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Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Anesthetic regimens commonly
administered during studies that assess cardiac structure and function
in mice are xylazine-ketamine (XK) and avertin (AV). While it is known
that XK anesthesia produces more bradycardia in the mouse, the effects
of XK and AV on cardiac function have not been compared. We
anesthetized normal adult male Swiss Webster mice with XK or AV.
Transthoracic echocardiography and closed-chest cardiac catheterization
were performed to assess heart rate (HR), left ventricular (LV)
dimensions at end diastole and end systole (LVDd and LVDs,
respectively), fractional shortening (FS), LV end-diastolic pressure
(LVEDP), the time constant of isovolumic relaxation (
), and the
first derivatives of LV pressure rise and fall
(dP/dtmax and dP/dtmin,
respectively). During echocardiography, HR was lower in XK than AV mice
(250 ± 14 beats/min in XK vs. 453 ± 24 beats/min in AV,
P < 0.05). Preload was increased in XK mice (LVDd:
4.1 ± 0.08 mm in XK vs. 3.8 ± 0.09 mm in AV,
P < 0.05). FS, a load-dependent index of systolic
function, was increased in XK mice (45 ± 1.2% in XK vs. 40 ± 0.8% in AV, P < 0.05). At LV catheterization, the
difference in HR with AV (453 ± 24 beats/min) and XK (342 ± 30 beats/min, P < 0.05) anesthesia was more variable,
and no significant differences in systolic or diastolic function were
seen in the group as a whole. However, in XK mice with HR <300
beats/min, LVEDP was increased (28 ± 5 vs. 6.2 ± 2 mmHg in
mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/dtmax: 4,402 ± 798 vs.
8,250 ± 415 mmHg/s in mice with HR >300 beats/min,
P < 0.05) and diastolic (: 23 ± 2 vs. 14 ± 1 ms in mice with HR >300 beats/min, P < 0.05)
function were impaired. Compared with AV, XK produces profound
bradycardia with effects on loading conditions and ventricular
function. The disparate findings at echocardiography and LV
catheterization underscore the importance of comprehensive assessment
of LV function in the mouse.
echocardiography; left ventricular function; murine physiology
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE MOUSE HAS EMERGED as an important animal model to study the cardiovascular effects of altered gene expression. It has been emphasized that careful cardiac physiological assessment of normal mice in basal states is a prerequisite to the accurate evaluation of genetically modified mice (13).
Anesthesia is commonly required for assessment of murine cardiac function. However, large animal studies have clearly documented significant effects of anesthesia on cardiovascular function. Many different regimens of general anesthesia have been used in mice, and a prior comparative study (5) suggested that the mixture of xylazine-ketamine (XK) is the most reliable in mice for inducing relaxation, sedation, and analgesia. A second commonly used anesthetic regimen is 2,2,2-tribromo-ethanol [avertin (AV)]. While it is known that XK produces profound bradycardia, its effects on cardiac function have not been directly compared with AV, which has also been reported to possess cardiodepressant effects (13). Thus the objective of this investigation was to compare the effects of the two commonly used anesthetic regimens, XK and AV, on cardiac structure and function as assessed by echocardiography and closed-chest left ventricular (LV) catheterization in normal adult mice.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All experimental procedures were designed in accordance with National Institutes of Health guidelines and approved by the Mayo Institutional Animal Care and Use Committee. Normal adult (10-23 wk old) male Swiss Webster mice (Harlan Sprague Dawley) weighing 28-44 g were studied.
Anesthesia protocol. The mice were randomly assigned to receive XK or AV anesthesia. A mixture of 1.6 ml xylazine (20 mg/ml)-5 ml ketamine (100 mg/ml) was administered at a minimal dose of 0.01 ml im. The ratio of xylazine to ketamine was selected based on the recommended anesthetic protocol printed by Transonic Systems (courtesy of Dr. Thomas L. Smith; Bowman Gray School of Medicine, Dept. of Orthopedic Surgery, Winston-Salem, NC). The ratio of 1.6 ml xylazine (20 mg/ml) to 5 ml ketamine (100 mg/ml), when given as 0.01 ml, yields 0.048 mg xylazine and 0.760 mg ketamine. With 0.03 ml administered in an average 35-g mouse from this study, this yielded a dose of ~4.1 mg/kg xylazine and 65 mg/ml ketamine (0.063:1 xylazine-to-ketamine ratio). AV (2.5%) was administered intraperitoneally at 0.015 ml/g body wt (11). Supplemental doses of anesthesia (minimum of one-half of the initial dose) was administered after the initial dose as needed to maintain an adequate level of anesthesia (absence of spontaneous movement and minimal response to toe pinch) up to a maximal total dose of 0.04 ml XK and 1.0 ml AV per animal. Mice were allowed to breathe spontaneously, and anterior chest hair was removed using a depilatory cream. The animal was kept warm using a heating lamp and secured to the surface of a warming table to maintain normothermia.
Echocardiographic assessment.
Transthoracic echocardiography by two independent observers (M. M. Redfield and C. Y. T. Hart) was obtained on mice anesthetized with AV (n = 6) or XK (n = 7) and
placed prone onto a stand containing a 1.25-cm standoff (Cincinnati
Standoff Acoustic Gel Pad). LV two-dimensional (2D) and M-mode images
were obtained with a 10-MHz ultrasonic transducer (Vingmed Systemsfive)
positioned under the left chest. LV M-mode tracings were obtained using
the 2D parasternal long-axis and 2D short-axis views close to the level
of the papillary muscles just distal to the mitral valve leaflet tips.
End diastole was defined as the maximal LV diastolic diameter, and end
sytole was defined as the peak of the LV posterior wall motion. M-mode measurements were made in accordance with the American Society of
Echocardiography leading-edge convention using the steepest continuous
endocardial echoes. Measurements included LV end-diastolic (LVDd) and
end-systolic dimensions (LVDs), septal wall end-diastolic (Sthd) and end-systolic thicknesses (Sths), and
posterior wall end-diastolic (PWthd) and end-systolic
thicknesses (PWths). Parameters of LV structure and
function were determined using an image-analysis system (EchoPAC,
Vingmed Ultrasound). The LV mass was calculated and indexed to body
weight using the following formula
![LV mass<IT>=</IT>1.04<IT>×</IT>[(LVDd<IT>+</IT>Sth<SUB>d</SUB><IT>+</IT>PWth<SUB>d</SUB>)<SUP>3</SUP><IT>−</IT>(LVDd)<SUP>3</SUP>]](/content/vol281/issue5/fulltext/H1938/img001.gif)
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(1) |
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(2) |
Echocardiographic observer variability. To determine the intraobserver variability of M-mode measurements, one observer repeated the LVDd, LVDs, Sthd, Sths, PWthd, and PWths measurements on the M mode on a second occasion (n = 9). Two individuals obtaining M-mode measurements in 13 echocardiographic studies determined the interobserver variability.
Hemodynamic assessment.
Mice were anesthetized with AV (n = 13) or XK
(n = 14). Invasive measurements of LV pressure were
obtained in anesthetized mice utilizing a closed-chest preparation.
Under a zoom stereo microscope (Olympus model SZ4045), a microtipped
1.4-Fr high-fidelity pressure transducer (model SPR-671, Millar
Instruments) was inserted into the right carotid artery and advanced
retrograde into the LV. The aortic pressure, LV systolic pressure, LV
end-diastolic pressure (LVEDP), and maximal rates of LV pressure rise
and fall (dP/dtmax and
dP/dtmin) were recorded at a minimum sampling
rate of 1,000 Hz (Sonometrics; London, Ontario, Canada). The time
constant of isovolumic relaxation () was derived from the period of
dP/dtmin to 5 mmHg above LVEDP assuming a
zero-pressure asymptote (25). End diastole was defined as
the relative minimum of LV pressure after the A wave.
XK effects on heart rate during LV catheterization. An initial group of mice (n = 3) was observed when administered three-fourths of the usual initial dose of XK. However, an initial dose of XK <0.01 ml did not provide adequate sedation. Another group of mice (n = 6) was administered the usual initial dose of 0.01 ml XK to determine the heart rate (HR) response to supplemental doses of XK during LV catheterization. Mice were administered 0.01 ml XK im, HR was recorded using limb surface eletrocardiographic leads, and the 1.4-Fr pressure transducer was inserted into the LV via the right carotid artery. After the catheter was inserted into the LV, HR was recorded. The level of sedation was assessed, and if spontaneous activity or more than minimal response to toe pinch was observed, a supplemental 0.01-ml dose of XK was administered and HR was recorded after the supplemental dose.
Statistical analysis. Data are averaged and reported as means ± SE unless otherwise stated. Comparisons of the two anesthesia groups were made by Student's unpaired t-tests. Paired t-test was used for intra- and interobserver comparisons. Differences were calculated between two sets of measurements and divided by the mean of the two measurements to determine the percent error. The mean of the differences is reported as the systematic error, and the standard deviation is reported as the random variability (2). Results were considered statistically significant in all analyses at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Echocardiographic observer variability.
Intra- and interobserver variability are summarized in Table
1. Variability was greatest for
interobserver measurements of interventricular septal
thickness. Overall, the differences between two determined
measurements, or the systematic error, and the random variability were
small for both inter- and intraobserver analysis between both
anesthetic regimens.
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Echocardiography in XK- versus AV-anesthetized normal mice.
Table 2 summarizes the echocardiographic
findings in XK- and AV-anesthetized mice. Body weight was similar
between the two groups. During echocardiography, HR were significantly
lower in XK mice (Table 2). LVDd was greater in XK mice, and the
load-dependent index of LV function, FS, was higher compared with
AV-anesthetized mice. Representative examples of 2D-derived M-mode
images from mice anesthetized with XK and AV are shown in Fig.
1. Among these mice, four were studied by
echocardiography twice utilizing XK and AV anesthesia regimens on
separate days. These studies demonstrated that the same mice indeed
responded differently to anesthetic regimens, with XK resulting in
lower HR than anesthesia with AV (244 ± 21 beats/min in XK vs.
489 ± 33 beats/min in AV, P < 0.05). Differences
in LVDd did not reach statistical significance (n = 4)
but showed a trend similar to the entire group (4.1 ± 0.09 mm in
XK vs. 3.8 ± 0.12 mm in AV, P > 0.05). However,
FS (43.1 ± 1.7% in XK vs. 40.3 ± 1.0% in AV,
P < 0.05) was higher in XK-anesthetized mice. The
relationships between LVDd and HR, and FS and HR, in all mice are shown
in Fig. 2.
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LV catheterization in XK- versus AV-anesthetized mice.
Invasive hemodynamic parameters are shown in Table
3. Representative hemodynamic tracings of
LV pressure and dP/dtmax during AV and XK
anesthesia are shown in Fig. 3. Body
weight was similar between the two groups. HR during closed-chest
cardiac catheterization were again lower in XK mice, but the degree of
bradycardia was more variable than observed at echocardiography.
Indeed, two mice were evaluated by echocardiography and cardiac
catheterization during XK anesthesia. During cardiac catheterization,
these two mice had higher HR (464 and 460 beats/min) than during
echocardiography (213 and 231 beats/min). Analyzed as a group, systolic
and diastolic function parameters in XK mice were similar to AV mice.
Whereas the maximum LV pressure was higher in XK mice, mean aortic
pressures were not different (78 ± 7 mmHg in XK vs. 71 ± 4 mmHg in AV, P > 0.05).
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and decreases in dP/dtmin. In addition, systolic function was reduced compared with mice with HR
maintained >300 beats/min, as indicated by the reduced
dP/dtmax. Indeed, in XK- and
AV-anesthetized mice, both diastolic function (Fig.
4A) and systolic function
(Fig. 4B) were related to HR.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We compared the effect of AV or XK anesthesia on LV function as assessed by transthoracic echocardiography and closed-chest cardiac catheterization in normal mice. As previously observed, a profound lowering of HR was seen in XK-anesthetized mice. Compared with AV, XK had no adverse effect on echocardiographically derived load-dependent indexes of LV systolic function despite its negative chronotropic effect. Indeed, a mild enhancement of FS was seen in association with increases in preload (LVDd). Under the stress of LV catheterization and the variable time interval from anesthesia induction to the LV catheter placement, the differences in HR observed with the two anesthetic regimens were less consistent and indexes of systolic and diastolic function were not significantly different between the two groups as a whole. However, when XK-anesthetized mice with HR similar to that observed at echocardiography (<300 beats/min) were analyzed separately, there was significant systolic and diastolic dysfunction that was associated with a marked increase in preload (LVEDP) compared with AV-anesthetized mice or XK-anesthetized mice with more physiological HR (>300 beats/min). These data indicate that both agents likely have myocardial depressant actions but that their differential effects on LV function are determined primarily by differential effects on HR rather than by disparate degrees of myocardial depression. Furthermore, these findings confirm that ejection phase indexes of LV systolic function may not reflect alterations in contractility when accompanied by HR-induced changes in load and underscore the need for comprehensive assessment of LV function. Finally, these data clearly indicate that measurements of LV function made at HR <300 beats/min are not reflective of normal physiology in the mouse.
Normal myocardial function in the mouse. Conscious studies in chronically instrumented animals allow characterization of myocardial function in the normal state without the confounding effects of anesthesia and acute instrumentation (15, 16). However, such methods are not yet feasible in the mouse. Transthoracic echocardiography is an established method of assessing LV structure and function in larger animals and humans (4, 23), where normal values are consistently reported. Because echocardiography is used to evaluate altered cardiac structure and function associated with genetic manipulation, it is essential that the expected value of parameters of LV structure and function be defined and that the variance in those parameters with different experimental conditions be established. Prior echocardiographic studies (7, 8, 12, 19, 24, 27) in the anesthetized normal mouse have reported a wide range in LV dimensions [LVDd, 3.1-4.1 mm; LVDs, 1.2-2.4 mm; and LV systolic function (FS), 33-58%]. The variance in these parameters may depend on age, size, and strain of the mice studied, innate differences in wild-type transgenic littermates compared with nontransgenic normal mice, gender-related differences, interstrain differences in response to anesthesia, and the anesthetic regimens used. In addition, echocardiography is very technique dependent, and this factor may contribute to the variation in reported normal values. While Yang et al. (27) reported their experience with echocardiography in the conscious mouse, further studies are needed to determine whether widespread use of conscious echocardiography in the mouse is feasible.
In addition to echocardiography, LV contractility is commonly assessed by parameters derived from LV pressure tracings obtained at closed-chest LV catheterization. In vivo studies utilizing the closed-chest technique in anesthetized normal mice have derived HR of 260-510 beats/min, LV dP/dtmax in the range of 6,200-7,800 mmHg/s, and LVEDP in the range of 3.8-11 mmHg (12, 17, 21). Again, a variety of mice and experimental conditions likely contributed to the variablity observed in these studies. The values obtained in the current study for LV size and function as assessed by echocardiography and closed-chest LV catheterization are within the ranges reported by other investigators in the normal mouse. Our variability analysis suggests that our echocardiographic measurements are consistent from observer to observer and at repeated assessment. Like others, we observed very low resting HR with XK anesthesia (19, 24, 27), but extended previous studies by comparing the HR and LV functional and structural parameters in normal mice during use of the two commonly used anesthetic regimens, XK and AV. At echocardiography, significant differences in LVDd and FS are noted with XK compared with AV anesthesia. Indeed, the magnitude of the differences in FS and LVDd observed with the different regimens is comparable with those reported to be due to genetic alteration in some mouse models (24). However, these differences appear most related to the differences in HR rather than differences in the direct myocardial effects of the two anesthetic regimens. A decrease in contractility might be expected at very low HR due to the force-frequency relationship. Indeed, our LV catheterization data suggest that HR similar to those observed with XK anesthesia during echocardiography are associated with depression of systolic and diastolic function. Yet, FS was maintained and actually modestly enhanced at echocardiography in the XK mice with the lower HR. We interpret these findings to indicate that the associated increase in preload (increased LVDd at echocardiography, increased LVEDP at catheterization) is adequate to maintain the ejection phase index, FS. Unfortunately, we did not measure LV pressure concomitantly with echocardiography to document the decrease in LV systolic pressure that would be expected with concomitant decreases in the slope of the end-systolic pressure-volume relationship and increases in the end-diastolic volume. However, peak LV systolic pressure did tend to be lower in XK mice with low HR at catheterization, and the observations are consistent with concomitant decreases in contractility and increases in preload according to the Frank-Starling relationship. Similarly, Barbee and colleagues (1) observed that anesthesia-induced bradycardia was associated with a tendency toward increases in stroke volume and preserved cardiac output, suggesting that ejection phase indexes are maintained despite a reduction in HR. Whereas XK-induced bradycardia was a consistent finding at echocardiography, the effect of XK on HR during the stress of catheterization was more variable. Hoit et al. (12) also observed variable HR at LV catheterization in mice anesthetized with a mixture of xylazine, ketamine, and morphine. In that study (12), the standard deviation of the mean HR (267 beats/min) was ±106 beats/min. Similarly, the observed dP/dtmax was also variable, with a mean value of 6,209 mmHg/s and a standard deviation of ±2,519 mmHg/s. While these data suggest that the bradycardia associated with XK anesthesia at catheterization was variable and associated with differences in dP/dtmax, the data were not analyzed according to HR. In the current study, there appeared to be a lower limit at which ventricular function is maintained in the normal mouse because HR <300 beats/min in XK-anesthetized mice were associated with significantly abnormal systolic (dP/dtmax) and diastolic function (, dP/dtmin) and preload
(LVEDP). Previous studies (9, 12, 21) have examined the
dependence of cardiac contractility (dP/dtmax) on HR in mice and have observed a biphasic force-frequency
relationship. In normal mice undergoing open-chest cardiac
catheterization and anesthetized with XK (12), there was a
steep ascending limb at HR from 150 to 325 beats/min, after which
the relationship flattened until ~400-450 beats/min, where
a descending curve began. Surprisingly, the force-frequency curve in
closed-chest preparations was shifted downward, and the relationship
between dP/dtmax and HR was less dramatic.
However, even in the closed-chest preparation, there was a clear
ascending limb that flattened at ~250 beats/min. In the closed-chest
mouse recovering from anesthesia, a linear relationship between HR and
dP/dtmax and no biphasic descending limb of the
force-frequency response was observed at the higher HR, which reached
600 beats/min (21). Thus these data support our
observation that HR <300 beats/min are associated with depressed contractility in the mouse. It is possible that the presence of disease
may alter the HR response to anesthesia and may further complicate the
assessment of altered physiology in genetically altered mice.
We must acknowledge that pressure-volume analysis would better define
the myocardial actions of these two anesthetic regimens (6, 14,
18). However, relatively few laboratories routinely perform such
studies, and the current findings may be useful to those who rely on
echocardiography or LV catheterization alone. Furthermore, these data
underscore the benefit of comprehensive assessment of LV function with
both techniques when pressure-volume analysis is not feasible.
Anesthetic regimens in the mouse. Further understanding of the various anesthetic regimens on cardiac function is essential in establishing expected normal values for indexes of cardiac structure and function in normal and genetically altered mice. Bradycardia and hypotension are known to occur with xylazine in addition to excellent muscle relaxation and analgesia, whereas ketamine induces analgesia but also tachycardia and an increase in blood pressure (5). Thus the XK combination is a widely used regimen because of its reliability in mice for inducing relaxation, sedation, and analgesia (5). Bradycardia is commonly observed (19, 24, 27) and indexes of systolic function are consistently lower during XK anesthesia compared with the conscious state. Whether the depression of systolic function is due to a direct negative inotropic effect of the anesthetic, its negative chronotropic properties or both have not been addressed. The effects on cardiac function may also be dose dependent; however, varying the ratio of ketamine to xylazine does not seem to alter HR (and thus cardiac function) response. Published studies (5, 20-22, 24, 27) have utilized a range of xylazine (2.5-20 mg/kg) and ketamine (50-150 mg/kg) (xyalazine-to-ketamine ratio in the range of 0.40:1 to 0.025:1). The most commonly used xyalzine-to-ketamine ratio is 0.050:1. In our study, we utilized a xylazine-to-ketamine ratio of 0.063:1. Oliver et al. (20) used a lower xylazine-to-ketamine ratio of 0.025:1 and reported HR and FS during echocardiography of 273 ± 21 beats/min and 37 ± 2%, values similar to ours (250 ± 14 beats/min and 45 ± 1.23%). In a study using closed-chest cardiac catheterization (21), a xylazine-to-ketamine ratio of 0.050:1 was used, with HR at 282 ± 21 beats/min observed. These HR are lower than we observed with the closed-chest catheterization despite their use of a lower xylazine-to-ketamine ratio. The dP/dtmax they observed were similar to our values. Together, these studies demonstrate the use of a range of xylazine-to-ketamine ratios of 0.025:1 to 0.063:1 that resulted in HR <300 beats/min, thereby suggesting that varying the ratio of xylazine to ketamine to over a fairly wide range does not alter HR (and thus cardiac function) response. While studies have compared indexes obtained under XK anesthesia to those obtained in the conscious state (6, 27), studies comparing XK to commonly used alternative anesthetic regimens such as AV are lacking.
AV is the other widely utilized anesthetic regimen in the mouse. Whereas echocardiographic studies have suggested that AV is free from significant chronotropic or myocardial effects (8), catheterization studies suggest adverse effects on myocardial function (14) and there are no previous studies comparing AV to XK. Fewer studies have utilized pentobarbital anesthesia for murine studies (18, 27). While pentobarbital appears to have modest effects on HR, myocardial depression and/or reductions in preload associated with pentobarbital appear likely, although not well described. An infrequently used anesthetic regimen reported to have minimal effects on cardiovascular function is
-chloralose-urethane (10, 26). Georgakapoulous et al. (10)
reported values of LV dP/dtmax of 11,777 ± 732 mmHg/s with HR of 634 ± 13.5 beats/min and preserved
diastolic function parameters ( = 6.2 ± 0.5 ms) during
open-chest catheterization in normal mice. Yang et al. (26) also observed higher HR (514 ± 16 beats/min)
and favorable systolic (LV dP/dtmax = 22,254 ± 1,035 mmHg/s) and diastolic ( = 1.36 ± 0.06 ms) function parameters during open-chest catheterization in young
adult mice. These data suggest that this regimen is free of significant
cardiodepressant activity, although some concern has been expressed
over the level of anesthesia maintained by -chloralose and its lack
of suitability for survival procedures (13).
In conclusion, in the current study, we provided comparative data on
the two most commonly used anesthetic regimens in the mouse and
reported their disparate effects on cardiovascular physiology. These
data highlight the likely presence of myocardial depressant effects
with both agents but underscore the unique effect of XK on HR and the
alterations in LV size and function that are associated with XK-induced
bradycardia. These data confirm the lower limit of physiological HR in
the mouse. Furthermore, these data illustrate the well-described
problems with the use of load-dependent indexes (FS) when concomitant
changes in myocardial function and preload occur and emphasize the need
for comprehensive evaluation of LV function rather than reliance of
echocardiography or invasive hemodynamic evaluation alone.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. M. Redfield, Div. of Cardiovascular Diseases and Internal Medicine, 200 First St. SW, Rochester, MN 55905 (E-mail: Redfield.margaret{at}mayo.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 12 March 2001; accepted in final form 13 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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