Effects of aging on cardiac output, regional blood flow,
and body composition in Fischer-344 rats
MICHAEL D. DELP,1 MARINA V. EVANS,2 AND CHANGPING DUAN3
of Health and Kinesiology and of Medical Physiology, Texas A&M University,
College Station, Texas 77843; 2National Health and Environmental Effects Research Laboratory,
US Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and
3Department of Surgery, Allegheny University for Health Sciences, Pittsburgh, Pennsylvania 15212
1Departments
maturation; strain differences
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
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solely to indicate this fact.
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NUMEROUS PHYSIOLOGICAL ALTERATIONS occur within the
cardiovascular system as a consequence of aging. According to Folkow and Svanborg (18), there are four
general manifestations of normal aging that have profound consequences on cardiovascular function. First,
there is a slow progressive reduction of central and
peripheral neuronal networks that can affect the central integration of the neurohormonal systems controlling cardiovascular performance (3). Second, there is a
decline in the number, strength, and speed of contraction of cardiac and vascular smooth muscle cells that
can affect cardiac performance and vascular responsiveness (1, 8). Third, there is a gradual decline in vascular
compliance, resulting from an increase in cross-bridge
connections between protein molecules and a reduction
in the proportion of distensible elements within the
vessel wall (22). And fourth, there is a decline in basal
metabolic rate and oxygen consumption per unit body
mass with advanced age (17, 39). The decrease in
oxygen consumption does not appear to be due to a
change in the cellular metabolic rate; rather it results
from the combined effects of a loss in skeletal muscle
mass and an increase in percent body fat (2, 17, 39).
If age-induced changes in whole body oxygen consumption are related to changes in body composition
rather than to cellular metabolism, then, on the basis of
the close relationship between organ perfusion rate and
metabolism, it would be expected that tissue blood flow
per unit mass would be unaltered by old age. Furthermore, age-related changes in body composition would
result in alterations in the distribution of cardiac
output. However, other factors associated with old age
and body composition also occur that could affect
central and regional cardiovascular hemodynamics.
For example, Schwartz et al. (35) found that percent
body fat and age were independent determinants of
increases in the rate of plasma norepinephrine appearance in elderly men. Unfortunately, the effects of
changes in body composition on cardiovascular hemodynamics are not well characterized in the elderly, in
large part due to the difficulty in quantitatively assessing body composition, cardiac output, and organ perfusion rates in humans. Therefore, the purpose of this
study was to determine the effects of maturation and
aging on central and regional hemodynamics and body
composition in the Fischer-344 rat. More specifically,
we sought to test the hypothesis that, in old age, tissue
blood flow per unit mass is unchanged but that changes
in body composition are associated with alterations in
the fractional distribution of cardiac output.
8750-7587/98 $5.00 Copyright r 1998 the American Physiological Society
1813
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Delp, Michael D., Marina V. Evans, and Changping
Duan. Effects of aging on cardiac output, regional blood flow,
and body composition in Fischer-344 rats. J. Appl. Physiol.
85(5): 1813–1822, 1998.—The purpose of this study was to
determine the effects of maturation and aging on cardiac
output, the distribution of cardiac output, tissue blood flow
(determined by using the radioactive-microsphere technique), and body composition in conscious juvenile (2-mo-old),
adult (6-mo-old), and aged (24-mo-old) male Fischer-344 rats.
Cardiac output was lower in juvenile rats (51 6 4 ml/min)
than in adult (106 6 5 ml/min) or aged (119 6 10 ml/min) rats,
but cardiac index was not different among groups. The
proportion of cardiac output going to most tissues did not
change with increasing age. However, the fraction of cardiac
output to brain and spinal cord tissue and to skeletal muscle
was greater in juvenile rats than that in the two adult groups.
In addition, aged rats had a greater percent cardiac output to
adipose tissue and a lower percent cardiac output to cutaneous and reproductive tissues than that in juvenile and adult
rats. Differences in age also had little effect on mass-specific
perfusion rates in most tissues. However, juvenile rats had
lower flows to the pancreas, gastrointestinal tract, thyroid
and parathyroid glands, and kidneys than did adult rats, and
aged rats had lower flows to the white portion of rectus
femoris muscle, spleen, thyroid and parathyroid glands, and
prostate gland than did adult rats. Body mass of juvenile rats
was composed of a lower percent adipose mass and a greater
fraction of brain and spinal cord, heart, kidney, liver, and
skeletal muscle than that of the adult and aged animals.
Relative to the young adult rats, the body mass of aged
animals had a greater percent adipose tissue mass and a
lower percent skeletal muscle and skin mass. These data
demonstrate that maturation and aging have a significant
effect on the distribution of cardiac output but relatively little
influence on mass-specific tissue perfusion rates in conscious
rats. The old-age-related alterations in cardiac output distribution to adipose and cutaneous tissues appear to be associated with the increases in percent body fat and the decreases
in the fraction of skin mass, respectively, whereas the decrease in the portion of cardiac output directed to reproductive tissue of aged rats appears to be related to a decrease in
mass-specific blood flow to the prostate gland.
1814
AGING AND CARDIAC OUTPUT DISTRIBUTION
MATERIALS AND METHODS
Table 1. Hemodynamic variables before and after the sequential infusion
of microspheres in juvenile and adult rats
Juvenile
Cardiac output, ml/min
Heart rate, beats/min
Mean arterial pressure, mmHg
Adult
Preinfusion
Infusion 1
Infusion 2
405 6 7
111 6 4
47 6 6
399 6 4
114 6 3
45 6 4
395 6 8
112 6 4
Preinfusion
Infusion 1
Infusion 2
393 6 11
117 6 4
118 6 9
386 6 9
119 6 4
110 6 8
390 6 12
114 6 5
Values are means 6 SE for 6 juvenile and 6 adult rats. Juvenile rats were infused with 2 sequential microsphere infusions, each containing
0.5 million microspheres. Adult rats were sequentially infused with 1.0 million (infusion 1) and 0.5 million (infusion 2) microspheres.
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The methods employed in this study were approved by the
Texas A&M University Institutional Animal Care and Use
Committee. The investigation conforms with the National
Institutes of Health (NIH) Guide for the Care and Use of
Laboratory Animals [DHHS Publication No. (NIH) 85–23,
Revised 1985, Office of Science and Health Reports, Bethesda,
MD 20892.]
Animals and surgical procedures. Juvenile (2-mo-old, n 5
6), adult (6-mo-old, n 5 7), and aged (24-mo-old, n 5 7) male
Fischer-344 rats (National Institutes of Aging Colony and
Charles River Laboratories, Raleigh, NC) were used. These
ages were chosen to correspond to the normal life span and
sexual development of the Fischer-344 rat; 1.5- to 2-mo-old
rats are juvenile, 3- to 6-mo-old rats are young mature adults,
and 24-mo-old or older rats are considered aged (11). Their
life expectancy is ,29 mo, with a maximal survival time of
,36 mo (5). The animals were individually housed in an
environmentally controlled room (23 6 2°C) with a 12:12-h
light-dark cycle and given food (commercial rat chow) and
water ad libitum.
Under methoxyflurane anesthesia (Metofane), a catheter
(Dow Corning, Silastic; ID 0.6 mm, OD 1.0 mm) filled with
heparinized (200 U/ml) saline and connected to a pressure
transducer and chart recorder was advanced into the left
ventricle of the heart via the right carotid artery as previously
described (9). This catheter was subsequently used for the
infusion of radiolabeled microspheres to measure tissue blood
flow and for the recording of intraventricular pressure. A
second polyurethane catheter (Braintree Scientific, Microrenathane; ID 0.36 mm, OD 0.84 mm), used for the withdrawal of a reference blood sample and the recording of
arterial pressure, was implanted in the caudal artery of the
tail and filled with heparinized saline as previously described
(7). Both catheters were externalized and secured on the
dorsal cervical region.
Experimental protocol. After the animals had recovered for
2 days from the surgical procedure, all catheters and instrumentation were connected while the animals remained in
their cages. The rats were allowed 20 min to stabilize after
the instrumentation procedure before the microsphere infusion was performed. Pulsatile intraventricular pressures
(and, hence, heart rates) were monitored during this period,
which was sufficient for heart rate to stabilize. When the
microsphere infusion and reference-sample withdrawal were
completed, pentobarbital sodium (35 mg/kg) was infused
through the carotid catheter, and the animals were euthanized by exsanguination. Tissue samples were excised,
weighed, and placed in counting vials for blood flow determination. During the dissection, the carcass was kept moist to
minimize evaporative weight loss. The purpose of this study
was to account for total cardiac output distribution in the
animals. Accordingly, all organs and all tissues from the
carcass were weighed and analyzed.
Blood flow and cardiac output measurements. Radiolabeled
(95Nb or 103Ru) microspheres (New England Nuclear) with a
15.5 6 0.2-µm diameter were used for blood flow and cardiac
output measurements as previously described (16, 27, 29).
Microspheres were suspended in physiological saline with
,0.5% Tween 80 and mixed before infusion by 10 min of
sonication followed by 1–2 min of agitation on a vortex mixer.
A reference blood sample from the caudal artery was started
at a rate of 0.618 ml/min with an infusion-withdrawal pump
(Harvard). Ten seconds later, ,1.0 million spheres suspended
in 0.4 ml saline were infused into the juvenile rats, and 1.5
million spheres suspended in 0.6 ml saline were infused into
the left ventricular catheter of adult and aged rats over a 15to 20-s period. One milliliter of warm (37°C) saline was
infused over a 30- to 60-s period immediately after the
microsphere infusion; withdrawal of the reference blood
sample continued for at least 1 min after the saline flush.
Fewer microspheres were infused into the juvenile rats
because of their smaller body size and vascular transport
capacity to minimize the possible adverse hemodynamic
effects from the microspheres. After euthanasia and tissue
dissection, tissue samples were counted in a gamma counter
(Packard Minaxi Auto-Gamma 5000) and flows were computed (IBM personal computer) from counts per minute and
tissue wet weights. Microsphere mixing with the blood was
assessed by comparing bilateral kidney flows. Mixing was
considered adequate if bilateral flows were within 15% of
each other. No data were discarded in this study because of
inadequate mixing.
Typically, in a 350-g rat, blood flow distribution is measured by infusing 0.5 million microspheres per experimental
treatment, and up to three to four treatments can be made in
a single animal (e.g., Refs. 7, 9, 29). In the present study, the
infusion of 1.0 million microspheres in juvenile rats and 1.5
million microspheres in the two groups of adult rats for a
single blood flow measurement was done to ensure that
small-mass tissue samples contained sufficient numbers of
spheres for accurate flow determinations. To determine
whether the infusion of these numbers of microspheres
disturbed the cardiovascular system or altered the distribution of blood flow within or among tissues, we made two
sequential blood flow measurements by using two different
radiolabeled-microsphere species in a preliminary group of
juvenile (n 5 6) and 6-mo-old adult (n 5 6) animals. In the
juvenile rats, blood flow was sequentially measured with two
infusions of 0.5 million microspheres per infusion; in the
adult rats, flow was measured with one infusion containing
1.0 million microspheres and a second containing 0.5 million
microspheres. In both the juvenile and adult animals, heart
rate and blood pressure were similar before and ,1 min after
each of the two microsphere infusions (Table 1). In addition,
cardiac output (Table 1) and tissue blood flows (data are not
shown but are similar to that in Tables 6 and 7) were similar
between the first and second infusions, indicating there were
1815
AGING AND CARDIAC OUTPUT DISTRIBUTION
Table 2. Body and tissue masses from juvenile
(2-mo-old), adult (6-mo-old), and aged (24-mo-old) rats
Juvenile
Adult
Aged
379 6 8e
Body mass
187 6 3
438 6 9e,f
Adipose
15.2 6 0.8
41.6 6 1.4e
69.8 6 5.8e,f
Adrenal
0.04 6 0.00
0.07 6 0.01e
0.08 6 0.00e
Bone
14.4 6 0.8
25.9 6 0.7e
31.3 6 0.6e,f
Brain and spinal cord
2.2 6 0.1
2.9 6 0.1e
3.3 6 0.1e,f
Heart
0.61 6 0.03
0.98 6 0.03e
1.15 6 0.02e,f
Kidney
1.8 6 0.1
2.9 6 0.1e
3.6 6 0.1e,f
Liver
9.2 6 0.4
16.5 6 0.5e
18.2 6 0.7e
Splanchnica
9.3 6 0.7
16.2 6 0.5e
22.5 6 1.6e,f
Lungb
1.16 6 0.04
1.43 6 0.05e
2.53 6 0.18e,f
Skeletal muscle
72.0 6 1.4
134.6 6 4.0e
141.7 6 3.9e
Reproductivec
2.2 6 0.1
4.0 6 0.1e
4.6 6 0.8e
Salivary gland
0.32 6 0.04
0.98 6 0.04e
0.90 6 0.05e
Skin
31.6 6 0.9
61.0 6 1.9e
63.4 6 2.0e
Thyroid and parathyroid glands
0.019 6 0.001 0.036 6 0.002e 0.051 6 0.002e,f
Otherd
5.3 6 0.2
9.6 6 1.6e
10.1 6 0.4e
Values are means 6 SE in g. a Splanchnic tissues consist of
esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, pancreas, mesentery, and spleen. b Includes lungs and trachea.
c Includes testes, prostate gland, and seminal vesicles. d Includes
eyes, urethra, urinary bladder, and other miscellaneous tissues.
e Group mean is different from juvenile group mean, P , 0.05. f Group
mean is different from adult group mean, P , 0.05.
Table 3. Percent body mass distribution of juvenile,
adult, and aged rats
Juvenile
Adult
Aged
11.2 6 0.3f
Adipose
8.2 6 0.4
15.2 6 1.0f,g
Adrenal
0.02 6 0.00
0.02 6 0.00
0.02 6 0.00
Bone
7.7 6 0.5
6.9 6 0.1
7.1 6 0.1
Brain and spinal cord 1.17 6 0.04
0.76 6 0.02f
0.75 6 0.02f,g
Heart
0.33 6 0.02
0.26 6 0.00f
0.26 6 0.01f
Kidney
0.98 6 0.05
0.75 6 0.02f
0.82 6 0.01f
Liver
4.9 6 0.2
4.4 6 0.0f
4.2 6 0.2f
Splanchnica
5.0 6 0.4
4.3 6 0.1
5.1 6 0.3
Lungb
0.62 6 0.02
0.38 6 0.01f
0.58 6 0.04g
Skeletal muscle
38.6 6 0.8
35.6 6 0.7f
32.4 6 0.7f,g
Reproductivec
1.15 6 0.05
1.06 6 0.04
1.04 6 0.19
Salivary gland
0.17 6 0.02
0.26 6 0.01f
0.21 6 0.01
Skin
16.9 6 0.6
16.1 6 0.3
14.5 6 0.4f,g
Thyroid and parathyroid glands
0.010 6 0.000 0.009 6 0.001 0.012 6 0.001g
Otherd
2.9 6 0.1
2.5 6 0.4
2.3 6 0.1
Tissue contentse
5.6 6 0.5
4.7 6 0.4
4.6 6 0.5
Values are means 6 SE. a Splanchnic tissues (see Table 2 for
included tissues). b Includes lungs and trachea. c Includes testes,
prostate gland, and seminal vesicles. d Includes eyes, urethra, urinary bladder, and other miscellaneous tissues. e Includes contents
contained in gastrointestinal tract, urinary bladder, and seminal
vesicles. f Group mean is different from juvenile group mean, P ,
0.05. g Group mean is different from adult group mean, P , 0.05.
(mmHg) by the cardiac output (ml/min) derived from summing individual tissue flows. Cardiac index (ml · min21 · kg21 )
was calculated by using total body mass (kg) and cardiac
output (ml/min) derived from individual tissue flows. Stroke
volume (ml/beat) was calculated from cardiac output (ml/min)
and heart rate (beats/min) measurements.
Statistical analysis. To determine whether the infusion of
1.0 and 1.5 million microspheres induced hemodynamic disturbances in juvenile and young adult rats, respectively, a
one-way analysis of variance with repeated measures was
used to compare mean arterial pressure and heart rate means
across conditions (preinfusion vs. infusion 1 vs. infusion 2),
and a paired t-test was used to compare cardiac output and
tissue blood flow means between conditions (infusion 1 vs.
infusion 2). To determine the effects of maturation and aging,
a one-way analysis of variance was used to compare variable
means (cardiac output, arterial pressure, systemic vascular
resistance, heart rate, cardiac index, stroke volume, tissue
blood flows, and body and tissue masses) across groups
(juvenile vs. adult vs. aged). Duncan’s new multiple-range
test was used to determine the significance of differences
among means. For all analyses, the 0.05 level was used to
indicate statistical significance.
RESULTS
Body mass increased as a function of age (Table 2). In
mature rats, this resulted from increases in all tissue
masses, whereas, with old age, the increase in body
mass was primarily associated with increases in adipose tissue, bone, brain and spinal tissue, heart, kidney, splanchnic organ, and lung masses (Table 2). In
comparison to juvenile rats (Table 3), the two groups of
adult rats had a body composition with a higher percent
mass of adipose tissue and salivary gland (young adult
only), and a lower percent mass of brain and spinal
tissue, myocardium, kidney, liver, lung (young adult
only), skeletal muscle, skin (aged only), and thyroid
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no hemodynamic disturbances induced by the infusion of 1.0
and 1.5 million microspheres in juvenile and adult rats,
respectively.
Cardiac output was assessed in two ways in the experimental animals. The first was a direct measurement of cardiac
output with the method described by Ishise et al. (27), by
using the following equation: cardiac output (ml/min) 5
[reference-sample withdrawal rate (ml/min) · injected isotope
counts (counts/min)] 4 reference blood sample counts (counts/
min). The second was to sum individual tissue flows (ml/min)
as previously described (9). Most tissue flows were measured
from the entire organ, e.g., brain, heart, and viscera; flow to
bilateral organs, such as skeletal muscle, feet, skin, and bone,
were measured unilaterally and doubled.
Because of the difficulty in separating some bones from
muscle and connective tissue with blunt dissection (e.g.,
vertebrae and feet), the bones from a separate group of rats
(juvenile, n 5 3; adult, n 5 3; aged, n 5 3) were dissected
identically to the groups of rats used to measure blood flow.
The bone samples were then weighed and placed in a boiling
2% KOH solution for several minutes to dissolve excess
muscle and connective tissue. The bones were then blotted
and reweighed to determine the proportion of bone in the
original samples. Because of the similarity in the perfusion
rates per unit mass of bone and muscle, flow (ml/min) to
bone-muscle samples was partitioned in proportion to the
bone and muscle composition of the sample.
Arterial pressure, heart rate, systemic vascular resistance,
cardiac index, and stroke volume measurements. Mean arterial pressure was electronically averaged from pulsatile pressure measurements from the caudal catheter. Heart rate was
estimated from pulsatile left intraventricular pressure tracings. Pressure recordings, made with pressure transducers
(Electromedical) and recorded on a polygraph (Gould 2800),
were made immediately before and after the microsphere
infusion and averaged, because simultaneous pressure measurements and withdrawal of a reference blood sample were
not possible. Systemic vascular resistance (mmHg · ml21 ·
min) was calculated by dividing mean arterial pressure
1816
AGING AND CARDIAC OUTPUT DISTRIBUTION
Table 5. Fractional distribution of cardiac output
in tissues from juvenile, adult, and aged rats
Table 4. Hemodynamic variables and tissue blood
flows in juvenile, adult, and aged rats
adult rats, and 125 6 14 ml/min in aged animals. Thus
there was only an 8, 6, and 5% difference between the
two methods of assessing cardiac output in the juvenile,
adult, and aged rats, respectively. Differences of this
magnitude are similar to those previously reported (9).
Cardiac index was different among groups (Table 4).
However, stroke volume was lower and systemic vascular resistance was higher in the juvenile group compared with the two adult groups.
Heart rate and mean arterial pressure were also not
different among groups (Table 4). In addition, preinfusion heart rates (pre- vs. postinfusion: juvenile, 395 6 7
vs. 390 6 7 beats/min; adult, 397 6 6 vs. 394 6 8
beats/min; aged, 371 6 16 vs. 365 6 12 beats/min) and
arterial pressures (pre- vs. postinfusion: juvenile, 115 6 3
vs. 114 6 4 mmHg; adult, 118 6 6 vs. 115 6 6 mmHg;
aged, 116 6 3 vs. 114 6 3 mmHg) were not different
from that measured ,1 min after the infusion of the
microspheres.
Adipose tissue, which made up 8, 11, and 15% of the
total body mass in juvenile, adult, and aged rats,
respectively (Table 3), received 5, 8, and 11% of cardiac
output, respectively (Table 5). Mass-specific blood flow
(ml · min21 · 100 g21 ) to visceral abdominal, subcutaneous, and epididymal fat was not different among groups
(Table 6).
The adrenal glands, which made up ,0.02% of body
mass in all groups (Table 3), received between 0.25 and
0.30% of cardiac output (Table 5). Mass-specific blood
flows to the adrenal cortex and the adrenal medulla
were not different among groups (Table 6).
The skeletal system, which made up ,7% of body
mass in all groups (Table 3), received ,7% of cardiac
output (Table 5). The brain and spinal cord made up
,1% of body mass in all groups (Table 3) and received
Juvenile
Cardiac output,
ml/min
Cardiac index,
ml · min21 · kg21
Heart rate, beats/min
Stroke volume, µl/beat
Mean arterial pressure, mmHg
Systemic vascular
resistance,
mmHg · ml21 · min
Tissue flows, ml/min
Adipose
Adrenal
Bone
Brain and spinal
cord
Heart
Kidney
Liver, hepatica
Liver, splanchnicb
Lungc
Skeletal muscle
Reproductived
Salivary gland
Skin
Thyroid and parathyroid glands
Othere
Adult
Aged
51 6 4
106 6 5f
119 6 10f
275 6 22
393 6 5
130 6 11
281 6 14
396 6 8
269 6 15f
273 6 17
368 6 15
309 6 19f
115 6 3
117 6 5
115 6 3
2.3 6 0.2
1.1 6 0.1f
1.0 6 0.1f
2.7 6 0.6
0.13 6 0.03
2.8 6 0.4
8.7 6 0.7f
0.31 6 0.06f
7.3 6 0.5f
13.8 6 2.2f,g
0.29 6 0.04f
8.2 6 0.5f
2.1 6 0.1
2.7 6 0.4
6.6 6 0.4
0.55 6 0.15
10.5 6 1.0
0.6 6 0.2
17.0 6 1.7
0.44 6 0.05
0.16 6 0.02
3.5 6 0.6
2.9 6 0.2
4.7 6 0.5
14.5 6 0.4f
0.88 6 0.23
24.7 6 1.7f
1.6 6 0.3
27.4 6 2.0f
1.11 6 0.08f
0.58 6 0.02f
8.3 6 0.9f
3.3 6 0.5
6.3 6 0.8f
15.8 6 2.2f
1.41 6 0.34
23.8 6 2.5f
2.1 6 0.6
32.5 6 1.9f
0.93 6 0.20
0.39 6 0.09f
6.7 6 1.2
0.10 6 0.01
1.1 6 0.2
0.30 6 0.04f
2.6 6 0.5
0.25 6 0.05f
3.6 6 0.5f
Values are means 6 SE. a Represents blood flow through hepatic
artery. b Represents blood flow through splanchnic tissues (see Table
2 for included tissues). c Includes blood flow to lungs and trachea.
d Includes blood flow to testes, prostate gland, and seminal vesicles.
e Includes blood flow to eyes, urethra, urinary bladder, and other
miscellaneous tissues. f Group mean is different from juvenile group
mean, P , 0.05. g Group mean is different from adult group mean, P ,
0.05.
Adipose
Adrenal
Bone
Brain and spinal cord
Heart
Kidney
Liver, hepatica
Liver, splanchnicb
Lungc
Skeletal muscle
Reproductived
Salivary gland
Skin
Thyroid and parathyroid glands
Othere
Juvenile
Adult
Aged
5.1 6 0.8
0.25 6 0.04
5.4 6 0.5
4.2 6 0.3
5.8 6 1.1
13.2 6 0.9
1.2 6 0.4
20.5 6 1.0
1.2 6 0.3
33.3 6 1.2
0.85 6 0.05
0.30 6 0.03
6.7 6 0.6
8.2 6 0.4
0.30 6 0.06
6.9 6 0.3
2.7 6 0.2f
4.5 6 0.6
13.8 6 0.6
0.9 6 0.2
23.3 6 1.1
1.6 6 0.3
25.7 6 1.3f
1.05 6 0.04
0.55 6 0.02f
7.7 6 0.6
11.3 6 1.3f,g
0.25 6 0.03
7.0 6 0.5
2.7 6 0.3f
5.2 6 0.5
12.9 6 0.9
1.1 6 0.3
19.7 6 1.0
1.6 6 0.4
27.4 6 1.4f
0.74 6 0.11g
0.31 6 0.05g
5.4 6 0.6g
0.19 6 0.01
2.1 6 0.3
0.28 6 0.03
2.5 6 0.5
0.20 6 0.03
3.2 6 0.6
Values are means 6 SE in %. a Represents portion of cardiac output
via hepatic artery. b Represents portion of cardiac output via splanchnic tissues. c Includes portion of cardiac output to lungs and trachea.
d Includes portion of cardiac output to testes, prostate gland, and
seminal vesicles. e Includes portion of cardiac output to eyes, urethra,
urinary bladder, and other miscellaneous tissues. f Group mean is
different from juvenile group mean, P , 0.05. g Group mean is
different from adult group mean, P , 0.05.
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and parathyroid glands (aged only). The percent masses
of the adrenal glands, skeleton, splanchnic tissue,
reproductive tissue, and tissue contents (which consisted of the contents within the gastrointestinal tract,
urinary bladder, and seminal vesicles) were not different among groups.
Dissected tissue masses accounted for 88.5 6 1.2% of
total body mass in the juvenile rats, 84.4 6 1.6% in the
adult rats, and 85.1 6 1.3% in the aged rats; this was
not different among groups. The contents within the
gastrointestinal tract, urinary bladder, and seminal
vesicles (Table 3) accounted for 5.6 6 0.5, 4.7 6 0.4, and
4.6 6 0.5% of total body mass in the juvenile, adult, and
aged rats, respectively. The remaining 5.9, 10.7, and
10.3% body mass of the juvenile, adult, and aged rats,
respectively, presumably consisted of blood lost during
euthanasia and water lost through tissue dehydration
during dissection. The blood has been reported to
represent ,7.4% of body mass in an adult rat (4).
Cardiac output, calculated as the sum of all body
tissue blood flows (Table 4), was lower in juvenile rats
relative to the two adult groups; there was no difference
in cardiac output between these latter two groups. By
using the method of Ishise et al. (27), cardiac output
was 55 6 4 ml/min in juvenile rats, 112 6 9 ml/min in
AGING AND CARDIAC OUTPUT DISTRIBUTION
Table 6. Tissue blood flows from juvenile, adult,
and aged rats
Tissue
Adult
Aged
26 6 4
18 6 4
11 6 2
23 6 3
21 6 2
18 6 2
28 6 4
20 6 5
11 6 3
495 6 58
511 6 71
362 6 69
94 6 11
575 6 83
493 6 41
355 6 37
82 6 9
600 6 79
551 6 67
527 6 73
118 6 24
561
662
662
561
562
662
762
762
962
19 6 1
96 6 9
183 6 22
157 6 7
184 6 24
118 6 18
121 6 12
20 6 4
170 6 36
23 6 3
153 6 20*
257 6 17*
244 6 16*
250 6 22
114 6 29
204 6 16*
62 6 31
250 6 11
16 6 3
115 6 6
234 6 15
205 6 22
197 6 22
94 6 16
208 6 23*
29 6 3
103 6 19†
43 6 8
24 6 3
19 6 2
42 6 2
22 6 1
26 6 2
33 6 12
14 6 2*†
23 6 5
11 6 1
13 6 2
12 6 2
661
11 6 1
16 6 3
18 6 3
761
861
12 6 2
16 6 3
762
57 6 19
49 6 6
50 6 5
110 6 21
115 6 28
119 6 5*
90 6 32
75 6 27
86 6 20
517 6 53
813 6 139
70 6 13
359 6 15
365 6 14
21 6 7
661
823 6 83*
744 6 125
118 6 33
511 6 17*
510 6 17*
15 6 3
761
492 6 90†
689 6 122
101 6 20
434 6 54
446 6 59
15 6 4
11 6 4
Values are means 6 SE in ml · min21 · 100 g21. * Group mean is
different from juvenile group mean, P , 0.05. † Group mean is
different from adult group mean, P , 0.05.
,4, 3, and 3% of cardiac output in juvenile, adult, and
aged rats, respectively (Table 5). Blood flow distribution patterns within the skeletal system and brain will
be published separately.
The heart made up 0.33, 0.26, and 0.26% of the total
body mass in juvenile, adult, and aged rats, respectively (Table 3), and received ,5% of cardiac output
(Table 5). Mass-specific blood flows to the heart were
not different among groups (Table 6).
The kidneys made up ,1.0, 0.8, and 0.8% of the total
body mass in juvenile, adult and aged rats, respectively
(Table 3), and received 13–14% of cardiac output (Table
5). Renal flow in the juvenile rats was less than that in
adult rats but was similar to that in aged rats (Table 6).
The liver, which made up ,5, 4, and 4% of the total
body mass in juvenile, adult, and aged rats, respectively (Table 3), received ,1% of cardiac output through
the hepatic artery (Table 5). There was no difference in
hepatic arterial flow among the different lobes of the
liver. The splanchnic tissues made up ,5% of the total
body mass in all groups (Table 3) and received 20–23%
of cardiac output (Table 5). Therefore, the liver received
a total of 22, 24, and 21% of cardiac output in juvenile,
adult, and aged rats, respectively, via the hepatic
artery and splanchnic circulations. Mass-specific blood
flow to splanchnic tissues tended to be lower in juvenile
animals (Table 6). In addition, flow to the spleen in aged
animals was less than that in adult rats.
The lung made up ,0.6, 0.4, and 0.6% of the total
body mass in juvenile, adult, and aged rats, respectively (Table 3), and received 1–2% of cardiac output
(Table 5).
Skeletal muscle, which composed ,39, 36, and 32%
of the total body mass in juvenile, adult, and aged rats,
respectively (Table 3), received 33, 26, and 27% of
cardiac output, respectively (Table 5). Blood flow to the
superficial gluteal muscle was lower in the aged rats
than in juvenile rats (Table 7), and flow to the white
portion of rectus femoris muscle was lower in the old
rats than in young adult animals.
Male reproductive tissues made up ,1% of body
mass in all groups (Table 3) and received ,0.9, 1.1, and
0.7% of cardiac output in juvenile, adult, and aged rats,
respectively (Table 5). Blood flow to the seminal vesicles
and testes was not different among groups, but flow to
the prostate gland was lower in aged rats than in adult
animals.
The skin made up ,17, 16, and 15% of the total body
mass in juvenile, adult, and aged rats, respectively
(Table 3), and received 7, 8, and 5% of cardiac output,
respectively (Table 5). Mass-specific blood flow to skin
tissue was not different among groups (Table 6).
The salivary gland, thyroid and parathyroid glands,
eyes, urethra, urinary bladder, and other miscellaneous tissues made up ,3% of body mass among groups
(Table 3) and collectively received 3–4% of cardiac
output (Table 5). Blood flows to the salivary and thyroid
and parathyroid glands were lower in juvenile animals
than young adult rats (Table 6), and flow to the thyroid
and parathyroid glands in the aged rats was lower than
that in the adult rats.
DISCUSSION
The purpose of the present study was to test the
hypothesis that maturation, and in particular old age,
does not alter tissue blood flows per unit mass in
conscious Fischer-344 rats at rest but that alterations
in body composition may result in changes in the
fractional distribution of cardiac output. With few
exceptions, the data support the hypothesis that old
age does not alter tissue perfusion rates per unit mass.
Furthermore, there were relatively few changes in body
composition among the organ systems associated with
old age. In some of those tissues where proportional
changes in body mass did occur, such as with adipose
and cutaneous tissues, there were corresponding
changes in the fractional distribution of cardiac output.
However, a change in the proportion of body mass did
Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 18, 2017
Adipose
Visceral abdominal fat
Subcutaneous fat
Epididymal fat
Heart
Left ventricle
Septum
Right ventricle
Atria
Liver
Left lobe
Medial lobe
Right lobe
Splanchnic
Esophagus
Stomach
Duodenum
Jejunem and ileum
Cecum
Colon and rectum
Pancreas
Mesentery
Spleen
Reproductive
Seminal vesicles
Prostate gland
Testis
Skin
Hindlimb
Forelimb
Head and neck
Tail
Other
Lungs
Trachea
Salivary glands
Thyroid and parathyroid
glands
Adrenal cortex
Adrenal medulla
Right kidney
Left kidney
Urinary bladder
Urethra
Juvenile
1817
1818
AGING AND CARDIAC OUTPUT DISTRIBUTION
Table 7. Skeletal muscle blood flows from juvenile,
adult, and aged rats
Muscle
Adult
Aged
20 6 4
38 6 8
22 6 5
12 6 2
73 6 4
27 6 3
23 6 3
22 6 2
22 6 2
20 6 2
17 6 2
27 6 3
962
862
16 6 3
52 6 11
26 6 6
12 6 3
62 6 15
22 6 4
19 6 4
23 6 5
22 6 3
22 6 7
15 6 3
22 6 2
10 6 2
20 6 6
21 6 3
56 6 6
24 6 1
862
92 6 9
21 6 2
16 6 3
19 6 2
28 6 2
16 6 2
16 6 3
29 6 3
13 6 3
13 6 5
22 6 2
14 6 1
16 6 2
14 6 2
22 6 2
13 6 1
16 6 1
21 6 4
57 6 4
19 6 3
13 6 2
20 6 2
16 6 2
15 6 2
44 6 6
19 6 1
12 6 2
18 6 1
16 6 1
11 6 1*
51 6 3
20 6 1
961
20 6 1
125 6 16
35 6 4
54 6 10
24 6 3
12 6 3
35 6 9
16 6 4
96 6 8
25 6 3
53 6 10
24 6 2
14 6 1
41 6 4
22 6 1
94 6 13
26 6 1
40 6 4
24 6 2
13 6 1
23 6 3
14 6 1†
108 6 10
34 6 8
51 6 6
26 6 4
12 6 3
56 6 11
24 6 4
27 6 4
28 6 4
95 6 14
24 6 2
49 6 5
24 6 2
17 6 2
42 6 6
23 6 4
24 6 4
23 6 2
85 6 5
661
32 6 7
82 6 14
862
35 6 5
101 6 8
30 6 4
59 6 6
25 6 1
16 6 2
34 6 4
19 6 2
34 6 6
25 6 2
Fig. 1. Percent body mass and cardiac output composed of or directed
to adipose tissue in juvenile (2-mo-old), adult (6-mo-old), and aged
(24-mo-old) rats. Values are means 6 SE. † Group mean is different
from corresponding juvenile group mean, P , 0.05. * Aged group
mean is different from corresponding adult group mean, P , 0.05.
function of age, and there was a corresponding increase
in the fraction of cardiac output going to adipose tissue.
The third pattern, an inverse of the second, occurred in
cutaneous tissue (Fig. 2). The proportion of body mass
93 6 10
761
52 6 13
Values are means 6 SE in ml · min21 · 100 g21. * Group mean is
different from juvenile group mean, P , 0.05. † Group mean is
different from adult group mean, P , 0.05.
not always translate into a proportional change in
cardiac output.
Five patterns emerged that illustrate the various
relationships between changes in body composition and
alterations in the fractional distribution of cardiac
output in major organ systems of adult rats. The first is
a pattern that occurred in most organ systems, such as
the skeleton, brain and spinal cord, heart, kidneys,
liver, and splanchnic tissues, and it is that neither the
proportion of body mass (Table 3) nor the fraction of
cardiac output received by these tissues (Table 5) is
altered by age in adult animals. The second pattern
illustrates changes that occurred in adipose tissue (Fig. 1).
The percent body mass of fat pads increased as a
Fig. 2. Percent body mass and cardiac output composed of or directed
to skin tissue in juvenile (2-mo-old), adult (6-mo-old), and aged
(24-mo-old) rats. Values are means 6 SE. † Group mean is different
from corresponding juvenile group mean, P , 0.05. * Aged group
mean is different from corresponding adult group mean, P , 0.05.
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Arm, shoulder, neck, and facial
Triceps brachii, lateral head
Triceps brachii, long head, red
Triceps brachii, long head, mixed
Triceps brachii, long head, white
Triceps brachii, medial head
Biceps brachii
Brachialis
Forearm extensors
Forearm flexors
Latissimus dorsi
Pectoralis
Other shoulder and neck muscles
Temporalis
Masseter
Trunk and hip
Intercostals, obliques and ribs
Abdominals
Lumbar longissimus and psoas
major
Superficial gluteal
Medial gluteal, red
Medial gluteal, white
Tensor fasciae latae
Abductors and adductors
Thigh
Vastus intermedius
Vastus medialis
Vastus lateralis, red
Vastus lateralis, mixed
Vastus lateralis, white
Rectus femoris, red
Rectus femoris, white
Leg
Soleus
Plantaris
Gastrocnemius, red
Gastrocnemius, mixed
Gastrocnemius, white
Tibialis anterior, red
Tibialis anterior, white
Extensor digitorum longus
Flexors
Other
Diaphragm
Cremaster
Tongue
Juvenile
AGING AND CARDIAC OUTPUT DISTRIBUTION
Fig. 3. Percent body mass and cardiac output composed of or directed
to skeletal muscle in juvenile (2-mo-old), adult (6-mo-old), and aged
(24-mo-old) rats. Values are means 6 SE. † Group mean is different
from corresponding juvenile group mean, P , 0.05. * Aged group
mean is different from corresponding adult group mean, P , 0.05.
Fig. 4. Percent body mass and cardiac output composed of or directed
to reproductive tissue in juvenile (2-mo-old), adult (6-mo-old), and
aged (24-mo-old) rats. Values are means 6 SE. * Aged group mean is
different from corresponding adult group mean, P , 0.05.
resistance arteries (12, 34), carotid arteries (24), and
cerebral arterioles (32) of the rat, as well as in coronary
(13) and forearm muscle (19) resistance arteries of
humans. In addition, aging in rats has been shown to
result in rarefaction (36), reduced arteriolar crosssectional area and distensibility (22), and diminished
vasodilation elicited by metabolites (6). In light of the
seemingly global reduction in endothelium-mediated
dilation, as well as other vascular alterations that
would serve to increase vascular resistance, it was
surprising that blood flow was reduced to so few
tissues, i.e., the spleen, prostate gland, thyroid and
parathyroid glands, and 2 of 41 muscle and muscle
parts examined in the aged rats. The maintenance of
blood flow through old age is perhaps attributable to
the redundancy of vascular control mechanisms in
tissues (30).
There are few other animals studies describing hemodynamic alterations induced by old age in conscious
animals. For example, of the studies reporting regional
blood flows in mature young and old rats (23, 33, 38, 41)
and dogs (20, 21), one-half used anesthetized animals
(20, 23, 41), and most measured blood flow to only a
relatively few tissues. In the conscious rat, McDonald
et al. (33) found that blood flow to the heart, kidneys,
liver, pancreas, spleen, tibia, four muscle samples, and
four fat deposits was not different between 12-mo-old
and 24-mo-old male Fischer-344 rats. In addition,
Tuma and co-workers (38) reported that flow to the
heart, kidneys, liver, duodenum, stomach, lungs, brain,
and five muscle samples (grouped as a single observation) was not different between 12-mo-old and 24-moold female Fischer-344 rats but that splenic blood flow
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made up of skin decreased with age, and the fraction of
cardiac output directed to cutaneous tissue was lower
in aged rats relative to their young adult peers. The
fourth pattern reflected changes that occurred in skeletal muscle (Fig. 3). The proportion of body mass made
up of skeletal muscle was lower with increasing age,
but the relative proportion of cardiac output directed to
skeletal muscle was not different between young and
old adult animals. And fifth, in the male reproductive
tissues, there was no change in the proportion of body
mass made up by these tissues, but the fraction of
cardiac output going to the reproductive tissues was
lower in aged compared with adult rats (Fig. 4). Unlike
the other organ systems, this change in the fractional
distribution of cardiac output resulted from age-related
changes in mass-specific tissue blood flow, i.e., a decrease in flow to the prostate gland.
Our hypothesis that tissue blood flows per unit mass
are not altered by old age was based on the observation
that age-induced changes in whole body oxygen consumption result from changes in body composition
rather than from cellular metabolism (17, 39). Therefore, if cellular metabolic rate is unaltered, we postulated that tissue perfusion would be unaltered. This is
based on the assumption that metabolic rate will be the
primary determinant of tissue perfusion and that other
factors that regulate organ perfusion will not be altered
during normal aging. This is clearly not the case. For
example, in skeletal muscle and other tissues, endothelium-derived relaxing factors are important determinants of resting perfusion rates (30). Aging has been
shown to diminish endothelium-dependent relaxation
in the abdominal aorta (8), mesenteric conduit and
1819
1820
AGING AND CARDIAC OUTPUT DISTRIBUTION
there appear to be animal strain differences that could
be important for modelers. For example, in regard to
body composition, young adult male Sprague-Dawley
and Fischer-344 rats are similar in most respects.
However, the percent body fat and bone are quite
different between the two rat strains. The Fischer-344
rats have over twice as much adipose tissue, and the
Sprague-Dawley rats have over twice as much bone. In
our previous study of Sprague-Dawley rats (9), we did
not determine the extent of muscle and other soft tissue
on bone via chemical means. Therefore, on the basis of
our experience in the present study, we believe the
skeletal mass of the Sprague-Dawley rats was previously overestimated by 10–20%.
One technical concern when microspheres are used
to measure regional distribution of blood flow is the
possible hemodynamic disturbances that large numbers of microsphere can induce. For example, Stanek et
al. (37) reported that the net infusion of 1.44 million
microspheres did not alter cardiac output, blood pressure or total peripheral resistance, but it did result in a
decrease in heart rate. These investigators also reported that the infusion of 0.72 million microspheres in
a single dose resulted in transient reductions in cardiac
output and heart rate that persisted 3–5 min. In
designing the present study, we wanted to infuse a
large number of microspheres into the rats to maximize
our ability to get sufficient numbers of spheres into the
small tissue samples but not so many as to induce those
hemodynamic disturbances reported by Stanek et al.
Therefore, we conducted a preliminary study to determine whether the infusion of 1.0 million spheres in
juvenile rats and 1.5 million spheres in adult rats
induced hemodynamic disturbances. We found that
infusions of this number of microspheres did not alter
heart rate, mean arterial pressure, cardiac output
(Table 1), or tissue blood flows (data not shown).
Although the cardiac output and heart rate results
appear to be at odds with those of Stanek et al., there
are several important differences between the two
studies that may explain the discrepancies. First, the
adult animals used by Stanek et al. were ,100 g lighter
than the adult animals in the present study. This is a
potentially significant difference because body size is
an important factor for limiting the total number of
microspheres that can be infused. A second, and perhaps more important, difference is that Stanek et al.
suspended their microspheres in a dextrose solution.
Stanek et al. reported that infusion of dextrose solution
without microspheres resulted in no hemodynamic
disturbances. However, in our experience, we have
found that microsphere suspensions containing dextrose result in feet and facial swelling in rats, and in
some cases the animals temporarily collapse during
infusion. Elimination of dextrose from the microsphere
suspension has eradicated swelling and collapse. Flaim
et al. (15) have also reported microsphere suspensions
containing dextran to have adverse effects. Thus the
hemodynamic disturbances reported by Stanek et al.
(37) may be due to the combined effects of the microspheres and dextrose. Other factors may also contrib-
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was lower in aged animals. Therefore, the preponderance of evidence from conscious rats is that, despite
vascular alterations that occur with advancing age
(31), blood flow is well maintained in most tissues at
rest. However, it is possible that these apparent agerelated vascular ‘‘deficits’’ may not impact tissue perfusion when the animal is at rest but could adversely
affect blood flow and cardiac output distribution during
periods of altered metabolism, such as during exercise
(40). In support of this hypothesis, Irion et al. (25)
reported that skeletal muscle blood flow of anesthetized
aged male rats was lower than that of young adult rats
during stimulation-induced tetanic contractions.
We are unaware of any studies documenting the
effect of gender differences on central and peripheral
hemodynamics in association with body composition in
aged rats. However, the results of the present study of
conscious 24-mo-old male Fischer-344 rats and that of
Tuma et al. (38) of conscious 24-mo-old female Fischer344 rats afford an opportunity to make several comparisons. First, cardiac output in male rats is almost twice
that of the females, although cardiac index is virtually
identical. Mean blood flows to skeletal muscle and
visceral tissues are also similar between genders. However, myocardial perfusion rates may be different.
Mean ventricular flow in aged female rats is 57%
higher than that in aged male rats. Support for this
being a true gender difference comes from the observation that there is a similar blood flow pattern in active
skeletal muscle of aged rats. Irion and co-workers (25)
demonstrated that muscle blood flow elicited during
tetanic contractions was lower in 24-mo-old male rats
than in 12-mo-old male rats but that muscle blood flow
in 24-mo-old female rats was similar to that of 12-moold females (26). In addition, questions regarding gender-specific differences in body composition remain
unresolved. For example, we know that, in the aged
male rat, the proportion of total body fat increases with
age (Fig. 1), as does the percentage of visceral abdominal fat (juvenile: 1.5 6 0.2%, adult: 2.1 6 0.3%, aged:
3.9 6 0.5%). This may be biologically significant because, in humans, men accumulate greater deposits of
visceral abdominal fat than women do (14), and the
level of visceral adipose tissue is an important correlate
for several prevalent diseases, such as diabetes (28)
and cardiovascular disease (10).
To our knowledge, the present study represents the
most thorough description in the literature of the body
composition and distribution of cardiac output among
tissues in an immature and aged animal. Knowledge of
total organ and/or tissue masses and their respective
blood flows is necessary for a variety of biological
modeling procedures that include tissue mass and
perfusion as variables. For example, knowledge of
tissue volumes and the respective fractional distribution of cardiac output is critical as input variables for
pharmacokinetic models (2, 4). We have previously
published these variables in young adult male SpragueDawley rats (9). However, the paucity of data for
immature and aged rats make these models unreliable
for estimating toxicity in these age groups. In addition,
AGING AND CARDIAC OUTPUT DISTRIBUTION
This work was supported by National Aeronautics and Space
Administration Grants NAGW-4842 and NAG5–3754 and by US
Environmental Protection Agency Service Contract 5D2283NAEX.
The research described in this article has been reviewed by the
National Health and Environmental Effects Research Laboratory,
US Environmental Protection Agency and approved for publication.
Approval does not signify that the contents necessarily reflect the
views and policies of the agency, nor does mention of trade names or
commercial products constitute endorsement or recommendation for
use.
Address for reprint requests: M. D. Delp, Dept. of Health and
Kinesiology, Texas A&M Univ., College Station, TX 77843 (E-mail:
[email protected]).
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Received 6 March 1998; accepted in final form 15 June 1998.
22.
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ute to the different cardiac output and heart rate
responses between studies, such as the density of the
microsphere suspension infused into the heart [2.5
million spheres/ml in present study vs. an unknown
density in the study of Stanek et al. (37)] or perhaps the
severity of surgical instrumentation (carotid and caudal catheters in present study vs. ascending aortic flow
probe and carotid, femoral, and left atrial catheters in
the study of Stanek et al.), which might affect the
animals’ ability to maintain a stable cardiac output and
heart rate. Regardless of the factor(s) responsible, the
results of the present study indicate that the infusion of
1.0 million spheres in juvenile rats and 1.5 million
spheres in adult rats does not disrupt heart rate,
arterial pressure, cardiac output, or tissue blood flow.
In conclusion, the present study demonstrates that
old age does not alter mass specific perfusion rates in
most tissues. Blood flows to the spleen, prostate gland,
thyroid and parathyroid glands, and the superficial
gluteal and white portion of the rectus femoris muscles
were, however, lower in aged rats. In addition, the
proportion of body mass and the fraction of cardiac
output going to most tissues does not change with old
age. However, adipose and lung tissue made up a
greater proportion of body mass in the old animals,
whereas skeletal muscle and skin tissue accounted for
a lower percent of body mass. Finally, old-age-related
alterations in the proportional distribution of cardiac
output occurred in adipose, cutaneous, and reproductive tissues. The age-related alterations in cardiac
output distribution to adipose and cutaneous tissues
appear to be associated with the increases in percent
body fat and the decreases in the fraction of skin mass,
whereas the decrease in the proportion of cardiac
output directed to reproductive tissue of aged rats was
unrelated to a change in total mass but resulted from a
decrease in blood flow per unit mass.
1821
1822
AGING AND CARDIAC OUTPUT DISTRIBUTION
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