Skip Navigation

Cardiovascular Research 2004 61(2):325-332; doi:10.1016/j.cardiores.2003.11.020
© 2004 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Behnke, B.J
Right arrow Articles by Musch, T.I
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Behnke, B.J
Right arrow Articles by Musch, T.I
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2004, European Society of Cardiology

Effects of chronic heart failure on microvascular oxygen exchange dynamics in muscles of contrasting fiber type

B.J Behnkea, M.D Delpa, P McDonoughb, S.A Spiera, D.C Pooleb and T.I Muschb,*

aDepartments of Health and Kinesiology, and Medical Physiology, Texas A&M University, College Station, TX, USA
bDepartments of Anatomy and Physiology, and Kinesiology, Kansas State University, 228 Coles Hall, Manhattan, KS 66506-5802, USA

* Corresponding author. Tel.: +1-785-532-4523; fax: +1-785-532-4557. musch{at}vet.ksu.edu

Received 13 June 2003; revised 5 November 2003; accepted 20 November 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
In rat spinotrapezius muscle, chronic heart failure (CHF) speeds microvascular O2 pressure (pO2; index of O2 delivery-to-O2 uptake) dynamics across the rest–contractions transition [Cardiovasc. Res. 56 (2002) 479]. Due to the mosaic nature of this muscle, the effect of CHF on microvascular pO2 dynamics in different fiber types remains unclear. Objective: Based upon derangements of endothelial function and blood flow responses, we hypothesized that CHF would speed microvascular pO2 dynamics (reduced O2 delivery-to-O2 uptake ratio) in type I muscle (soleus, ~84% type I), but not in type II muscle (peroneal, ~86% type II [J. Appl. Physiol. 80 (1996) 261]). Methods: Using phosphorescence quenching, microvascular pO2 was measured at rest and across the rest–contractions transition (1 Hz) in soleus and peroneal of non-infarcted control (control; n = 7), and Sprague–Dawley rats with moderate (moderate; elevated left ventricular end-diastolic pressure (LVEDP) 10±2 mm Hg; n = 10) and severe (severe; LVEDP 28±4 mm Hg; n = 5) CHF. Results: The microvascular pO2 mean response time (time delay+time constant) was progressively speeded with increasing severity of CHF in soleus (control, 38.7±2.0; moderate, 29.1±1.5; severe, 22.5±3.9 s; P≤0.05), but not in peroneal (control=moderate=severe). Conclusion: As type I fibers are recruited predominately for moderate intensity exercise, the more rapid lowering of soleus microvascular pO2 in CHF would reduce the blood-muscle O2 driving gradient, exacerbate phosphocreatine and glycogen breakdown, and provide a mechanism for slowed O2 uptake kinetics and premature fatigue in CHF.

KEYWORDS Phosphorescence quenching; Oxygen exchange; Soleus; Peroneal

Abbreviations: CHF, chronic heart failure • pO2, partial pressure of oxygen • Control, non-infarcted rats • Moderate, rats with moderate levels of CHF • Severe, rats with severe levels of CHF • LVEDP, left ventricle end-diastolic pressure • RV, right ventricle • MRT, mean response time (time delay+time constant) • T63, time to 63% of final response • TD, time delay • {tau}, time constant • krpO2, rate constant of pO2 change ({Delta}pO2/{tau}) • {Delta}pO2, change in microvascular pO2 from non-contracting values to nadir


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The dynamics of pulmonary O2 uptake in response to exercise are slowed in patients with chronic heart failure (CHF) vs. their healthy counterparts [1,2], contributing to premature fatigue. In addition, when a CHF patient undergoes heart transplantation (and cardiac output is improved), pulmonary O2 uptake kinetics are not accelerated [3], indicating an impairment in muscle metabolism. Indeed, in rat spinotrapezius muscle, the ability to match O2 delivery to O2 uptake (measured via microvascular pO2) is altered in rats with CHF vs. healthy controls across the rest–contractions transient [4]. Moreover, the precipitous drop in spinotrapezius microvascular pO2 at stimulation onset observed in moderate heart failure lowers the O2 pressure head that facilitates blood–myocyte O2 diffusion and provides a mechanistic explanation for the increased phosphocreatine breakdown demonstrated in CHF [5]. Unfortunately, due to the mosaic nature of the spinotrapezius (i.e., fiber type distribution ~33% I, IIa and IIb [6]), differences in microvascular pO2 dynamics due to fiber type in CHF could not be elucidated in that investigation (i.e., Ref. [5]) and therefore remain unclear.

CHF elicits gross deficiencies in endothelial function (e.g., decreased vasoreactivity to endothelium-dependent vasodilators (e.g., acetylcholine [7–9]). In addition, as arterioles isolated from type I (slow-twitch) vs. type II (fast-twitch) muscle show greater sensitivity and maximal responsiveness to endothelium-dependent compounds (i.e., acetylcholine [10–12]), the deleterious effects of CHF would be expected to have a greater impact on endothelial function (and by inference regulation of O2 delivery) in type I vs. type II muscle. Indeed, in response to treadmill exercise, blood flow was reduced to the soleus (type I) but not changed in the peroneal (type II) muscle in rats with both moderate and severe CHF compared to control [13]. Moreover, the regional flow capacity (i.e., perfusion pressure–flow relationship) was reduced in soleus but remained unchanged in peroneal from rats with CHF compared to control animals [14]. These findings suggest that, in the CHF condition, the soleus has a reduced ability to match O2 delivery to O2 uptake with CHF (at least during steady-state exercise [13]) compared to the peroneal.

To investigate the effect of CHF on O2 exchange dynamics in muscles of contrasting fiber type we measured microvascular pO2 dynamics across the rest–contractions transition in the soleus (~84% type I fibers) and peroneal (~86% type II [6]) of non-infarcted control, and rats with moderate and severe CHF. More specifically, based upon demonstrated endothelial dysfunction [8,9] and blood flow responses [13] present in CHF, the following hypotheses were tested: (1) soleus would exhibit progressively faster microvascular pO2 dynamics (i.e., accelerated decline in microvascular pO2 due to decreased O2 delivery to O2 uptake ratio) with increasing severity of CHF and (2) microvascular pO2 dynamics would not be altered in the peroneal from CHF vs. control animals. As type I fibers are heavily recruited in low-to-moderate intensity exercise [6,15], if more rapid microvascular pO2 kinetics are present in the soleus in CHF, the transiently reduced blood-tissue O2 pressure gradient would exacerbate phosphocreatine and glycogen breakdown [16], providing a mechanistic explanation for the slowed pulmonary O2 uptake kinetics observed in CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Myocardial infarction procedures
Mature (i.e., ~6 months old) male Sprague–Dawley rats underwent myocardial infarction procedures as described previously [17]. Briefly, rats were anaesthetized with a 5% isoflurane/O2 mixture, intubated and connected to a rodent respirator (Harvard Model 680) and maintained on a 2% isoflurane/O2 mixture. A left thoracotomy was performed between the fifth and sixth ribs (~1.5 cm in length) to expose the heart. The pericardial sac was opened and the heart was exteriorized. A 6-O suture was used to encircle and ligate the left main coronary artery approximately 2–4 mm distal to its origin. The lungs were hyperinflated and the ribs approximated with 3-O gut. The muscles of the thorax were sewn together with 4-O gut and the skin incision closed with 3-O silk. The opportunity for infection was reduced by the administration of antibiotics (Ampicillan, 200 mg/kg). Anesthesia was withdrawn and the rats were extubated and monitored for 8–12 h post-operation. As no differences have been observed between control (non-infarcted) and sham-operated animals [18], we chose to use non-infarcted animals as our control group (control; n = 7). All procedures were approved by the Kansas State University Institutional Animal Care and Use Committee (IACUC) in accordance with National Institutes of Health (NIH) guidelines.

2.2. Experimental protocol
Six to ten weeks after myocardial infarction procedures, the rats were anesthetized with pentobarbital sodium (30 mg/kg i.p., supplemented as needed). A 2-French catheter-tip pressure manometer (Millar Instruments) was used to cannulate the right carotid artery. The manometer was advanced into the left ventricle in a retrograde fashion to measure left ventricular end-diastolic pressure (LVEDP) and the rate of pressure change within the chamber (LV dP/dt). Subsequently, the manometer was replaced with a fluid-filled catheter (PE-50) to monitor arterial blood pressure for the duration of the experiment (Digi-Med BPA Model 200). This fluid-filled catheter was used for the administration of additional anesthesia and sampling of arterial blood as well as infusion of the phosphorescent probe. Rectal temperature was monitored and maintained at 37 °C with a heating pad.

Upon completion of the experiment, each rat was killed with an overdose of anesthesia (pentobarbitol sodium) administered via carotid artery catheter. The thorax was opened and the lungs and heart were excised. The right ventricle (RV) was separated from the left ventricle and all tissues were weighed and normalized to the body weight of each animal.

2.3. Surgical preparation for microvascular pO2 measurement
A lateral incision (frontal plane) of the skin and overlying fascia was made to expose the tibialis anterior and biceps femoris of the left hindlimb. Subsequently, the distal portion of the biceps femoris was reflected (3-O silk suture) to expose the soleus and peroneal muscles. Platinum wire electrodes were attached (6-O suture) to the proximal (cathode) and distal (anode) regions of each muscle in order to elicit bipolar muscle stimulation. The foot was stabilized (adhesive tape) to minimize leg movement during electrical stimulation. The exposed tissues, which were not contracted, were protected with Saran Wrap (Dow, Indianapolis, IN). The soleus and peroneal were superfused with a Krebs–Henseleit bicarbonate buffered solution equilibrated with 5% CO2/95% N2 at 38 °C.

2.4. Protocol
The phosphorescent probe palladium meso-tetra(4-carboxyphenyl)porphyrin dendrimer (R2) was infused at 15 mg/kg via the arterial cannula approximately 15 min before the first stimulation period. Following a 10–15-min post-surgery stabilization period, twitch muscle contractions (2–4 V, 2 ms pulse duration) were elicited in either the soleus or peroneal muscle (random order) at 1-Hz frequency for 3 min using a Grass S88 stimulator (Quincy, MA). After the 3-min stimulation period, there was a stimulation-free recovery period for both muscles of 30 min. Subsequently, the non-stimulated muscle during the first period was contracted (stimulation parameters held constant). Microvascular pO2 was determined at 2-s intervals across the rest–contractions transient for both muscles. Blood samples were taken immediately upon completion of the final stimulation period.

2.5. Microvascular pO2 measurement
The oxygen dependence of the probe phosphorescence can be described quantitatively through the Stern–Volmer relationship [19]. Microvascular pO2 was determined using a PMOD 1000 Frequency Domain Phosphorometer (Oxygen Enterprises, Philadelphia, PA) with the common end of the bifurcated light guide placed ~2–3 mm above the medial region of the peroneal or soleus. 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 s to ~2.5 ms. In the frequency mode (i.e., excitation light modulated at a designated frequency 524 nm), 10 scans totaling 100 ms were used to acquire the resultant lifetime of the phosphorescence (at 700 nm) and repeated every 2 s [20]. The phosphorescence lifetime 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 [21].

The R2 phosphorescent probe is bound to albumin in the blood and is negatively charged which restricts it to the vascular compartment (i.e., principally the capillary bed) within skeletal muscle. The probe is assumed to be uniformly distributed in the blood plasma and provides a signal corresponding to the volume-averaged O2 pressure within the capillary blood. Microvascular pO2 values were curve-fit to a mono-exponential plus delay model [22] using an iterative least-squares technique by means of a commercial graphing/analysis package (KaleidaGraph 3.5). For the KaleidaGraph analysis program, a user-defined function to the data was fit using the equation as follows:

Formula
where pO2(t) is the microvascular pO2 at time t, pO2(b) is baseline microvascular pO2, {Delta}pO2(ss) is the change in microvascular pO2 from baseline to the steady-state contracting value, TD is the time delay and {tau} is the time constant of the response. The same model was applied to microvascular pO2 responses from both muscle stimulation periods. In addition, the overall time taken to reach 63% of the final response (T63) was measured directly from the response to provide an indication of the time course of microvascular pO2 change independent of any modeling procedure. From the mathematical modeling results the mean response time (MRT; time delay+time constant) and microvascular pO2 rate of fall (krpO2; {Delta}pO2/{tau}pO2) were calculated.

2.6. Citrate synthase activity
Citrate synthase activity, a mitochondrial enzyme and marker of muscle oxidative potential, was measured in duplicate from soleus and peroneal muscle homogenates according to the method of Srere [23]. Citrate synthase activity, expressed as micromoles per minute per gram wet weight, was measured spectrophotometrically (Spectramax 190 Molecular Devices plate reader) in 300-µl aliquots mixtures at 30 °C.

2.7. Animal groupings and statistical analysis
Rats with a myocardial infarction were categorized further into moderate (moderate) or severe (severe) CHF groups based on lung congestion (lung weight to body weight ratio: LW/BW) and right ventricular hypertrophy (RV to body weight ratio: RV/BW) prior to analysis of microvascular pO2 profiles. Rats with a LW/BW and RV/BW greater than 4 standard deviations (S.D.) above the mean for control were placed in the severe CHF group, while the remaining myocardial infarcted rats were placed in the moderate CHF group. Microvascular pO2 values during resting and steady-state contractions (e.g., baseline and delta), modeling-dependent (e.g., TD, {tau}, MRT) and -independent (e.g., T63) results were analyzed by a two-way analysis of variance (ANOVA). In addition, a reanalysis of the data from Hirai et al. [24] for the change (delta) in blood flow and conductance with L-NAME administration to the soleus and peroneal muscles in Sham operated and rats with small and large MI's data was performed using a two-way analysis of variance. When a significant F-value was demonstrated by the ANOVA, a Student–Newman–Keul (SNK) procedure was performed to determine differences among mean values. The {tau} of the microvascular pO2 response for the soleus and peroneal was regressed against RV/BW using linear regression analysis. Statistical significance was accepted at P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Indices of heart failure
Of the 15 animals that received the myocardial infarction surgery, 5 were placed in the severe CHF category (severe) based upon the predetermined criteria (i.e., LW/BW and RV/BW product greater than 4 standard deviations from mean of control). Thus, data are presented from 7 control, 10 rats with moderate (moderate) CHF and 5 rats with severe CHF. LVEDP was elevated significantly in both myocardial infarction groups (Table 1) compared to control. In addition, LVEDP was higher in severe CHF (28±4 mm Hg) compared to moderate (10±2 mm Hg; P<0.05). There were no differences in LW/BW and RV/BW between moderate CHF and control. However, both LW/BW and RV/BW were significantly elevated for severe CHF vs. both moderate CHF and control (Table 1). No differences were observed between the three groups for body weight or arterial blood gases (Table 1). Citrate synthase activity was reduced only in the severe group vs. control in both muscles (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 1
 

View this table:
[in this window]
[in a new window]

  		Table 2
 
3.2. Microvascular pO2
The delay followed by a single exponential provided an excellent fit to the microvascular pO2 data from all groups as demonstrated by the high coefficient of determination (i.e., r2-value, ≥0.98) and low sum of squared residuals (i.e., {chi}2<20; Table 2) as well as visual inspection (Figs. 1 and 2)Go. In addition, there were no differences between the MRT (model-dependent) and T63 (model-independent), thereby providing confidence that the computer modeling accurately described the observed response.


Figure 1
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Representative peroneal microvascular pO2 dynamics for control, moderate and severe CHF animals. Time 0 represents the onset of contractions. The dynamics of the microvascular pO2 response is not altered by heart failure in this muscle. Solid lines are microvascular pO2 response to contractions, whereas the dashed lines are model fits to the microvascular pO2 response.

 

Figure 2
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Representative microvascular pO2 dynamics for control, moderate and severe CHF animals in soleus muscle. Time 0 represents the onset of contractions. Note the progressively faster microvascular pO2 response (shorter time delay and more rapid drop in microvascular pO2) with the increasing severity of heart failure in the soleus, which is not apparent for peroneal muscle (see Fig. 1). Solid lines are microvascular pO2 response to contractions, whereas the dashed lines are model fits to the microvascular pO2 response.

 
3.3. Peroneal
Fig. 1 shows representative microvascular pO2 responses (solid lines) to twitch contractions in the peroneal of control, moderate and severe CHF animals. Compared to the control soleus, the control peroneal demonstrated a shorter TD, {tau} and MRT, as well as a faster rate of fall (krpO2; control peroneal ~1.03, control soleus ~0.45 mm Hg/s; P<0.05; Table 2). No differences were observed in the baseline or delta ({Delta}) microvascular pO2 between control, moderate and severe CHF groups in the peroneal (Table 2). In addition, there was no significant difference in any of the peroneal microvascular pO2 kinetic variables (i.e., TD, {tau}, MRT, krpO2) in either CHF group vs. control (Figs. 1, 3 and 4GoGo; Table 2).


Figure 3
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Comparison of the time constant ({tau}) of the exponential decrease in microvascular pO2 for soleus vs. peroneal muscle with and without CHF. *P<0.05 vs. peroneal; #P<0.05 vs. control condition for the same muscle.

 

Figure 4
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Effect of presence and degree of CHF on the microvascular pO2 mean response time (time delay+{tau}) for soleus and peroneal. Zero on ordinate reflects MRT of control animal peroneal or soleus. There was no statistical significance (P>0.1) between control and the CHF groups for peroneal muscle.

 
3.4. Soleus
In contrast to the peroneal, CHF evoked a profound effect in the microvascular pO2 response of the soleus (Fig. 2). Specifically, compared with control, the baseline non-contracting microvascular pO2 was reduced (~17%, P<0.05) and the TD shortened (~42%, P<0.05; Table 2) in the severe group. Moreover, the TD of the severe soleus group (~9 s) was sufficiently shortened from control soleus that it was not different from that observed in any of the peroneal groups (Table 2). In addition, the {tau} microvascular pO2 was significantly faster in both moderate (16.7±1.3 s) and severe CHF (13.8±1.1 s) compared to control (23.6±2.0 s, P≤0.05; Fig. 3 and Table 2). The MRT (TD+{tau}) was progressively shortened in moderate and severe vs. control (i.e., MRT control>moderate>severe; Fig. 4 and Table 2). In addition, the soleus microvascular pO2 {tau} was significantly correlated (P<0.05) with the severity of CHF (RV/BW) as shown in Fig. 5. In contrast, no correlation was observed for {tau} microvascular pO2 vs. RV/BW in peroneal (P>0.1).


Figure 5
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Correlation between the severity of heart failure as assessed by right ventricle-to-body weight ratio and the speeding of the microvascular pO2 time constant ({tau}) for the soleus. There was no significant correlation between severity of CHF and {tau} microvascular pO2 for the peroneal (P>0.1).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The present investigation examined the effect of CHF on the O2 exchange characteristics (via microvascular pO2) in two muscles of contrasting fiber types across the rest–contractions transition. The principal novel findings of the present investigation include: (1) CHF did not significantly alter the microvascular pO2 profile in the peroneal muscle ((Fig. 1); and 2) in the soleus, CHF elicited an accelerated microvascular pO2 decline with both a shorter time delay and mean response time (i.e., MRT control>moderate>severe; Table 2 and Figs. 2–4GoGo). The more precipitous microvascular pO2 decline in CHF vs. control soleus implies a compromised ability to match O2 delivery to demand across the rest–contractions transition in this muscle. In contrast, the O2 delivery to O2 uptake relationship was not discernibly altered by CHF in the peroneal. These findings are consistent with a reduced O2 delivery response in soleus concomitant with an unchanged O2 delivery response in the peroneal at the onset of contractions in rats with CHF vs. their healthy counterparts [13]. In addition, the temporarily reduced blood-tissue O2 pressure head observed across the transition in soleus from animals with moderate and severe CHF is expected to exacerbate phosphocreatine breakdown [16], thereby potentially contributing to the premature fatigue observed in CHF.

4.1. Plasticity of microvascular pO2 dynamics in heart failure
In accordance with Fick's Law, microvascular pO2 is determined by the spatial and temporal relationship between muscle O2 delivery and O2 uptake (for a detailed analysis, see Ref. [22]). In healthy muscle, the dynamics of O2 delivery are such that, across the rest–contractions transition, O2 delivery does not limit muscle O2 uptake kinetics [21,25]. In contrast, Diederich et al. [4] have demonstrated, in rat spinotrapezius with moderate CHF, that the speed at which O2 delivery increases is relatively sluggish compared to that of muscle O2 uptake. This sluggish O2 delivery response results in a more rapid microvascular pO2 decline across the rest–exercise transition in moderate CHF muscle vs. control. However, as the spinotrapezius is comprised of both types I and II fibers [6], it was not possible to make inferences regarding the effect of CHF on microvascular pO2 kinetics within specific muscle fiber types. In the present investigation, the effect of moderate CHF on the soleus produced microvascular pO2 profiles very similar to that observed in the spinotrapezius of moderate CHF animals (i.e., faster microvascular pO2 kinetics with CHF vs. control). Accordingly in the soleus, similar conclusions can be made for perturbations in the O2 delivery to O2 uptake relationship as that shown for the spinotrapezius, i.e., that O2 delivery dynamics in the soleus with CHF are slowed compared to that of muscle O2 uptake. In contrast, the CHF condition did not induce alterations in the microvascular pO2 and by inference the O2 delivery to O2 uptake relationship in the peroneal. These findings are consistent with deficits found in soleus muscle blood flow [13] and vascular transport capacity [14] in CHF which are absent in peroneal (this issue is dealt with directly in the following section). CHF reduced citrate synthase activity in both the peroneal and soleus with severe CHF rats. Therefore, in the severe peroneal group, the unchanged microvascular pO2 profile compared with control suggests that any slowing of O2 delivery was matched to that of O2 uptake i.e., a parallel down regulation of vascular function and mitochondrial oxidative capacity (as expected from the reduced citrate synthase activity).

4.2. O2 delivery to O2 uptake relationship in soleus and peroneal
In healthy skeletal muscle, the mechanisms which act to elevate blood flow in response to contractions differ substantially between muscles comprised of mainly slow vs. fast-twitch fibers [26]. Briefly, arterioles isolated from slow-twitch (soleus) vs. fast-twitch (gastrocnemius) muscles exhibit a greater vascular response (i.e., sensitivity) to endothelium-dependent vasoactive mediators (e.g., acetylcholine [10–12]). Conversely, arterioles from fast-twitch muscle demonstrate a greater endothelium-independent vascular response vs. those from slow-twitch fibers [10,12]. Moreover, McAllister [27] has demonstrated that, in response to acetylcholine, the soleus exhibits a significant increase in vascular conductance (double control values), whereas no change is observed in the peroneal.

These varying vascular control mechanisms culminate in distinct microvascular pO2 profile in the soleus and peroneal (Figs. 1 and 2Go, control). We believe, based upon the similar oxidative capacity of these two muscles, that the faster microvascular pO2 dynamics in healthy peroneal results predominantly from different muscle blood flow dynamics (slower O2 delivery dynamics in peroneal vs. soleus) rather than an altered muscle O2 uptake profile [28]. Accordingly, the endothelial dysfunction (i.e., decreased sensitivity) induced by CHF (canine [29], hamster [30], rat [9], human [7]) would be expected to impact muscle blood flow dynamics in slow-twitch muscles to a greater extent than occurs in fast-twitch muscle. To address this specific issue, we have reanalyzed the data of Hirai et al. [24] for the soleus and peroneal muscles (Figs. 6 and 7)Go. The Hirai et al. study determined the effects of L-NAME infusion on muscle blood flow and vascular conductance in CHF rats running at 20 m/min (10% grade). Regarding the impact of CHF on NO-induced vasodilation, the reduction in blood flow (Fig. 6) and vascular conductance (Fig. 7) under L-NAME conditions was significantly decreased in soleus with moderate and severe CHF. These reductions were two- to three-fold greater (P<0.05) than seen in the peroneal. Unlike in the soleus in moderate CHF, the effect of L-NAME was not significantly reduced for either blood flow or vascular conductance in peroneal. Indeed, the only effect of CHF in peroneal muscle was a modest, though significant, reduction in the magnitude of the L-NAME-induced blood flow decrease seen in the severe CHF condition. Therefore, inasmuch as shear-stress mediated release of nitric oxide is considered to represent a principal contributor to the exercise hyperemic response [31], it is not surprising that the soleus demonstrates a reduced O2 delivery to O2 uptake ratio (i.e., faster microvascular pO2 dynamics) that becomes more extreme with increasing severity of heart failure (Figs. 2, 4 and 5)GoGo. This effect likely results, at least in part, from the decreased bioavailability of nitric oxide in CHF [32].


Figure 6
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 Change in blood flow from control (i.e., no inhibition of nitric oxide synthase) to that after administration of L-NAME in the soleus and peroneal. *P<0.05 vs. soleus. {Psi}P<0.05 vs. sham. Data reanalyzed from Hirai et al. [24]. MI rats divided into groups with a small (<35%) or large (>35% of left ventricular endocardial circumference infarcted) myocardial infarction.

 

Figure 7
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 7 Change in vascular conductance to L-NAME administration. *P<0.05 vs. soleus. {Psi}P<0.05 vs. sham. Data reanalyzed from Hirai et al. [24]. MI rats divided into groups with a small (<35%) or large (>35% of left ventricular endocardial circumference infarcted) myocardial infarction.

 
4.3. Mechanistic interpretation
In rat hindlimb musculature during electrical stimulation, there are greater perturbations of the phosphocreatine/(phosphocreatine+inorganic phosphate) ratio of CHF compared with control animals [5]. Unfortunately, it was not possible to discern contributions of individual fiber types to the increased phosphocreatine breakdown in that investigation [5] as the gastrocnemius–soleus–plantaris complex was sampled in total. The lower microvascular pO2 observed at all points (after time delay) in moderate and severe soleus vs. control across the rest–contractions transition provides a mechanistic basis for the greater perturbation of the intracellular milieu (e.g., decreased phosphocreatine and phosphocreatine/(phosphocreatine+inorganic phosphate) ratio and increased glycogen breakdown) in slow twitch muscle in CHF. Indeed, this response is expected based upon findings in isolated mitochondria [16] and intact human muscles [33] under conditions of reduced pO2. In this regard, the still faster microvascular pO2 dynamics in severe CHF soleus compared to moderate CHF soleus (Figs. 2 and 4)Go is consistent with the greater perturbations in the phosphocreatine/(phosphocreatine+inorganic phosphate) relationship that Arnolda et al. [5] demonstrated in rats with larger compared to smaller myocardial infarctions. Therefore, the reduced microvascular O2 pressure head in the soleus in CHF (and resultant increased phosphocreatine breakdown [16,33]) provides one potential mechanism for the slowed pulmonary VO2 uptake kinetics in heart failure patients, although additional studies in humans are necessary to confirm this finding.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Chronic heart failure induces a precipitous drop in the microvascular pO2 of the soleus (type I fibers) following the onset of contractions, and the magnitude of this effect is correlated significantly with the degree of left ventricular dysfunction present as assessed by increased LW/BW and RV/BW. In contrast, no speeding of microvascular pO2 kinetics with heart failure occurs in the peroneal (type II fibers). The findings of the current investigation are consistent with a reduced bulk blood flow [13] and vascular transport capacity [14], which are manifested at the onset of contractions in the soleus in CHF, but not in the peroneal.


   Acknowledgements
 
The authors thank K. Sue Hageman for her excellent technical assistance and Emily Diederich for her help with data collection. This work was supported, in part, by grants from the National Institutes of Health (NIH Grants HLBI-50306 and AG-19228) and the American Heart Association (AHA-Heartland Affiliate 51321Z).


   Notes
 
Time for primary review 28 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Riley M., Porszasz J., Stanford C.F., Nicholls D.P. Gas exchange responses to constant work rate exercise in chronic cardiac failure. Br. Heart J. (1994) 72:150–155.[Abstract/Free Full Text]
  2. Sietsema K.E., Ben-Dov I., Zhang Y.Y., Sullivan C., Wasserman K. Dynamics of oxygen uptake for submaximal exercise and recovery in patients with chronic heart failure. Chest (1994) 105:1693–1700.[CrossRef][ISI][Medline]
  3. Grassi B., Marconi C., Meyer M., Rieu M., Cerretelli P. Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. J. Appl. Physiol. (1997) 82:1952–1962.[Abstract/Free Full Text]
  4. Diederich E.R., Behnke B.J., McDonough P., Kindig C.A., Barstow T.J., Poole D.C., et al. Dynamics of microvascular oxygen partial pressure in contracting skeletal muscle of rats with chronic heart failure. Cardiovasc. Res. (2002) 56:479–486.[Abstract/Free Full Text]
  5. Arnolda L., Brosnan J., Rajagopalan B., Radda G.K. Skeletal muscle metabolism in heart failure in rats. Am. J. Physiol. (1991) 261:H434–H442.[ISI][Medline]
  6. Delp M.D., Duan C. Composition and size of type I, IIA, IID/X, and IIB fibers and citrate synthase activity of rat muscle. J. Appl. Physiol. (1996) 80:261–270.[Abstract/Free Full Text]
  7. Kubo S.H., Rector T.S., Bank A.J., Williams R.E., Heifetz S.M. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation (1991) 84:1589–1596.[Abstract/Free Full Text]
  8. Drexler H., Hayoz D., Munzel T., Just H., Zelis R., Brunner H.R. Endothelial function in congestive heart failure. Am. Heart J. (1993) 126:761–764.[CrossRef][ISI][Medline]
  9. Didion S.P., Mayhan W.G. Effect of chronic myocardial infarction on in vivo reactivity of skeletal muscle arterioles. Am. J. Physiol. (1997) 272:H2403–H2408.[ISI][Medline]
  10. Wunsch S.A., Muller-Delp J., Delp M.D. Time course of vasodilatory responses in skeletal muscle arterioles: role in hyperemia at onset of exercise. Am. J. Physiol, Heart Circ. Physiol. (2000) 279:H1715–H1723.[Abstract/Free Full Text]
  11. Woodman C.R., Schrage W.G., Rush J.W., Ray C.A., Price E.M., Hasser E.M., et al. Hindlimb unweighting decreases endothelium-dependent dilation and enos expression in soleus not gastrocnemius. J. Appl. Physiol. (2001) 91:1091–1098.[Abstract/Free Full Text]
  12. McCurdy M.R., Colleran P.N., Muller-Delp J., Delp M.D. Effects of fiber composition and hindlimb unloading on the vasodilator properties of skeletal muscle arterioles. J. Appl. Physiol. (2000) 89:398–405.[Abstract/Free Full Text]
  13. Musch T.I., Terrell J.A. Skeletal muscle blood flow abnormalities in rats with a chronic myocardial infarction: rest and exercise. Am. J. Physiol. (1992) 262:H411–H419.[ISI][Medline]
  14. McAllister R.M., Laughlin M.H., Musch T.I. Effects of chronic heart failure on skeletal muscle vascular transport capacity of rats. Am. J. Physiol. (1993) 264:H689–H691.[Medline]
  15. Gollnick P.D., Piehl K., Saltin B. Selective glycogen depletion pattern in human muscle fibres after exercise of varying intensity and at varying pedalling rates. J. Physiol. (Lond.) (1974) 241:45–57.[Abstract/Free Full Text]
  16. Wilson D.F., Erecinska M., Drown C., Silver I.A. Effect of oxygen tension on cellular energetics. Am. J. Physiol. (1977) 233:C135–C140.[ISI][Medline]
  17. Musch T.I., Moore R.l., Leathers D.J., Bruno A., Zelis R. Endurance training in rats with chronic heart failure induced by myocardial infarction. Circulation (1986) 74:431–441.[Abstract/Free Full Text]
  18. Symons J.D., Stebbins C.L., Musch T.I. Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats. J. Appl. Physiol. (1998) 87:574–581.[ISI]
  19. Rumsey W.L., Vanderkooi J.M., Wilson D.F. Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue. Science (1988) 241:1649–1651.[Abstract/Free Full Text]
  20. Vinogradov S., Fernandez-Searra M.A., Dugan B.W., Wilson D.F. Frequency domain instrument for measuring phosphorescence lifetime distributions in heterogeneous samples. Rev. Sci. Instrum. (2001) 72:3396–3406.[CrossRef][ISI]
  21. Bevington P.R. Data reduction and error analysis for physical sciences. (1969) New York, NY: McGraw-Hill.
  22. Behnke B.J., Kindig C.A., Musch T.I., Koga S., Poole D.C. Dynamics of microvascular oxygen pressure across the rest–exercise transition in rat skeletal muscle. Respir. Physiol. (2001) 126:53–63.[CrossRef][ISI][Medline]
  23. Srere P.A. Citrate synthase. Methods Enzymol. (1969) 13:3–5.
  24. Hirai T., Zelis R., Musch T.I. Effects of nitric oxide synthase inhibition on the muscle blood flow response to exercise in rats with heart failure. Cardiovasc. Res. (1995) 30:469–476.[Abstract/Free Full Text]
  25. Behnke B.J., Barstow T.J., Kindig C.A., McDonough P., Musch T.I., Poole D.C. Dynamics of oxygen uptake following exercise onset in rat skeletal muscle. Respir. Physiol. Neurobiol. (2002) 133:229–239.[CrossRef][ISI][Medline]
  26. Delp M.D., Laughlin M.H. Regulation of skeletal muscle perfusion during exercise. Acta Physiol. Scand. (1998) 162:411–419.[CrossRef][ISI][Medline]
  27. McAllister R.M. Endothelium-dependent vasodilation in different rat hindlimb skeletal muscles. J. Appl. Physiol. (2003) 94:1777–1784.[Abstract/Free Full Text]
  28. Behnke B.J., McDonough P., Padilla D.J., Musch T.I., Poole D.C. Oxygen exchange profile in rat muscles of contrasting fibre types. J. Physiol. (Lond) (2003) 549(2):597–605.[Abstract/Free Full Text]
  29. Kaiser L., Spickard R.C., Olivier N.B. Heart failure depresses endothelium-dependent responses in canine femoral artery. Am. J. Physiol. (1989) 256:H962–H967.[ISI][Medline]
  30. Crespo M.J., Altieri P.I., Escobales N. Altered vascular function in early stages of heart failure in hamsters. J. Card. Fail. (1997) 3:311–318.[CrossRef][Medline]
  31. Duling B.R., Dora K. The lung: Scientific foundations. Crystal R.G., West J.B., Barnes P.J., Weibel E.R., eds. (1997) 2nd ed. Philadelphia: Lippincott-Raven. 1935–1944.
  32. Drexler H., Hornig B. Importance of endothelial function in chronic heart failure. J. Cardiovasc. Pharmacol. (1996) 27:S9–S12.[CrossRef][ISI][Medline]
  33. Haseler L.J., Richardson R.S., Videen J.S., Hogan M.C. Phosphocreatine hydrolysis during submaximal exercise: the effect of FIO2. J. Appl. Physiol. (1998) 85:1457–1463.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Behnke, B.J
Right arrow Articles by Musch, T.I
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Behnke, B.J
Right arrow Articles by Musch, T.I
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?