we describe how basic hemodynamic function
can be measured in conscious conditions in mice. Second, we focus on the integrative role of autonomic nerves in control of blood pressure in the mouse, and finally, we depict the opportunities and insights provided by genetic modification in this area.
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INTRODUCTION |
THE DEVELOPMENT OF TECHNIQUES to
genetically modify mammals has boosted research to identify the
molecular mechanisms involved. The number of candidate genes identified
by gene array studies is accelerating and need for screening is rapidly
expanding. For technical reasons, the functional consequence of gain or
loss of one or more genes is generally assessed in the mouse. Because of its small size, determination of the cardiovascular phenotype is not
easy. In the last decade, however, many techniques that were developed
to study hemodynamics in larger species have been miniaturized. In this
process, studies were initially restricted to in vitro techniques. Now,
in vivo approaches are feasible and aspects of cardiac and vascular
function can be measured in conscious mice.
In this review, we will mainly focus on the integrative role of
autonomic nerves in control of blood pressure in the mouse. After a
detailed description of basic hemodynamic function in the mouse, we
will discuss the genotypes that affect control of blood pressure by
altering sensory, central, and efferent processing of autonomic nervous
activity. The impact of anesthesia on cardiovascular parameters in the
mouse is such that it could easily overshadow subtle changes induced by
gene manipulation. Therefore, observations will be discussed that have
been acquired primarily in conscious conditions in mice.
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BASIC HEMODYNAMIC CHARACTERISTICS IN MICE |
Is the mouse just a small rat? Can we, by using mathematical
scaling techniques, make predictions on hemodynamic characteristics in
the mouse? Are all mice equal? Are reported differences between mouse
strains of physiological relevance or do they mirror shortcomings of
previous technology as we proceed to improve ways to monitor physiological processes in the mouse? These questions are of relevance, certainly as we intend to extrapolate the results of our studies in
mice to the human situation. Presently, several hundred strains and
substrains of mice are known, and many new inbred strains are being
expected, accepting the nomenclature rules that a strain should be
regarded as inbred when it has been mated brother × sister for 20 or more consecutive generations (11, 36). Even within a
single strain, a large degree of genetic diversity may exist. For
example, the genetic variance in mice of the 129 strain, which is of
importance in creating knockout and other targeted mutant mice,
was so large that the International Committee on Standardized Genetic
Nomenclature for Mice introduced a new nomenclature to distinguish
between the different parental lines and related 129 strains
(187, 200).
In our view, differences between techniques and methodology have been a
major source for disagreement in blood pressure levels between strains.
However, we expect that improving technology will take away many
inconsistencies, certainly in the cardiovascular area where hemodynamic
parameters are known to depend heavily on experimental conditions. For
instance, a recent report by Mattson (132) showed that
blood pressures of five strains of mice (Swiss Webster, A/J, C57BL/6J,
C3HeBFe/J, and SWR/J) were unexpectedly very comparable [range of mean
arterial pressure (MAP): 108-114 mmHg], when measurements
were performed in the conscious state using chronic catheterization
techniques. For this reason, we avoided reviewing potential strain
differences. Rather, we will focus on the opportunities that are
available now to characterize hemodynamics in mice in the conscious state.
In global terms, cardiac and vascular morphology differences between
mouse, rat, and human species are only subtle. Also, many physiological
parameters are very comparable. This is illustrated in Table
1 in which functional physiological
characteristics that have been recently measured in mice are compared
with those predicted by allometric formulas (180, 188). It
appears that many of the hemodynamic values observed in the mouse are
within the range as predicted by the formulas, supporting the view that physiological mechanisms in mice are closely related to those of
humans. The table is completed with values for arterial pressure that
are independent of scale. Parameters that can be measured in mice in
the conscious state are discussed in the next section.
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Table 1.
Comparison of physiological parameters in humans and mice based on
allometric scaling equations as well as in vivo measurements
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ELECTROCARDIOGRAM |
In conscious mice, the most reliable indexes of cardiovascular
function are obtained by telemetry. This technique offers the ability
to record hemodynamics for relatively long periods of time in
conscious, freely moving animals without the limitations of restraint
or anesthesia (139, 204). Perhaps the most accessible measure that can be obtained in this way is the electrocardiogram (ECG). Depending on the manufacturer, the subcutaneous implantation of
a single device may simultaneously render values for temperature and
locomotor activity, making the device attractive for behavioral studies
too (9, 82, 90, 91, 192, 221). Characteristic for the
mouse ECG is that a clear ST segment is absent and that the T wave
merges with the final part of the QRS complex. Mouse ECG changes in
response to myocardial ischemia are comparable to those
observed in rats, showing R wave enlargement and ST-segment elevation
(219). Until recently, the view was held that the size of
the mouse atrium was too small to induce fibrillation via reentrant circuits. However, as shown by Wakimoto et al. (211),
sustained atrial tachycardia and fibrillation could be induced with
endocardial pacing after cholinergic agonist administration. The
genetic aspects and application of the ECG technique to assess
anti-ischemic and antiarrhythmic interventions have been
reviewed in detail by Wehrens et al. (219).
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BLOOD PRESSURE |
Telemetric recording of murine blood pressure is technically more
challenging. So far, only a few reports have been published (17,
18, 60, 108, 129, 138, 139, 183). After the implantation of the
pressure sensor, blood pressure and heart rates (HRs) are slightly
elevated for 4-5 days (17). After this recovery
period, day-night rhythms are reestablished with daytime blood
pressures being ~20 mmHg lower than nighttime blood pressures.
Average 24-h blood pressure values obtained by telemetry are usually in
the range of 90 to 115 mmHg in wild-type control mice. Average 24-h HR
values are usually between 550 and 650 beats/min. Comparable pressures
and day-night pressure variations have been reported when tethering
techniques were applied for continuous long-term blood pressure
monitoring (88, 112, 131, 132). Also, with tethering
techniques, blood pressure and HR rhythms needed 4-5 days to
become fully expressed again (88).
With telemetric devices, blood pressures have been recorded up to 150 days after implant (139). With tethering techniques, the
recording period is limited (~3 wk), but it allows the simultaneous implantation of a venous line and assessment of drug effects without disturbing the animal. In most studies using telemetric devices, mice
have not received additional catheters and need to be handled each time
a drug or substance needs to be administered. However, handling of the
mouse disturbs hemodynamics considerably and may obscure acute drug
effects. Even entering the test room for only 5 min has been shown to
increase locomotor activity, HR, and temperature in mice for 30 min
(13). In our experience, mice are more active than rats
when kept in standard laboratory cages. To minimize arousal, animals
are accustomed to human sounds by playing the radio in the animal rooms
during daytime hours. Furthermore, mice are allowed to settle for
1 h after they have been connected to the measuring equipment.
Despite these efforts, baseline hemodynamics are easily disturbed by
movement of the mouse. Figure 1
illustrates the variability in hemodynamics one may observe when a
mouse is actively moving through the cage. As can be seen in that
tracing, blood pressure variability (within a 10-s period) can be quite large. Even when mice are sleeping, average blood pressure may vary up
to 10 mmHg between nonrapid eye movement and rapid eye movement sleep
stages (179). Measurements in resting conditions are
required when the investigation aims to uncover subtle effects introduced by genetic or pharmacological intervention. Alternatively, long recording periods are required to identify small differences. In
many experimental settings, continuous blood pressure measurements are
either not feasible or unnecessary. In this type of study, blood
pressure may be recorded from arterial catheters that are guided to the
neck of the mouse and extended from the cage on the day of the
measurement. Preferably, the arterial catheter should be inserted into
the abdominal aorta via the femoral artery and not via a carotid
artery, because the chance of microembolisms causing problems is much
greater in the latter approach (32).
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Fig. 1.
Hemodynamic variability in a conscious C67Bl6 mouse
instrumented with a transit time flow probe to measure ascending aortic
blood flow, which is a measure of cardiac output (CO). Note the drops
in blood pressure that occurred when the animal was moving through the
cage (indicated by the arrows). HR, heart rate; MAP, mean arterial
pressure; SV, stroke volume.
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Estimates of systolic blood pressures in mice can be achieved by the
noninvasive tail-cuff technique (92, 109). Mice are usually restrained and heated to obtain adequate pulsatile pressure signals in this peripheral organ that is very responsive to sympathetic influences. Individual readings of this method vary considerably and
repeated measurements are required. For these reasons, this method is
not very accurate in assessing true values of blood pressure in mice.
Also, in rats, this method is not regarded as very reliable
(81). The tail-cuff method may be useful when pressure
levels between groups have to be compared repeatedly over long time periods.
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CARDIAC OUTPUT |
Cardiac output (CO) has been assessed in mice with various
techniques ranging from traditional indicator-dilution techniques (7, 14, 166, 178, 208, 215, 220) up to noninvasive
echocardiography (45, 210, 226) and magnetic resonance
imaging (222, 223). Whereas most of the dilution-based
methods need multiple blood sampling, which is limited in the mouse,
the noninvasive imaging techniques cannot be applied continuously and
are in many cases performed under anesthesia. Because most anesthetic
drugs reduce HR by more than 200 beats/min, reliable estimates of CO
have not been achieved yet in conscious mice. Recently, we used
miniaturized transit time flow probes as well as electromagnetic flow
probes to measure ascending aortic flow in adult conscious mice
weighing 30 to 40 g (87). In that study, stroke
volume (SV) ranged from 20 to 46 µl and CO from 12 to 27 ml/min. When
normalized for body weight, the average (means ± SE,
n = 7) SV index and cardiac index amounted to 846 ± 173 µl/kg and 532 ± 103 ml · min
1 · kg1,
respectively. Now, we are also able to implant these probes in mice
weighing 20-30 g (Fig. 2). In mice,
the cardiac index is nearly twice the value found in rats and even 10 times greater than observed in humans (see Table 1). These differences
are entirely due to HR. SVs are ~1 µl/g body wt across the three
species. Thus, in an adult mouse with a blood volume of 2.5-3 ml
(70 ml/kg) and a CO of 20 ml/min, blood is rapidly recirculating seven
to eight times per minute. These hemodynamic characteristics fit the
allometric predictions (Table 1).
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Fig. 2.
CO, SV, MAP, and HR as measured in resting conditions (Rest) in
conscious C57BL6 mice (n = 6) instrumented with transit
time flow probes placed on the ascending aorta. To stimulate CO (Stim),
measurements were also made during volume loading (intravenous Ringer
solution 2 ml in 1 min, solid bars) and during intravenous infusion of
dobutamine (0.5 µg · kg1 · min1). Values
in the open bars give the maximally induced changes under these
conditions. Values are means ± SE. Values obtained during volume
loading were compared with those obtained with dobutamine using
unpaired t-tests. Statistical significance was accepted at
*P < 0.05.
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To characterize cardiac function, we explored ways to record maximal
values of CO in mice. Exercising instrumented and tethered mice is
difficult. Therefore, we chose to stimulate CO by increasing circulating volume. This is achieved by infusing intravenously warmed
Ringer solution at a rate of 2.5 ml/min for 40-50 s.
Alternatively, CO can be increased by infusing the inotropic agent
dobutamine. Applying both stimuli in C57Bl6 mice, we observed maximal
CO values being 30-45% above their resting values (Fig. 2).
Remarkably, the increase of CO induced by volume loading appeared to
depend on a rise in SV rather than a rise in HR, whereas during
dobutamine infusion, the reverse was true. These findings suggest that
the present protocols may underestimate true maximal values of CO. Evidence from studies on force-frequency modulation of heart function in the mouse (54) supports the view that ventricular
filling is a critical determinant of CO. With the use of miniaturized pressure-volume catheters, it was found that end-diastolic volume declined progressively with increasing HRs in mice (54).
Therefore, at HRs above 700, a limited ventricular filling may prevent
a further increase of CO and cardiac contractility. This may also be
the reason that, in contrast to humans in whom CO can increase four to
five times, mice have a limited ability to increase CO.
Because of the limited cardiac reserve, rapid changes in venous return
may influence CO and arterial blood pressure considerably. To explore
this further, we examined the effects of intravenous bolus injections
of fluid on hemodynamics in mice. As can be seen in Fig.
3, following a 100-µl bolus injection
of saline, maximal changes in pressure and HR were relatively small.
However, SV and CO increased for a few seconds up by 10-15%. In
addition, we repeatedly observed that in actively moving mice, blood
pressure may fall within seconds by more than 20 mmHg, especially when the animal stretches its body forward or compresses its thorax otherwise. As indicated by the arrows in Fig. 1, there is a concomitant fall in SV, CO, and MAP, which is not buffered by acute changes in HR.
To quantify to which extent variations in CO depend on those occurring
in HR or in SV, we computed coherence values between HR and CO on the
one hand and SV and CO on the other (87). The results
indicated that, at frequencies lower than 0.1 Hz, fluctuations in SV
and HR contribute evenly to fluctuations in CO. At frequencies above
0.1 Hz, however, variations in CO were mainly determined by those
occurring in SV. Thus, in mice, control of CO seems to be hampered by
the sensitivity of SV to rapid changes in venous return (e.g.,
behaviorally induced) and limited ventricular filling at high HRs.
However, it should be noted that this accounts only for very short-term
fluctuations and is probably not distressing the mouse because of its
horizontal position. As we will illustrate further below, the response
time of reflex mechanisms is such that they are unable to buffer these
fast beat-to-beat changes in hemodynamics.
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Fig. 3.
Maximal hemodynamic changes induced by a 100-µl iv
injection of saline in conscious mice (n = 6). TPR,
total peripheral resistance.
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CARDIAC DIMENSIONS AND EJECTION FRACTION |
Although echocardiography and Doppler techniques are usually
applied in the anesthetized state, some groups are now able to use
these techniques in conscious restraint conditions (76, 86, 165,
196, 227). In this condition, CO is comparable to the stimulated
values observed by our direct measurements (87). Pentobarbital sodium and ketamine/xylazine depress cardiac function parameters by more than 30% (196, 227). Especially HR can
be severely reduced by high doses of ketamine/xylazine. According to
Hart et al. (65), murine cardiac function becomes abnormal when HR is lower than 300 beats/min. If measurements in conscious conditions are not feasible, then volatile- (196) or
-chloralose-urethane-based (55) anesthetic regimens are
a reasonable alternative to sustain HR. Various aspects of the
echocardiographic technology and its application in mouse studies have
recently been reviewed by Hoit (76).
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REGIONAL BLOOD FLOWS |
Distribution of CO has been assessed in mice using microspheres
(6, 7, 142, 166, 178, 215). The mouse brain receives ~2-4% of CO (166), whereas in humans, 11-13%
is found. However, given the relative smaller brain size of the mouse,
this is not surprising. Splanchnic blood flow and renal blood flow
(RBF) were 14 and 11% of total CO, respectively. These values are
lower than those generally observed in humans (25 and 20%,
respectively), suggesting that other organ beds are relatively
overperfused in mice. The insertion of a catheter into the left
ventricle may be stressful and may be associated with renal and
mesenteric vasoconstriction, certainly when these measurements are
performed in conscious conditions (6). In general,
indicator-dilution techniques require repeated sampling from body
compartments. Given the sensitivity of CO to volume changes, the
results should be interpreted with care. Recently, Hallemeesch et al.
(63) refined such methods and were able to determine
metabolic fluxes and blood flow across several organs without waste of
blood. Values for liver, renal, and hindquarter blood flow by their
methods were 1.2 ± 0.3, 1.0 ± 0.1, and 1.1 ± 0.3 ml · 10 g body wt1 · min1, respectively.
RBF estimates obtained by microspheres or para-aminohippurate clearance
techniques vary roughly between 1 and 2 ml/min (23, 166),
which is ~10-20% of CO. In terms of flow per gram kidney weight, values ranging from 3 to 8 ml · min1 · g1 have been
found. Comparable values have been obtained by direct measurements of
RBF using miniaturized transit time flow probes placed around the main
renal artery (2, 59, 61, 138). Up to now, this was only
possible in anesthetized conditions. Very recently, Callahan et al.
(unpublished observations) were able to implant such a probe
chronically in a mouse allowing continuous RBF measurements in
conscious conditions (Fig. 4). Glomerular filtration rate (renal inuline clearance, anesthetized conditions) ranges from 0.7 to 1 ml · min1 · g kidney
wt1 (15, 153, 154). When scaled to body
weight, renal function parameters of mice and humans are comparable
(188) (see Table 1). This suggests that volume handling by
the kidney is similar in mice and humans and makes the mice apt to
study human pathology. The renal physiology of the mouse has been
reviewed in more detail by Meneton et al. (135) and Lorenz
(119).
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Fig. 4.
Tracing of renal blood flow (RBF) in a conscious mouse
several weeks after chronic implantation of a miniaturized transit time
flow probe (Transonic). Courtesy by M. Callahan and T. Smith,
Departments of Orthopedic Surgery and Physiology and Pharmacology, Wake
Forest University School of Medicine, Winston-Salem, NC 27157.
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WEBSITES ON MOUSE PHYSIOLOGY |
In the past few years, websites are emerging that are part
of commercial or scientific initiatives, and they display a variety of
information on mouse physiology. In Table
2, we listed some of these sites that may
be of help for researchers interested in mouse physiology. The topics
vary widely and on these pages useful links to other sites are often
supplied.
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Table 2.
List of websites with additional information on scientific and
methodological aspects of mouse physiology
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ASSESSMENT OF AUTONOMIC FUNCTION IN MICE |
The autonomic nerves are crucial for maintaining
cardiovascular homeostasis. However, assessment of autonomic nervous
activity in mice is complicated. The approaches that have been used in this species are summarized below.
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MEASUREMENT OF CATECHOLAMINE CONCENTRATIONS IN PLASMA |
Traditionally, sympathetic activity has been assessed by
measuring plasma or tissue catecholamine levels. Plasma
norepinephrine (NE) concentrations range widely in mice. Values
as low as 0.2 ng/ml (101) up to 70 ng/ml (79)
have been reported. In the first study, the method of blood sampling
was not explained; in the latter study, blood was taken under ether
anesthesia. When blood is sampled via arterial catheters, plasma NE
concentrations usually range between 0.5 and 2 ng/ml (70, 126,
127). Other groups have reported baseline plasma NE values
~5-15 ng/ml (35, 69, 234). From these data, it
seems that plasma NE levels are about a factor 3 to 10 higher in mice
than in rats or humans. Whether this elevation is due to artifacts
in taking the blood samples or due to real species differences is
not clear. The methods of blood sampling and types of anesthesia do
certainly influence baseline catecholamine levels. On the basis of
the present data, it cannot be concluded whether circulating
catecholamines are really elevated in mice and indicative of enhanced
ongoing sympathetic nerve activity.
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DIRECT MEASUREMENTS OF AUTONOMIC NERVE ACTIVITY |
In the mouse, direct measurements of sympathetic nerve
activity have been obtained under anesthetized conditions only
(117, 229). Baroreceptor and chemoreceptor control of
renal sympathetic nerve activity (RSNA) were compared between rats and
mice during urethane anesthesia (117). Although HR was
~200 beats/min higher in the mouse than in the rat, basal RSNA was
reduced in the mouse. Obviously, the renal nerves are thinner in the
mouse than in the rat. There is no information about the caliber or
number of axons of renal nerves in this species. Therefore, it is
difficult to decide from such multifiber preparations whether the
reduced firing frequency is real or merely reflects the lower number of
axons in a preparation.
In relative terms, RSNA responses to baroreceptor loading and
unloading were comparable in the mouse and in the rat. Only the
baroreflex gain (in %
RSNA/mmHg) was slightly enhanced, being 2.4 ± 0.2 in mice vs. 1.9 ± 0.1 in rats. RSNA changes
evoked by hypoxia and hypercapnia were quite similar in both species.
It was recently shown that in mice ongoing levels of RSNA may depend on
circulating levels of ANG II (122). Ma et al.
(123) showed that ANG II was able to increase RSNA
substantially before and after ganglionic blockade, suggesting that the
hormone may directly activate postganglionic renal sympathetic
neurons. Although no data were shown, they reported that
similar effects could also be elicited by ANG II injections in rats.
This novel effect of ANG II was recently confirmed by studying the
cellular responses to ANG II in subpopulations of sympathetic neurons
isolated from murine aortic-renal ganglia. Thus, at least in the mouse
and rat, locally produced or high circulating levels of ANG II may
influence ongoing RSNA and hence mediate renin release, sodium
reabsorption, and RBF. To which extent this mechanism is involved in
controlling renal hemodynamics in conditions of elevated ANG II levels
has not been established yet. Baseline plasma ANG II
concentrations are ~20 fmol/ml in mice (28, 37, 189) and
do not differ much from values obtained in humans. Thus circulating
levels of ANG II do not seem to be responsible for the suggested
elevated sympathetic activity in the mouse.
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ASSESSMENT OF BARORECEPTOR REFLEX FUNCTION |
The baroreflex is one of the most potent regulators of
blood pressure. This reflex buffers blood pressure fluctuations by adapting CO and vascular resistance and is of eminent significance for
adequate perfusion of the brain, especially in species that are erect
most of the time. In the mouse, baroreflex-mediated parasympathetic and
sympathetic control of HR can be demonstrated by applying the classical
technique of injections of short-term vasoconstrictor or vasodilator
agents. Bradycardic responses to an intravenous bolus injection of
phenylephrine are found invariably. However, the rise of HR in response
to a bolus injection of nitroprusside is easily masked when the animal
is aroused or when resting hemodynamics have been disturbed otherwise
(159). As illustrated in Fig.
5, following an intravenous bolus
injection of phenylephrine, HR decreased within 1 s to near
minimal values after the initiation of the pressure ramp. In response
to sodium nitroprusside, HR increased even before the pressure fall
occurred. However, the rate of change in HR was much slower than
following pressure increments. In this example, following phenylephrine
injection, HR returned to near control values within 5 s before it
fell again, yet, less outspoken. From the bimodal characteristic of the
HR response, one may infer that the relatively fast parasympathetic
(activation) was followed by a slower sympathetic (withdrawal)
response. However, in the presence of atropine, HR never decreased
(88). Thus, at least in our setup, HR responses to rapid
pressure increments are mainly parasympathetically mediated and not due
to sympathetic withdrawal. The bimodal temporal pattern is probably the
result of a pharmacokinetic phenomenon. Given the fast circulation time of the blood in a mouse (~5 s), it is likely that after the first passage of phenylephrine, the agent reappeared in responsive tissue before its distribution was complete and, hence, caused a secondary increase in blood pressure and consequent decrease in HR.
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Fig. 5.
Tracings illustrate the effects of an intravenous bolus injection
of phenylephrine (A) and sodium nitroprusside (B)
on MAP and HR in a conscious mouse. Note the biphasic response in MAP
and HR following phenylephrine (indicated by arrows). For further
explanations, see text. (Figure is redrawn from Ref.
88.)
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Baroreflexes have also been studied in mice using short-term (~2 min)
infusions of vasoconstrictor and vasodilator agents to produce gradual
ramps in blood pressure (136). The advantage of this
method above bolus injections is that sufficient time is allowed for
full sympathetic adjustments. In addition, this method allows the
construction of sigmoidal curves to assess limits and gain of the
cardiac baroreflex (117, 136). Unlike for the rat
(68) or rabbit (167), the effect of blockade
of parasympathetic and sympathetic components has not been studied in
mice. There are no data yet demonstrating the feasibility of chronic
arterial baroreceptor denervation in the mouse. Only in acute
preparations, by whole vagotomy, baroreceptor-independent renal
sympathetic reflexes have been studied (122).
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ASSESSMENT OF CARDIOVASCULAR RESPONSES TO AUTONOMIC BLOCKING AGENTS |
The contribution of autonomic nerves to blood pressure control has
been examined by recording hemodynamic changes to autonomic blockers.
In conscious mice, acute ganglionic and -adrenoceptor (AR) blockade
decreases baseline blood pressure by ~20 mmHg (88, 95).
Blood pressure is not altered by acute muscarinergic receptor or 
-AR
blockade in mice. These blood pressure responses are not different from
those observed in rats, suggesting that vascular sympathetic tone is
similar in the species. HR responses to autonomic blockers, however, do
differ between mice and rats. During daytime hours, when mice are
resting, HR is generally higher than intrinsic HR, whereas in resting
rats, values are usually lower or close to intrinsic HR
(157). We estimated intrinsic HR as the resultant (±SD)
value obtained by averaging HRs across several studies using combined
muscarinergic and -blockade [516 ± 74 beats/min,
n = 5 (3, 52, 88, 124, 202)] or
ganglionic blockade [503 ± 86 beats/min, n = 4 (88, 124, 173, 202)]. In rats, intrinsic HR is
~350 beats/min (157). In mice, resting values of HR are usually found in the range of 550 beats/min or higher. Therefore, it is
not surprising that only limited tachycardic responses to atropine have
been obtained, and profound reductions in HR (usually 150-200
beats) to both ganglionic or -AR blockade have been reported. These
data suggest that cardiac sympathetic tone is higher in the
TOP
ABSTRACT
INTRODUCTION
1-ADRENERGIC RECEPTORS
-ADRENERGIC RECEPTORS
