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Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan, Kansas 66506-5802
Submitted 16 December 2002 ; accepted in final form 21 February 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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capillary hematocrit; microvascular oxygen exchange; Brown Norway rat; red blood cell velocity and flux
In contrast to the responses detailed above, very little is known about the effects of aging on the distribution and hemodynamics of red blood cells (RBCs) within the muscle capillary network. Such information is crucial for modeling blood-myocyte O2 exchange and elucidating how this process might be impacted by the structural and functional sequelae of the aging process. For example, O2 delivery is dependent on capillary RBC flux (FRBC) within and between different capillaries. RBC velocity (VRBC) affects the transit time of RBCs in the capillary, and the elegant modeling of Groebe and Thews (24) suggests that capillary hematocrit is a key determinant of the capacity for blood-myocyte O2 diffusion.
Aged muscle presents a challenge to the microscopist, in part because the proliferation of collagenous tissue over the muscle surface obscures underlying structures. Removal of this tissue may disrupt the structural and functional integrity of the preparation (40). Tyml and colleagues (54) circumvented this problem by judicious selection of a relatively deep muscle (extensor digitorum longus, EDL) that remains free from collagenous overgrowth. Their elegant investigation demonstrated a threefold higher capillary VRBC in EDL muscle of senescent (28 mo old) Fischer 344 rats compared with their middle-aged (12 mo old) counterparts. Although these authors did not quantify capillary FRBC or hematocrit, the VRBC and laser-Doppler measurements indicate that blood flow was increased close to 300%. Other measurements of muscle blood flow with different methodologies (25, 28, 29, 46, 58) do not corroborate the findings of Tyml et al. (54), including blood flow to the EDL (18), which suggests that they may be related to some aspect of the muscle preparation per se.
The rat spinotrapezius muscle represents a classic muscle for intravital studies of the microcirculation (2). The spinotrapezius is comprised of a mosaic of different muscle fiber types (41% type I, 7% IIA, 17% IID/X, 35% IIB; Ref. 17) and can be exteriorized without disruption of the nervous or principal vascular supplies (2, 44). This preparation possesses the following advantages. First, exteriorization permits transmission light microscopy for enhanced visualization of capillary structures and hemodynamics. Second, muscle sarcomere length can be measured and set to remove the confounding effects of different sarcomere lengths on the microcirculation (31, 44). Finally, pertinent to the present investigation, either the dorsal or the ventral surface can be visualized. The ventral surface is relatively free of the connective tissue overgrowth that precludes observation of the microcirculation from the dorsal surface.
Using this preparation, we tested the primary hypothesis that capillary VRBC and FRBC would be elevated in the spinotrapezius muscle of senescent rats. If these changes occur in the absence of increased total muscle FRBC, there must be a reduced lineal density of RBC-perfused capillaries as suggested by the available structural data (16, 25). Because of the observation that capillary hyperemia elevates capillary hematocrit (see, e.g., Ref. 33), a secondary hypothesis was that any increased VRBC would be accompanied by an increased capillary hematocrit.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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All procedures were approved under Kansas State University animal handling guidelines. All surgical interventions were conducted under general anesthesia with pentobarbital sodium (28–30 mg/kg ip) supplemented as necessary before the animal was positioned on the observation platform. The carotid artery was cannulated with polyethylene-50 tubing (Intra-Medic polyethylene tubing, Clay Adams, Sparks, MD) to monitor arterial blood pressure and facilitate blood sampling and fluid replacement.
Muscle preparation. The spinotrapezius muscle originates in the lower thoracic and upper lumbar region of the middorsum of the rat and inserts on the spine of the scapula. The spinotrapezius muscle was prepared according to previously described methods (23) as modified by Poole et al. (44) with minimal fascial removal to limit tissue damage and microcirculatory disturbances. The muscle was then sutured at five equidistant points to a horseshoe manifold. The manifold was attached to a swivel and a muscle stretching apparatus that permitted precise length changes along the longitudinal axis of the muscle. This prevented any structural and hemodynamic alterations due to changes or alterations in muscle length. The rat was placed on a Lucite platform heated to 38°C with the spinotrapezius reflected so that the ventral surface was uppermost, and this was superfused with a Krebs-Henseleit bicarbonate-buffered solution equilibrated with 95% N2-5% CO2. All exposed surrounding tissue was protected with Saran Wrap (Dow Brands, Indianapolis, IN). Sarcomere length was set to <2.7 µm to prevent any stretch-induced capillary blood flow reductions (44). Simultaneous measurements of sarcomere length, capillary geometry, and flow dynamics were then obtained.
Intravital video microscopy. Microcirculatory images were obtained via an intravital video microscope (Nikon Eclipse E600-Fn, Tokyo, Japan) equipped with a noncontact illuminated lens (x40, numerical aperture 0.8) and viewed on a high-resolution color monitor (Sony Trinitron PVM-1954Q, Ichinoniya, Japan) under a final magnification of x1,184. This was confirmed by calibration of the system with a stage micrometer (MA285, Meiji Techno). Images were time referenced by frame and stored on videocassettes (JVC S-VHS Master XG) for subsequent off-line analysis via a videocassette recorder (JVC BR-S822U, Elmwood Park, NJ).
Experimental design. Two to four fields that demonstrated good
clarity were each observed for 
60–180 s, and images were recorded
for subsequent analysis. Total experimental duration was no longer than
1.5–2.0 h, during which up to 1.5 ml of sterile isotonic saline was
infused intra-arterially to counteract dehydration.
Capillary and fiber structural measurements. Within each preparation only those fields that displayed the best overall clarity were selected for further study. Sarcomere length was determined from sets of 10 consecutive in-register sarcomeres measured parallel to the muscle fiber longitudinal axis. This procedure was performed several times on each muscle fiber and on every muscle fiber where sarcomeres were visible to obtain a mean sarcomere length. These fields were traced directly from the video monitor screen onto acetate paper. The details traced included muscle fiber boundaries and the lower margin of the capillary endothelium where it was continuously visible. For each muscle fiber in which both sarcolemmal boundaries were visible on screen, the apparent fiber width perpendicular to the longitudinal muscle fiber axis was measured and associated capillaries (i.e., those with and without RBC flow) were counted. These values were used to calculate lineal density (i.e., the number of capillaries per unit muscle width). To ensure that the number of capillaries per fiber was not overestimated, capillaries were counted between the midpoints of two adjacent muscle fibers. Where the capillary endothelium was clearly visible on both sides of the lumen, capillary diameter was measured with calipers accurate to ±0.25 mm (±0.17 µm at x1,184 magnification) at several random locations per capillary and the mean value was recorded.
Capillary geometry. Capillary geometry was determined with techniques described previously (4, 31, 44). These measurements provided a value analogous to the capillary anisotropy coefficient obtained by ex vivo morphometric methods (38). This measurement provides the additional capillary length arising from nonanisotropic components of the capillary bed (i.e., tortuosity and branching).
Hemodynamic data collection. RBC flow was observed in real time
and with playback and frame-by-frame techniques. The percentage of
RBC-perfused vessels was established as (no. of capillaries supporting RBC
flow ÷ total no. of visible capillaries per area) x 100. All
hemodynamic data were obtained from at least two different areas per muscle.
Capillary VRBC was determined in all capillaries that were
continuously RBC perfused and that could be continuously monitored over
several frames (5–10 capillaries/area). Capillary
FRBC was also determined by counting the number of RBCs
that passed by an arbitrary point in the capillary per second. On average,
capillary VRBC was measured twice per capillary and
FRBC was measured three times per capillary.
Capillary tube hematocrit. In each muscle, capillary tube
hematocrit (Hctt) was measured as: Hctt = (RBC volume
· FRBC) ÷ [
·
(dc /2)2 · Vrbc],
where dc is capillary diameter. RBC volume was taken to be
61 µm3 (1), and
capillaries were assumed to be circular in vivo.
Microvascular PO2. Microvascular
PO2 (PO2m) was determined in the
exposed left spinotrapezius within a subset of young and old rats with the
phosphorescence probe palladium meso-tetra-(4-carboxyphenyl)porphyrin
dendrimer (R2) as described by Behnke and colleagues
(6,
7). The oxygen dependence of
the probe phosphorescence can be described quantitatively through the
Stern-Volmer relationship
(50). R2 was infused
arterially at 15 mg/kg, and it binds tightly to albumin
(37). In addition, R2
possesses a negative charge that, when coupled with the high albumin
reflection coefficient of skeletal muscle (0.99; Ref.
47), will act to restrict it
to the vascular compartment.
PO2m was determined with a PMOD 1000 frequency domain
phosphorometer (Oxygen Enterprises, Philadelphia, PA) with the common end of
the bifurcated light guide placed 1.5–2 mm above the medial region
of the exposed spinotrapezius. The PMOD 1000 uses a sinusoidal modulation of
the excitation light (524 nm) at frequencies between 100 Hz and 20 kHz, which
allows phosphorescence lifetime measurements from 10 µs to 2.5 ms. In
the single-frequency mode, 10 scans (100 ms) were used to acquire the
resultant lifetime of the phosphorescence (700 nm; Ref.
55) and measurements were
repeated at 2-s intervals to acquire PO2m. The
phosphorescence lifetime, which is independent of probe concentration
(37), was obtained by taking
the logarithm of the intensity values at each time point and fitting the
linearized decay to a straight line by the least-squares method
(8).
Calculated O2 consumption. Muscle
O2 consumption
(
O2m) was calculated with
the Fick equation by assuming that PO2m is an
appropriate analog for venous PO2
(5).
O2m was estimated by
using arterial blood gases, PO2m, and the measured
lineal FRBC (rat RBC hemoglobin content of 17 
g; Ref.
1) from the observable
capillary field and is reported in microliters of O2 per minute per
millimeter of muscle. The dissolved contribution of O2 is
anticipated to be <5%, and this was omitted because plasma flow could not
be measured within the field.
Statistical analysis. All data are presented as means ± SE. Data were linearly regressed with a standard least-squares regression technique. Comparisons were made between O and Y groups by unpaired Student's t-tests. A significance level of P ≤ 0.05 was accepted for differences between individual capillaries. Where there was clear precedence for an a priori directional hypothesis (i.e., FRBC and Vrbc; Ref. 46), a one-tailed test was used. For all other comparisons, a two-tailed test was used.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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O2 between groups (Y: 552
± 30, O: 623 ± 45 µl · min-1 · mm
muscle-1; P > 0.05). Muscle fiber and capillary structural comparisons. There were no differences between Y and O rats with respect to sarcomere length (Y: 2.0 ± 0.1, O: 2.1 ± 0.1 µm), fiber width (Y: 60.3 ± 4.0, O: 51.9 ± 3.3 µm), capillary diameter (Y: 6.0 ± 0.1, O: 6.0 ± 0.1 µm), or the percentage of capillary length arising from tortuosity and branching (Y: 13 ± 2%,O:13 ± 2%) (Table 1). The lineal density of all (i.e., those with and without RBC flow) capillaries was significantly less (P < 0.05) in the O (30.4 ± 4.1 capillaries/mm) vs. Y (39.4 ± 2.3 capillaries/mm) rats.
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Hemodynamic comparisons. There was no difference in the percentage of flowing capillaries in O vs. Y rats (Y: 78 ± 3%, n = 6; O: 75 ± 2%, n = 6; P > 0.05). However, the lineal density of RBC-perfused capillaries was reduced (P < 0.05) in the O (22.8 ± 3.1 capillaries/mm, n = 6) compared with the Y (30.7 ± 1.8 capillaries/mm, n = 6) rats (Table 1). In RBC-perfused capillaries within individual muscles, VRBC (Y: 233 ± 24, O: 312 ± 27 µm/s) and FRBC (Y: 29.1 ± 3.2, O: 42.5 ± 6.0 cells/s) were both significantly greater in the O rats (n = 6) than in their Y counterparts (n = 6) (P < 0.05) (Figs. 1 and 2A). In individual capillaries (Y: n = 66, O: n = 78), both VRBC (Y: 219 ± 12, O: 310 ± 14 µm/s) and FRBC (Y 27.1 ± 1.8, O: 40.9 ± 2.4 RBC/s) were greater in O than Y rats (Figs. 2B, 3, and 4). VRBC and FRBC were significantly correlated in individual muscles (r = 0.92; Fig. 2A) as well as individual capillaries (r = 0.88; Fig. 2B). The slope of this relationship determines capillary hematocrit, and there was no significant difference in capillary hematocrit among individual muscles (Y: 0.27 ± 0.01, O: 0.29 ± 0.02; Fig. 1) or individual capillaries (Y: 0.26 ± 0.01, O: 0.28 ± 0.01) between the Y and O rats. When the coefficient of variation was used as a measure for blood flow heterogeneity within the muscle, there was no difference between Y and O rats with respect to VRBC (Y: 0.45, O: 0.39, P > 0.05) or FRBC (Y: 0.55, O: 0.51, P > 0.05). When the product of lineal density of RBC flowing capillaries and capillary FRBC was calculated, the blood flow per unit of muscle was not different between Y and O rats (Y: 894 ± 111, O: 887 ± 118 cells · s-1 · mm-1 muscle; P > 0.05). The percentage of vessels exhibiting countercurrent RBC perfusion was significantly (P < 0.05) reduced in O (16 ± 2%) compared with Y (23 ± 2%) rats.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Comparison with previous research. To our knowledge, the F334xBN
rat has not been used previously for muscle microcirculation studies, and
comparisons discussed below should be interpreted with this in mind. Moreover,
to compare young adult rats with their senescent counterparts, the Y rats in
the present investigation were slightly older (6–8 mo) and larger
(420 g) than those used in many other studies (i.e., <3 mo, 250
g; Refs. 31 and
44).
Intravital microscopy investigations have demonstrated that, in different muscles, the great majority of capillaries support a continuous RBC perfusion at rest (15, 31, 44), and this is consistent with the 75–78% value found in the Y and O muscles examined herein. In the presence of unaltered muscle fiber width, the reduced lineal density of total and flowing capillaries in O muscles suggests that capillary involution had occurred. This conclusion coheres with that of Degens et al. (16) and also Haidet and Parsons (25) but is at apparent odds with the similar density of RBC-perfused capillaries reported for EDL muscle of middle-aged (12 mo) and O (28 mo) F344 rats by Tyml et al. (54). It is pertinent, however, that the significant reduction in EDL mass, indicative of fiber atrophy, may have masked a loss of total capillaries in that investigation.
Despite the similarity of capillary VRBC values measured in O muscle capillaries by Tyml and colleagues (320 µm/s) and the present investigation (310 µm/s), one principal contrast between our and their findings is the percentage increase in VRBC between Y and O animals. Specifically, in the Tyml et al. study (54), there was a 190% increase of VRBC in O vs. Y rats compared with 42% in the present investigation. Obviously, the difference is attributable to the values obtained for the Y rats, and the capillary VRBC values reported in Tyml et al.'s "Y" rats were extremely low (mean 111 µm/s) in comparison with literature values (15, 30, 31, 32, 51).
With respect to capillary hematocrit, the mean values found in the present
investigation for Y and O rats (0.26–0.29) were slightly higher than the
0.22 we reported previously for the spinotrapezius muscle of young (2–3
mo, 250 g) female Sprague-Dawley rats
(31). Although no difference
was found between Y and O rats, it is possible that this higher hematocrit
reflects a systematic difference between strains of rat or, alternatively,
that capillary hematocrit increases between 3 and 6 mo of age in the rat. Our
second hypothesis, namely, that an elevated VRBC in O
capillaries would be accompanied by a higher capillary hematocrit in O vs. Y
muscles, was not supported by the data. This hypothesis was based on the
observation that hyperemic states that elevate VRBC cause
a corresponding increase in capillary hematocrit
(33). We found that the 42%
increase of VRBC in O spinotrapezius capillaries measured
here did not elevate hematocrit above that seen in Y capillaries. It is
possible that this represents an age-related change in the endothelial cell
glycocalyx (thought to be integral in differentiating capillary from systemic
hematocrit; Ref. 19) and is
deserving of future study.
The percentage of capillaries exhibiting countercurrent RBC perfusion in Y rats (23%) was higher than that previously reported for the Sprague-Dawley rat spinotrapezius (8%; Ref. 31). Again, this may represent a between-strain variation between the Sprague-Dawley and F344xBN rats or an aging effect occurring between 3 and 6 mo that remains to be evaluated systematically.
Implications for vascular control and blood-myocyte O2 transfer. The senescent rats sustained a similar total FRBC (i.e., FRBC per capillary x lineal density of RBC-perfused capillaries) compared with that observed in their younger counterparts. Because mean arterial pressure was not altered by aging, muscle vascular conductance was not changed. No measurements of arteriolar density or arteriolar luminal diameter were made in the present investigation; however, it is quite possible that the capillary involution (Table 1; Refs. 16 and 25) was accompanied by an arteriolar rarefaction. Aging-induced arteriolar rarefaction has been demonstrated in skeletal muscle (42) and other tissues, e.g., cerebellum (52). If this was indeed the case, the remaining arterioles would have had to increase their luminal diameter to sustain vascular conductance at a level commensurate with their younger counterparts. Consistent with this notion, Muller-Delp and colleagues (43) showed that the myogenic responsiveness of both soleus and gastrocnemius arterioles is reduced in aged rats. Moreover, those investigators found that skeletal muscle arterioles from aged rats demonstrated a reduction in endothelium-dependent flow-induced vasodilation (gastrocnemius and soleus) as well as an impaired ACh-induced vasodilation (soleus) compared with young rats. In addition, within gastrocnemius arterioles these investigators (42) believe that these age-related adaptations were the result of an increased intravascular blood flow and shear stress produced by a reduction in arteriolar density. Interestingly, the results of the present investigation (i.e., the increases in VRBC and FRBC) are consistent with their hypothesis and provide the potential mechanistic basis for the vascular adaptations found in the most recent study by Muller-Delp and colleagues (42).
In the absence of a mitochondrial translocation toward the sarcolemma, the reduced lineal density of RBC-perfused capillaries found in senescent muscle will serve to increase mean O2 diffusion distances. However, over the last two decades, cryomicrospectro-photometric measurements of myoglobin O2 saturation have revealed that during exercise intramyocyte PO2 values are very low (<3 mmHg) and PO2 gradients projecting either radially or longitudinally from the capillary have not been detected (27). The absence of such gradients indicates that the majority of the PO2 drop between RBC and mitochondria (and therefore the principal site of diffusional O2 resistance) occurs in that short physical space between the RBC and the immediate subsarcolemmal cytoplasmic space. Consequently, muscle O2 diffusional properties (O2-diffusing capacity, DO2) will be determined principally by the available capillary surface area (39) and the number of RBCs contained within those capillaries (24).
In the present investigation, the elevated VRBC and
decreased proportion of capillaries supporting countercurrent RBC perfusion
also have the potential to impair O2 delivery in senescent muscle.
Specifically, Wagner and colleagues
(48,
56) showed that fractional
O2 extraction is determined by the relationship between
DO2 and blood flow (
)
such that O2 =
O
2 (1 -
e-DO2/
)
and therefore
O2/O2
= O2 extraction = 1 -
e-DO2/,
where is the slope of the O2 dissociation curve in the
physiologically relevant range. As discussed above, the unchanged capillary
hematocrit in aged muscle suggests that DO2 for a given
capillary is unaltered. However, within that capillary both
VRBC and FRBC (and thus
) are elevated and this will reduce the ratio
DO2/ and thus
fractional O2 extraction. This consideration may assume greater
importance during exercise when, for a given muscle
capillary VRBC and
FRBC may increase substantially more in senescent muscle.
Under these circumstances, either fractional O2 extraction will be
compromised or intracellular PO2 will fall to a lower
level in older rats to generate the greater O2 flux density
necessary to achieve a given
O2 in the face of a
decreased capillary RBC transit time. A reduction in intramyocyte
PO2 exacerbates changes in intracellular phosphates and
phosphate-linked controllers of mitochondrial function
(59), which stimulates
glycolysis and thus enhances glycogen degradation and cellular acid-base
disturbances associated with contractile impairments.
In the present investigation, we found that the resting microvascular
PO2 and muscle
O2 are not different in Y
and O rats. However, the reduction in lineal density of RBC-perfused
capillaries in senescent muscle is expected to decrease maximal
DO2, and thus the capacity for blood-myocyte
O2 transfer, under conditions of maximal exercise hyperemia where
capillary RBC transit time may become limiting. We believe that one important
finding of the present investigation is that the reduced lineal density of
capillaries that support RBC flux will reduce the reserve capacity for
DO2 (and therefore O2 extraction at very high
flows). Specifically, at equivalent levels of exercise-induced muscle
hyperemia, VRBC and FRBC within
individual capillaries must be elevated in senescent vs. younger rats.
Consequently, for each capillary, the ratio
DO2/ or, more
correctly, DO2/VRBC, will fall
to a greater extent in senescent muscle. Because O2 extraction =
O2/O2
= 1 -
e-DO2/VRBC,
at equivalent very high blood flows O2 extraction would become
limited by short RBC transit times. Indeed, Proctor et al.
(46) noted that in aged humans
muscle blood flow is reduced at a given workload. This reduced blood flow will
act to lengthen RBC transit times and therefore preserve extraction even in
the face of a reduced volume of RBC flowing capillaries and
DO2 as supported by the present data.
Muscles with a high oxidative enzyme capacity such as cardiac
(10), diaphragm
(31), and select limb
(41) muscles exhibit a greater
capillary countercurrent RBC perfusion that will act to raise microvascular
(45), intracellular, and
venous (34)
PO2. Because skeletal muscle has a finite
DO2, maintenance of greater venous and microvascular
PO2 during severe intensity exercise is crucial for
achieving maximal O2
(26,
49,
56,
57). Consequently, the
decrease in the proportion of capillaries sustaining countercurrent RBC
perfusion may compromise the ability of senescent muscle to achieve high
maximal O2
(O2 max) values.
Implications for O2 exchange during
exercise. To our knowledge, there are no investigations of the effect of
aging on microcirculatory hemodynamics in contracting muscle. Obviously, this
is a technically challenging endeavor but not infeasible with the preparation
described in the present investigation. The age-related reduction in the
lineal density of RBC-perfused capillaries indicates that any increase of
muscle will elevate VRBC
and reduce capillary RBC transit time to a greater extent in senescent than in
young muscle. Consequently, senescent muscle will exhibit a reduced reserve
for blood-myocyte O2 transfer compared with that present in muscle
from younger rats. Future investigations might test this hypothesis and
evaluate whether any such reduction in capillary RBC transit time is
associated with a compromised fractional O2 extraction and an
elevated PO2m. The decreased RBCs adjacent to muscle
fibers (i.e., product of decreased lineal density of RBC-perfused capillaries
and their hematocrit) would indicate that DO2 in
senescent muscle must be compromised. Any such reduction in
DO2 acting in concert with a reduced capillary RBC
transit time would be expected to decrease the maximal capacity for
blood-myocyte O2 exchange (i.e.,
O2 max).
In conclusion, the present investigation has demonstrated that, in a muscle comprised of a mixed-fiber type population, the senescent rat exhibits a profoundly altered capillary hemodynamic profile compared with that seen in younger counterparts. These findings suggest that microcirculatory changes present in aged muscle may potentially constrain blood-myocyte O2 transfer particularly in contracting muscle.
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ACKNOWLEDGMENTS |
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This work was supported in part by National Institutes of Health Grants AG-19228 and HL-50306.
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FOOTNOTES |
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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.
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