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J Appl Physiol 99: 505-514, 2005. First published March 31, 2005; doi:10.1152/japplphysiol.00896.2004
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Impact of aging on muscle blood flow in chronic heart failure

Kevin E. Eklund, K. Sue Hageman, David C. Poole, and Timothy I. Musch

Clarenburg Research Laboratory, Departments of Kinesiology, Anatomy and Physiology, Kansas State University, Manhattan, Kansas

Submitted 18 August 2004 ; accepted in final form 26 March 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Chronic heart failure (CHF) is manifested principally in the elderly population. Therefore, to understand the causes of exercise intolerance in CHF patients, it is imperative to resolve the effects of aging on muscle blood flow (BF) in CHF. To address this issue, we determined the muscle BF response to submaximal treadmill exercise (20 m/min, 5% grade) in young (YCHF: 6–8 mo, 412 ± 11 g, n = 11) and old (OCHF: 27–29 mo, 494 ± 10 g, n = 8) Fischer 344 x Brown Norway rats with similar degrees of myocardial infarction-induced left ventricular (LV) dysfunction [resting LV end-diastolic pressure: YCHF = 24 ± 2, OCHF = 22 ± 2 mmHg; derivative of LV pressure over time: YCHF = 5,168 ± 285; OCHF = 5,050 ± 165 mmHg/s; lung weight normalized to body weight: YCHF = 9.14 ± 0.72; OCHF = 8.21 ± 0.29 mg/g (all P > 0.05)]. The exercising heart rate response was blunted in OCHF compared with YCHF rats (YCHF = 454 ± 8, OCHF = 395 ± 9 beats/min; P < 0.05). BF (radiolabeled microspheres) to the total hindlimb musculature and to each of the 28 individual muscles examined was similar between YCHF and OCHF rats under resting conditions. During exercise, BF to five of the hindlimb muscles that normally possess a majority of slow-twitch oxidative and fast-twitch oxidative glycolytic muscle fibers increased significantly less (–25 to –42%) for OCHF compared with YCHF rats. In contrast, BF to 14 of the hindlimb muscles that normally possess a majority of fast-twitch glycolytic muscle fibers was increased (+22 to +337%) for OCHF vs. YCHF rats, which contributed to a greater mass-specific total hindlimb BF response in OCHF rats (YCHF = 78 ± 5, OCHF = 100 ± 11 ml·min–1·100 g–1; P < 0.05) and coincided with greater reductions in BF to the kidneys and splanchnic organs during exercise in OCHF vs. YCHF. In conclusion, there appears to be a profound age-related redistribution of BF from the highly oxidative to the highly glycolytic muscles of the hindlimb during exercise in OCHF compared with YCHF rats. This phenomenon is qualitatively similar to that reported previously for healthy young and old rats.

myocardial infarction; exercise; fiber type; left ventricular dysfunction; exercise hyperemia

AGING AND CHRONIC HEART FAILURE (CHF) both elicit central and peripheral cardiovascular perturbations that reduce the maximal oxygen uptake (O2 max) and significantly alter the skeletal muscle blood flow (BF) response to exercise (18, 26, 27, 36, 37, 40, 42). Prominent among the cardiovascular changes associated with aging and CHF is a reduced cardiac output (13, 58) and an attenuation in skeletal muscle endothelium-dependent vasodilation (1, 14, 33, 56, 57). Whereas submaximal and maximal cardiac output is clearly impaired in individuals with CHF, aging studies using healthy sedentary subjects have demonstrated that it may or may not be attenuated with aging (13, 32, 41, 43, 44). In contrast, decrements in endothelium-dependent vasodilation are commonly found in both conditions. Together such perturbations would be expected to produce profound changes in the control and distribution of BF to active skeletal muscle.

Although our laboratory and the laboratories of others have shown that aging and CHF both alter the skeletal muscle BF response to exercise, the effect of aging in the presence of CHF has yet to be examined. Given that individuals 65 yr and older represent the fastest growing segment of the population (11) and that CHF is one of the leading causes of death in this age group (2), there is a pressing demand to study the effects of aging in a rat model of CHF. Therefore, the purpose of this investigation was to examine the effects of aging on the skeletal muscle BF response to a given level of submaximal exercise in young and old rats with the same degree of left ventricular (LV) dysfunction and CHF induced by myocardial infarction (MI). On the basis of previous results from our laboratory (36, 37), we anticipated that the skeletal muscle BF response to exercise would be 1) significantly altered in the old rats with CHF (OCHF) compared with young rats with CHF (YCHF) and 2) related to or dependent on the fiber-type composition of muscle. Specifically, we hypothesized that OCHF rats would demonstrate age-related reductions in BF to muscles that normally have a high oxidative capacity [i.e., muscles possessing a majority of slow-twitch oxidative (SO) and/or fast-twitch oxidative glycolytic (FOG) muscle fibers] compared with their younger counterparts (YCHF).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animal selection and care.   Twenty-three young (6–8 mo old) and 23 old (27–29 mo old) Fischer 344 x Brown Norway (F344/BN) rats were used in this investigation. These rats were specifically selected for this study because they represent young and old (senescent) rats according to the life span for the F344/BN strain (22). In addition, the F344/BN rat has the distinct advantage over the Fischer 344 rat because it does not develop many of the age-related pathologies that proliferate in their highly inbred Fischer 344 cousins (9, 28). Rats were maintained on a 12:12-h light-dark cycle and received food and water ad libitum. All experiments were conducted under the guidelines established by the National Institutes of Health, and all procedures were approved by Kansas State University’s Institutional Animal Care and Use Committee.

Surgical procedure.   All rats received an MI as described previously (37). Briefly, under aseptic conditions, rats were initially anesthetized with a 5% isoflurane-oxygen mixture, intubated, and connected to a rodent respirator and maintained on a 2% isoflurane-oxygen mixture. A left thoracotomy was performed between the fifth and sixth rib, allowing for access to the heart. The pericardium was then opened, and the left main coronary artery was ligated with 6-0 Ti-cron suture. The lungs were hyperinflated and the ribs were sutured back together using 2-0 gut. The muscles of the thorax along with the skin were sewn together using 4-0 gut and 3-0 silk suture, respectively. Lidocaine (1.5 mg/kg every 2 h for 8 h) and buprenorphine (0.03 mg/kg every 12 h for 24 h) was administered subcutaneously for postoperative pain alleviation, and ampicillan (50 mg/kg every 24 h for 10 days) was injected subcutaneously to minimize the chance for infection. After surgery, anesthesia was removed and animals were extubated. The rate of survival for the young and the old rats was 95.6% (22/23) and 47.8% (11/23), respectively.

After the recovery from surgery (5–6 wk) all rats were familiarized with running on a motor-driven treadmill. During these exercise bouts the animals performed moderate intensity (~20 m/min) running on a graded treadmill (5%) 4–5 days/wk for a duration of ≤5 min.

Instrumentation and final experimental protocol.   All rats were anesthetized with a 5% isoflurane-oxygen mixture and maintained on a 2% isoflurane-oxygen mixture. Under aseptic conditions, a shallow incision was made on the midline of the anterior portion of the neck to allow access to the carotid artery. The right carotid artery was exteriorized and cannulated with a 2-Fr-catheter-tipped pressure micromanometer (model TC-510, Millar Instruments). While heart rate (HR) and the arterial pressure waveform was being monitored, the pressure transducer was advanced into the LV in a retrograde fashion and LV end-diastolic pressure (LVEDP) and the derivative of the pressure wave form (LV dP/dt) were measured and recorded. After LVEDP and LV dP/dt measurements were completed the micromanometer was retracted, HR and arterial pressure were measured and recorded while the micromanometer was placed in the aortic arch, and then the micromanometer was removed. The right carotid artery along with the caudal tail artery were then catheterized (PE-10 connected to PE-50) as previously described (37). The right carotid and tail artery catheters were tunneled subcutaneously on the dorsal side of the cervical region and exteriorized via a small perforation in the skin. The incisions were closed with 3-0 silk suture, and the animal was taken off anesthesia and allowed a minimum of 90 min to recover. This period of recovery was selected because previous studies by Flaim et al. (12) showed that cardiac or circulatory dynamics, regional BF, arterial blood gases, and acid-base status are stable in the awake unrestrained rat 1–6 h after inhalatory anesthesia.

Subsequent to the recovery period, the final experimental protocol was initiated. Each rat was then placed on the treadmill, and after a period of stabilization (~15 min), the tail artery catheter was connected to a 1-ml plastic syringe that was connected to a Harvard infusion-withdrawal pump (model 55-2226). Exercise was initiated, and the speed of the treadmill was increased progressively during the next 30 s to a speed of 20 m/min (5% grade). The rat was then required to exercise steadily for another 3 min. After 3.5 min of total exercise time, blood withdrawal from the tail artery catheter was initiated at a rate of 0.25 ml/min. Simultaneously, HR and arterial blood pressure were measured via the carotid artery catheter. After 4 min of total exercise time, the carotid artery catheter was disconnected from the pressure transducer, and 0.5–0.6 x 106 microspheres with a 15-µm diameter (isotopes used were 46Sc, 85Sr, 113Sn, or 141Ce, in random order; Perkin-Elmer Life and Analytical Sciences, Boston, MA) were injected into the aortic arch to determine regional BF. Approximately 30 s after the injection, blood withdrawal from the tail artery catheter was stopped and exercise was terminated.

After a 60-min recovery period, hemodynamic variables were measured as the rats sat quietly on the treadmill. A second microsphere infusion was then performed under resting conditions with the same procedures as described above. This sampling strategy minimizes the potential for blood loss to affect the exercise response and facilitates "resting" measurements that do not reflect the preexercise anticipatory response (4).

On completion of the study, each animal was given an overdose of pentobarbital sodium (>50 mg/kg ia). The thorax was opened, and placement of the carotid artery catheter into the aortic arch was confirmed by anatomical dissection. The lungs were excised and weighed. The heart was removed and examined for scar tissue on the LV free wall for documentation that a large MI had been produced in the animal. The right ventricle (RV) was then separated from the LV and septum, and both tissues weighed. The kidneys, visceral organs, and muscles of both hindlimbs were identified, removed, weighed, and place immediately in counting vials. The hindlimb muscles included the following: 1) ankle extensors: soleus, plantaris, red portion of the gastrocnemius, white portion of the gastrocnemius, middle portion of the gastrocnemius, tibialis posterior, flexor digitorum longus, flexor hallucis longus; 2) ankle flexors: red portion of the tibialis anterior, white portion of the tibialis anterior, extensor digitorum longus, peroneals; 3) knee extensors: vastus intermedius, vastus medialis, red portion of the vastus lateralis, white portion of the vastus lateralis, middle portion of the vastus lateralis, red portion of the rectus femoris, white portion of the rectus femoris; 4) knee flexors: anterior portion of the biceps femoris, posterior portion of the biceps femoris, semitendinosus, red portion of the semimembranosus, white portion of the semimembranosus; and 5) thigh adductors: adductor longus, adductor magnus and brevis, gracilis, pectineus.

The radioactivity of each tissue was determined on a gamma scintillation counter (Packard Cobra II Auto-Gamma Spectrometer, Downers Grove, IL). Taking into account the cross-talk fraction between isotopes, BFs to each tissue were determined using the reference sample method (19, 37) and expressed as milliliters per minute per 100 g of tissue. Adequate mixing of the microspheres was verified for each injection by demonstrating a <15% difference between BF to the right and left kidneys and/or to the right and left hindlimb musculature.

Statistical analysis.   Rats with a large MI, severe LV dysfunction, and documented CHF on the basis of previously used criteria from our laboratory were included in the final data analysis (37, 38). Rats were considered to have severe LV dysfunction when LVEDP was elevated and LV dP/dt was depressed compared with previous non-MI sham-operated controls (non-MI sham: LVEDP = 8 ± 1 mmHg; LV dP/dt = 6,650 ± 538 mmHg/s, Ref. 16). In addition, rats were considered to have LV dysfunction of a chronic nature (i.e., CHF) when RV weight-to-body weight and lung weight-to-body ratios were increased compared with previous non-MI sham-operated counterparts (non-MI sham: RV weight/body weight = 0.58 ± 0.03 mg/g; lung weight/body weight = 4.99 ± 0.12 mg/g, Ref. 16). Criteria for inclusion resulted in the elimination of 11 young and 3 old rats from the final statistical analysis.

BF results from 11 young and 8 old rats with CHF were analyzed by an analysis of variance with a repeated-measured design. When a significant F value was present, a Student-Newman-Keuls post hoc procedure was performed to determine the differences between means. Alterations in the BF response between groups were further analyzed by linear regression to determine whether the disparity in BF during exercise was correlated with the normal fiber-type composition of selected skeletal muscles. Body weight, hemodynamic variables and tissue morphometrics were compared between groups via unpaired t-tests. All values are expressed as means ± SE, and the level of significance was set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Body weights of the OCHF rats were 20% greater than their younger counterparts (Table 1). However, tissue morphometrics were normalized to body weight to minimize any effects that may be ascribed to differences in body mass, and after this was done the only difference found between the YCHF and OCHF rats occurred with the RV because this variable was greater in the YCHF rats compared with their older counterparts (Table 1).


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  		Table 1. Body weight, heart morphometrics, and hemodynamic variables measured in anesthetized rats

 
Hemodynamic measurements made during isoflurane anesthesia were similar for YCHF and OCHF rats (Table 1). HR and mean arterial pressure (MAP) measured in awake resting rats were not different between YCHF and OCHF rats (Table 2). During exercise, HR was elevated in both groups of rats, but the HRs measured in YCHF rats were greater than those measured in OCHF rats. MAP was elevated from resting values during exercise for both YCHF and OCHF rats. However, MAP was not different between the two groups during the exercise.


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  		Table 2. Hemodynamic variables measured in conscious resting and exercising rats

 
BFs measured at rest to the total hindlimb musculature and to all of the individual muscles or muscle parts examined in this investigation were similar for the YCHF and OCHF rats (Fig. 1, Table 3). BF to the total hindlimb and the individual muscles increased from resting values during exercise. BF increased to a similar degree in 9 of the 28 individual muscles or muscle parts examined (Table 4). However, of the 28 individual muscles examined, BF increased during exercise to either a lesser (5 muscles) or greater (14 muscles) degree in the OCHF rats compared with their younger counterparts (Fig. 2).



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  		Fig. 1. Blood flow (BF) to the total hindlimb musculature measured at rest and during treadmill (20 m/min, 5% grade) exercise for young (YCHF) and old (OCHF) rats with chronic heart failure. During exercise, absolute BF to the total hindlimb of OCHF rats was greater (P < 0.05) than that of YCHF rats. Values are means ± SE. *P < 0.05 vs. YCHF rats.

 

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  		Table 3. Blood flow measured at rest in selected hindlimb muscle of young and old rats with CHF

 

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  		Table 4. Blood flow measured during exercise in selected hindlimb muscle of young and old rats with CHF for which there was no effect of age (P > 0.05)

 


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  		Fig. 2. Individual muscles and muscle parts that demonstrated significantly different BFs during treadmill (20 m/min, 5% grade) exercise in YCHF and OCHF rats. BF was reduced ({downarrow}) in 5 muscles (A) but increased ({uparrow}) in 14 muscles (B) of the hindlimb when OCHF were compared with YCHF rats. S, soleus; P, plantaris, GR, red portion of the gastrocnemius; TAR, red portion of the tibialis anterior; VI, vastus intermedius, GM, middle portion of the gastrocnemius; GW, white portion of the gastrocnemius; TP, tibialis posterior; EDL, extensor digitorum longus; VM, vastus medialis; VLM, middle portion of the vastus lateralis; VLW, white portion of the vastus lateralis; SMW, white portion of the semimembranosus; SMR, red portion of the semimembranosus; ST, semitendinosus; BFA, anterior portion of the biceps femoris; BFP, posterior portion of the biceps femoris; AMB, adductor magnus and brevis. Values are means ± SE. *P < 0.05 vs. YCHF rats.

 
The increases and decreases in BF response found in the OCHF rats appeared to be associated with the normal fiber-type composition of the muscle (Fig. 3) as the 5 muscles demonstrating a reduced BF response (Fig. 2A) normally contain a majority of SO and FOG fibers [range from 59 to 100% (SO + FOG), Ref. 5], whereas the 14 individual muscles demonstrating the enhanced BF response (Fig. 2B) normally contain a large proportion of FG fibers (range from 48 to 97% FG, Ref. 5). Consequently, the enhanced BF response found in the 14 predominantly FG muscles was sufficient to offset the attenuated BF response found in the five predominantly SO and FOG muscles such that BF to the total hindlimb was greater in the OCHF compared with the YCHF rats (Fig. 1).



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  		Fig. 3. Increases and reductions in BF ({Delta}BF) found in the 19 different locomotory muscles of the hindlimb for the OCHF rats compared with the YCHF were linearly related to the total percentage of slow-twitch oxidative (%SO) and fast-twitch oxidative glycolytic (%FOG) fibers found in each individual muscle. Muscles containing the greatest percentage of SO and FOG fibers (%SO + %FOG) demonstrated the greatest reductions in BF, whereas muscles containing the least percentage of SO and FOG fibers (%SO + %FOG) demonstrated the largest increases in BF.

 
BF to the kidneys and splanchnic organs (except spleen) at rest was similar between YCHF and OCHF rats (Fig. 4A). During exercise, BF to the kidneys was reduced; however, the reduction in BF was more profound in the OCHF compared with YCHF rats (Fig. 4B). Similarly, BF was reduced in all of the splanchnic organs during exercise, and, again, the reductions in BF were greater in the OCHF rats compared with their younger counterparts (Fig. 4B).



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  		Fig. 4. BF to the kidneys and organs of the splanchnic region measured at rest (A) and during treadmill (20 m/min, 5% grade) exercise (B) for YCHF and OCHF rats. Small Int, small intestines; Large Int, large intestines. Values are means ± SE. *P < 0.05 vs. YCHF rats. {dagger}P < 0.05 vs. Rest.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
To our knowledge, the present investigation is the first to evaluate the effects of aging on the skeletal muscle BF response to exercise in young (6–8 mo) and old (27–29 mo) rats with similar degrees of LV dysfunction and CHF. The main findings of the present study include the following: 1) resting BF to the total hindlimb and individual muscles or muscle parts of the hindlimb were not altered between YCHF and OCHF rats; 2) during exercise there was a greater reduction in BF to the splanchnic organs and kidneys in OCHF rats compared with YCHF rats; and 3) during exercise BF to the total hindlimb was augmented, and there existed a profound redistribution of BF from the highly oxidative slow- and fast-twitch muscles to the low-oxidative highly glycolytic fast-twitch muscles in the OCHF rats compared with the YCHF.

Degree of LV dysfunction and CHF in young and old MI rats.   For the purposes of the present investigation, it was crucial that similar degrees of LV dysfunction and CHF were produced in the YCHF and OCHF rats. Whereas LVEDP alone should not be used as the principal criterion for establishing CHF (48), when LVEDP is >15–20 mmHg in MI rats, LVEDP is a strong predictor of CHF sequelae, including LV dilation, LV and RV hypertrophy, low cardiac output, pulmonary edema, pleural effusions, ascites, and tachypnea (8, 39, 48). The YCHF and OCHF rats used herein had to meet predefined hemodynamic and morphometric criteria, including LVEDP >8 mmHg and LV dP/dt <6,650 mmHg/s along with RV and lung weight-to-body weight ratios exceeding 0.58 and 4.99, respectively. Although these criteria may be normally accepted as indicators of severe LV dysfunction and CHF in the MI rat (16), whether or not the YCHF and OCHF rats used herein had truly developed severe LV dysfunction and CHF could be challenged because noninfarcted controls were absent. To clarify this important issue, we compared LVEDP, LV dP/dt, RV and lung weight-to-body weight ratios of the YCHF and OCHF rats found in the present investigation with those measured from age- and strain-matched animals obtained from one of our previous studies (36). The results from this analysis (Fig. 5) support not only the conclusion that the YCHF and OCHF rats found in the present investigation had developed CHF but also the finding that the degree of LV dysfunction and congestive failure produced in these animals was not different between the two groups.



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  		Fig. 5. Hemodynamic [left ventricular end-diastolic pressure (LVEDP) and the derivative of left ventricular pressure over time (LV dP/dt)] and morphometric [right ventricular (RV) weight and lung weight normalized to body weight] measurements performed on the YCHF and OCHF rats found in the present investigation are compared with those measured on young (Y) and old (O) healthy rats of the same age and strain taken from a previous study from our laboratory (see Ref. 36). Compared with those animals, the YCHF and OCHF rats from the present study demonstrated severe LV dysfunction based on the elevations in LVEDP (A) and reductions in LV dP/dt (B). These rats also demonstrated congestive heart failure as indicated by the elevations in lung weight-to-body weight ratio (D), and this congestive failure was chronic in nature as demonstrated by the significant amount of RV hypertrophy found in these animals as indicated by the increases in RV weight-to-body weight ratio (C). *P < 0.05 vs. noninfarcted counterpart.

 
Exercise intensity.   In designing a study where the exercise capacity of subjects is tested, it is always debatable whether to test the subjects at the same absolute or relative work rates. In the present investigation, we decided to exercise the YCHF and OCHF rats at the same absolute running speed on the basis of the fact that both young and old individuals with CHF normally perform daily work tasks that are equivalent to one another in absolute terms (i.e., climbing a flight of stairs). This crucial consideration needs to be kept in mind when interpreting the results from the present investigation.

The most common symptom of CHF is a reduced exercise capacity, which is associated with significant reductions in O2 max, which in turn relate to the degree of LV dysfunction produced in rats as indicated by increases in LVEDP (38). Using the relationship between LVEDP and O2 max, we estimated the O2 max for YCHF rats to be ~62 ml·min–1·kg of body weight–1 (38). However, O2 max decreases with age, and although pertinent data regarding the effects of age on O2 max in F344/BN rat are nonexistent, it has been shown that O2 max declines by ~1.5%/mo in Fischer 344 rats once the animals have reached sexual maturity (30, 54). Using this rate of decline, we estimated that O2 max for the OCHF rats would be ~45 ml·min–1·kg of body weight–1. We and others (7, 10, 25, 35, 51) have shown that rats exercising at the same treadmill workload used in this study elicit an oxygen uptake of ~47–55 ml·min–1·kg of body weight–1. Therefore, our results suggest that the YCHF rats were exercising at a heavy workload (i.e., between 76–89% of their O2 max) and that the OCHF rats exercised in close proximity to their estimated O2 max.

HR response to exercise.   Similar to that described for healthy age- and strain-matched rats (36), the HRs measured during exercise were appreciably less in the OCHF compared with the YCHF rats. This phenomenon has been attributed to age-related declines in {beta}-adrenergic responsiveness found in the heart (21), which in turn has been associated with alterations in postreceptor adrenergic signaling (45). Lakatta (21) has suggested that the effects of aging in the healthy heart are mediated by many of the same biochemical and molecular pathways as those found in the failing heart (i.e., CHF), and these may explain the blunted HR response to exercise described herein.

BF to hindlimb musculature.   In support of our original hypothesis, we found that BF to the exercising hindlimb muscles that normally contain a majority of SO and FOG fibers was significantly reduced in OCHF (Fig. 2A). Because the YCHF and OCHF rats suffered from similar degrees of LV dysfunction (see Fig. 5), our results suggest that the reductions in BF found in these highly oxidative muscles of the OCHF rats were primarily due to the effects of aging. As such, these age-related reductions in BF could contribute to decreases in exercise capacity in elderly CHF patient populations and serve to demonstrate how peripheral circulatory mechanisms independent of central cardiac function may contribute to the exercise intolerance of CHF.

In contrast to the reductions in BF found in the highly oxidative muscles, we also found that BF was significantly elevated in 14 hindlimb muscles (Fig. 2B) that normally contain a majority of FG fibers. Thus those muscles that normally contain a large proportion of FG fibers demonstrated the greatest increases in BF, whereas the muscles that normally contain the largest proportion of SO and FOG fibers demonstrated the greatest decreases in BF during exercise when OCHF were compared with YCHF rats. The mechanisms responsible for these age-related changes in BF remain unclear at this time, but they may be associated with: 1) changes in vascular control and/or 2) changes in the recruitment pattern of the locomotor muscles during exercise.

Regarding age-related changes in vascular control, Muller-Delp and colleagues (33, 34) have shown that both flow- and acetylcholine-mediated vasodilation were attenuated in the isolated arterioles of old compared with young rats. Furthermore, we and others have shown that the muscles containing a majority of SO and FOG fibers possess a greater potential for endothelium-mediated vasodilation compared with muscles containing a majority of FG fibers (17, 31). Although the age-related declines in endothelial vasodilatory function may potentially explain the decrements in BF to the highly oxidative muscles of OCHF rats, the mechanistic basis for the increases in BF found in their FG counterparts is not clear. Two putative vascular control mechanisms could be contributing to this response. First, Muller-Delp and colleagues (34) have shown that the myogenic component of vasoregulation is attenuated in the muscles of old rats compared with young, even though the vasoconstrictor responses remain intact. Second, arteriolar rarefaction has been shown to occur in the muscles of old rats (33), and Muller-Delp and colleagues have suggested that this vascular rarefaction could increase BF and shear stress in the individual blood vessels (i.e., the white portion of the gastrocnemius), thereby producing increases in vessel maximal diameter and potentiating the endothelial-mediated vasodilator response. Recently, our laboratory confirmed that vascular rarefaction occurs in the low-oxidative moderately glycolytic spinotrapezius muscle of rats from a similar age and strain as those used in the present investigation (46). Therefore, the possibility exists that an enhanced endothelial-mediated vasodilation in conjunction with a diminished myogenic vasoconstrictor response could have contributed to the greater BF found in the various locomotor muscles examined in the present investigation.

Along with the potential for age-related changes in vascular control, alterations in muscle recruitment may have contributed to the redistribution of BF found within the total hindlimb musculature of the OCHF rats during exercise (Fig. 2). Important to this concept, Armstrong and Laughlin (3) have shown that increases in BF coincide with the recruitment and utilization of glycogen found in the locomotor muscles of rats during treadmill exercise. Moreover, there is a progressive recruitment of fibers from SO to FOG to FG as treadmill and, therefore, relative workloads increase (23), and there is a similar progression in fiber-type recruitment that occurs when rats exercise to the point of fatigue at relatively moderate work rates (6, 24). As demonstrated in the present investigation, age-related reductions in BF are produced in five locomotor muscles of OCHF rats that normally contain a majority of SO and FOG fibers during treadmill exercise. Because these muscles are recruited heavily even during moderate exercise (23), any age-related reductions in BF (and oxygen delivery) could result in the early onset of fatigue within these muscles thereby mandating recruitment of FG fibers to sustain exercise. The outcome would be an augmentation of BF that coincides with the further recruitment of muscles containing these FG fibers.

Potential role of sympathetic nervous system.   Whether age-related changes in the sympathetic nervous system (SNS) contributed to the redistribution of BF within and among the locomotor muscles in OCHF rats found in the present investigation remains unclear. In this regard, overall resting muscle sympathetic nerve activity has been shown to increase with old age (49), and more recently, it has been demonstrated that there is an enhanced sympathetic vasoconstriction in the exercising muscle of aged individuals (20). Aging also produces a decrease in muscle nitric oxide production and availability due to increases in oxidative stress (52, 55), and because functional sympatholysis is mediated via a nitric oxide-mediated pathway (53), further increases in skeletal muscle sympathetic vasoconstriction could be produced through this mechanism.

Close examination of our results suggests that resting SNS activity was not significantly different between the OCHF and YCHF rats. Specifically, resting BFs to the different muscles of the hindlimb, kidneys, and splanchnic organs were similar in YCHF and OCHF rats (Table 3, Fig. 4A). If overall SNS activity had been significantly augmented in the OCHF rats then we would have expected the resting BFs to have been less in OCHF rats compared with their younger counterparts. However, further experiments are needed to answer definitively this important question as changes in the vasoreactivity to NE and other vasoconstrictive and vasodilator compounds could have confounded this interpretation.

It is possible that the age-related reductions in exercising muscle BF along with the greater reductions in BF to the kidneys and splanchnic organs found in the OCHF rats can be ascribed to an enhanced SNS response to exercise. In support of this hypothesis, it is clear that OCHF rats were performing at a greater relative work rate than their younger counterparts, and it has been demonstrated previously that in healthy (29, 47, 50) and CHF (15) animals increases in SNS activity (and muscle sympathetic nerve activity) during exercise are highly dependent on the relative workload being performed. Thus we cannot discount the possibility that an enhanced sympathetic response was contributing to these augmented reductions in BF to the kidneys, splanchnic organs, and the highly oxidative skeletal muscles of the OCHF rats compared with their younger counterparts (15).

Contrary to this argument, one might expect that the enhanced sympathetic response would have been relatively universal in nature, thereby producing reductions in BF to nearly all of the muscles located in the hindlimb. Instead, we found that BF to a large number of muscles was actually increased in the OCHF rats compared with their younger counterparts (Fig. 2B). These increases in BF to the muscles that normally contain a majority of FG fibers have been shown to occur in healthy rats of a similar age and strain (36). At first, one may ascribe that these increases in BF may be related to the fact that the OCHF rats were exercising at a greater relative work rate compared with younger counterparts. But if this were true, then one would expect to find simultaneous increases in the BF response of the muscles that normally contain a majority of SO and FOG types of fibers (23), and this clearly did not occur. Accordingly, our results suggest that any role that the SNS may be playing in contributing to the redistribution of BF within and among the different locomotor muscles of the OCHF rat is complex and in need of further investigation.

Potential interactions between CHF and aging.   The experimental design and methodology used in the present investigation was identical to that used previously (36) to examine the effects of aging in healthy rats, and it is therefore possible to compare the BF responses found between the two studies. Because MAP measured at rest and during exercise was significantly different between the two studies, BF results were normalized to MAP and expressed as conductance. The combined data were then analyzed by a two-way ANOVA with a repeated-measures design and partitioned into main effects, simple effects, and interactions.

The primary main effects of CHF and aging on vascular conductance occurred in 12 and 18 of the 28 different muscles or muscle parts examined, respectively. Significant CHF x aging interactions occurred in only four of the hindlimb locomotor muscles. Three of these muscles (soleus, vastus intermedius, and red portion of vastus lateralis) normally contain a majority of SO and FOG types of fibers, and simple effects demonstrated that the effects of CHF were greatly attenuated in the old rats (Fig. 6A). Moreover, the conductance response found in the S was significantly lower in the OCHF compared with YCHF group of rats, demonstrating that the effects of aging were maintained in this muscle. The remaining muscle (extensor digitorum longus) normally contains a majority of FG types of fibers. Simple effects demonstrated again that the effects of CHF were attenuated in the old rats (results not shown). But, contrary to that found for the soleus, the conductance response to exercise in the extensor digitorum longus was significantly greater in the OCHF compared with the YCHF group of rats.



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  		Fig. 6. Skeletal muscle, renal, and splanchnic organ BF measurements made at rest and during exercise in the present investigation were normalized to mean arterial pressure, expressed as conductance, and compared with those made in normal rats of the same age and strain (see Ref. 36). Combined data were analyzed by a 2-way repeated-measures ANOVA, and results were partitioned into main effects, simple effects, and interactions. A: resting muscle BF or conductance was similar across all groups of rats and increased during exercise. CHF and aging main effects occurred in 12 and 18 of the 28 different muscles examined, respectively. However, CHF x aging interactions occurred in only 4 of the hindlimb muscles investigated. Three of these muscles [S, VI, and red portion of vastus lateralis (VLR)] normally contain a majority of SO and FOG types of fibers. Simple effects demonstrated that the vascular conductance response was significantly reduced in YCHF rats compared with normal Y rats. This reduction in vascular conductance did not exist in OCHF rats compared with normal O rats. Simple effects also demonstrated that the vascular conductance response was reduced in O rats compared with their Y counterparts, but this aging induced reduction in vascular conductance was only found in the S muscle when OCHF rats were compared with YCHF rats. B: resting renal and splanchnic organ BF or conductance was similar across all groups of rats and decreased during exercise. Aging main effects occurred in all of the organs examined. However, those organs were devoid of any CHF main effects, and CHF x aging interactions only occurred in the kidneys. Simple effects demonstrated that the renal conductance was reduced across all groups of rats during exercise, but the reductions were significantly greater for O, YCHF, and OCHF rats compared with Y. Moreover, aging exacerbated the reduction in renal conductance as the values found for O and OCHF rats were significantly less than those found for their Y and YCHF counterparts. Whereas the effects of CHF produced a greater reduction in renal conductance in Y rats (i.e., renal BF or conductance measured in YCHF rats during exercise was significantly less than that found for Y rats), this CHF effect was not found in O rats because the renal conductance measured in O was not different from OCHF.

 
The primary main effects of aging occurred in the kidneys and all of the splanchnic organs examined. However, these organs were devoid of the primary main effects of CHF. A significant CHF x aging interaction was found to occur in the kidneys, but not in any of the other organs investigated. Simple effects demonstrated that renal conductance during exercise was reduced more in the YCHF group of rats compared with their young counterparts (Fig. 6B). Moreover, renal conductance during exercise was reduced more in the old and OCHF rats compared with their younger counterparts. However, renal conductance during exercise was similar between the old and OCHF group of rats, demonstrating that the effects of CHF were attenuated in the old rats compared with the young. These results suggest that the degree of vasoconstriction produced in the kidneys during exercise in the old and OCHF rats were similar to one another, but whether these responses demonstrate some type of basement effect (i.e., renal BF or conductance cannot go any lower) due to a ceiling effect of sympathoexcitation remains a possibility.

The combined results from the two studies suggest that the effects of CHF and aging are primarily additive in nature. The fact that CHF x aging interactions were found to occur in only the kidneys and 4 of the 28 muscles and muscles parts examined support this conclusion, but this conclusion should be taken with caution because how these CHF x aging interactions may potentially affect exercise performance is uncertain and their mechanistic bases remain undetermined. However, the data presented herein do demonstrate that CHF may potentially affect older individuals in a significantly different manner than young individuals. The impact that these changes may have in regard to the decrements in exercise performance found in older individuals with CHF needs further elucidation and should be the focus of future research.

In conclusion, in exercising YCHF and OCHF rats with similar amounts of LV dysfunction, OCHF rats exhibited a greater vasoconstrictive response (lower BF) in the kidneys and splanchnic organs and a greater BF to the active skeletal musculature. Furthermore, within the active hindlimb musculature of OCHF rats, BF during exercise was redistributed from the more oxidative toward the more glycolytic muscles. This redistribution of muscle BF found in the OCHF rats is most likely due to age-related changes in the mechanisms that govern vascular control along with potential alterations in the recruitment pattern of the working skeletal muscles. These findings are directly pertinent to the ever-growing population of CHF patients, because the vast majority of them are elderly and their rehabilitation as well as their quality of life are dependent on preservation of skeletal muscle function.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This project was supported, in part, by National Institutes of Health Grants AG-19228 (T. I. Musch) and HL-50306 (D. C. Poole) and a grant-in-aid from the American Heart Association, Heartland Affiliate.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. I. Musch, Dept. of Anatomy and Physiology, College of Veterinary Medicine, 128 Coles Hall, 1600 Denison Ave., Manhattan, KS 66505-5802 (E-mail: musch{at}vet.ksu.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.


   REFERENCES
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 ABSTRACT
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