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Departments of Anatomy and Physiology and of Kinesiology Kansas State University, Manhattan, Kansas 66506
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Few studies have examined potential
for endothelium-dependent vasodilation in skeletal muscles of different
fiber-type composition. We hypothesized that muscles composed of slow
oxidative (SO)- and/or fast oxidative glycolytic (FOG)-type fibers have
greater potential for endothelium-dependent vasodilation than muscles composed of fast glycolytic (FG)-type fibers. To test this hypothesis, the isolated perfused rat hindlimb preparation was used with a constant-flow, variable-pressure approach. Perfusion pressure was
monitored continuously, and muscle-specific flows were determined by
using radiolabeled microspheres at four time points: control, at peak
effect of acetylcholine (ACh I; 1-2 × 10
4 M),
at peak effect of ACh after infusion of an endothelial inhibitor (ACh
II), and at peak effect of sodium nitroprusside (SNP; 4-5 × 104 M). Conductance was calculated by using pressure and
flow data. In the SO-type soleus muscle, conductance increased with ACh
and SNP, but the increase in conductance with ACh was partially
abolished by the endothelial inhibitor
NG-nitro-L-arginine methyl ester
(control, 0.87 ± 0.19; ACh I, 2.07 ± 0.29; ACh II,
1.32 ± 0.15; SNP, 1.76 ± 0.19 ml · min1 · 100 g1 · mmHg1;
P < 0.05, ACh I and SNP vs. control). In the FOG-type
red gastrocnemius muscle, similar findings were obtained (control,
0.64 ± 0.11; ACh I, 1.36 ± 0.21; ACh II, 0.73 ± 0.16;
SNP, 1.30 ± 0.21 ml · min1 · 100 g1 · mmHg; P < 0.05, ACh I and SNP vs. control). In the FG-type white gastrocnemius
muscle, neither ACh nor SNP increased conductance. Similar findings
were obtained when muscles were combined into high- and low-oxidative
muscle groups. Indomethacin had no effect on responses to ACh. These
data indicate that endothelium-dependent vasodilation is exhibited by
high-oxidative, but not low-oxidative, rat skeletal muscle.
Furthermore, endothelium-dependent vasodilation in high-oxidative
muscle appears to be primarily mediated by nitric oxide.
acetylcholine; sodium nitroprusside; nitric oxide; prostaglandins
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE ROLE OF ENDOTHELIUM-DEPENDENT vasodilation in the skeletal muscle blood flow response to acute exercise is uncertain. A majority of studies conducted in humans indicate that although the endothelium participates in control of muscle vasculature at rest, the hyperemia associated with exercise does not require endothelial participation (cf. Ref. 9). Results from studies conducted in animals are more supportive of a role for endothelium-dependent vasodilation during exercise. Both rats (8) and mice (14) exhibit reduced skeletal muscle blood flow during treadmill exercise after inhibition of endothelium-derived nitric oxide (EDNO) formation.
Although many studies have examined its role in the adjustment to acute exercise, there are few data available concerning potential for endothelium-dependent vasodilation in different skeletal muscles. This knowledge is important for interpreting the above-mentioned studies, because endothelial involvement during exercise may vary among muscles in proportion to its potential. Skeletal muscle varies widely, not only in its contractile and biochemical properties but also in its cardiovascular support; indeed, there is an impressive matching of muscle phenotype and blood flow (cf. Ref. 15). Muscles primarily composed of slow oxidative (SO)- and/or fast oxidative glycolytic (FOG)-type fibers exhibit severalfold greater hyperemic responses to acute exercise than those largely composed of fast glycolytic (FG)-type fibers (cf. Ref. 12). Hirai et al. (8) reported that, after inhibition of the formation of EDNO, rat hindlimb muscle blood flows during exercise were reduced. Furthermore, muscles composed of high-oxidative SO and/or FOG fibers suffered greater reductions in flow than did muscles composed of low-oxidative FG fibers. These data suggest that potential for endothelium-dependent dilation is greater in vasculature of high-oxidative muscle. In addition, recent studies by Delp et al. (5) and Wunsch et al. (22) indicate that endothelium-dependent dilation is greater in vessels isolated from a high-oxidative rat hindlimb muscle (soleus) than in those isolated from a low-oxidative muscle (superficial gastrocnemius).
The present study used the isolated perfused rat hindlimb preparation to determine potential for endothelium-dependent and -independent vasodilation in skeletal muscles of varying fiber-type composition. Vasodilation was induced with pharmacological agents that act specifically on endothelium and vascular smooth muscle. We tested the hypothesis that potential for endothelium-dependent vasodilation is greater in muscles primarily composed of SO and/or FOG fibers than in muscles composed of FG fibers.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Adult male Sprague-Dawley rats (Charles River) were used in this study. They were housed three per cage in a 20-21°C environment with a 12:12-h light-dark cycle. Rats were provided with food and water ad libitum.
Isolated perfused rat hindlimb preparation. Surgery required to isolate the single rat hindlimb for perfusion has been described in detail previously (7, 16). Catheters (Abbocath) were advanced into the left femoral artery and vein via the left common iliac artery and vein, respectively. Perfusate (see below) was pumped from a reservoir, by using a peristaltic pump (Gilson), through an oxygenator (Silastic tubing exposed to a 95% O2-5% CO2 gas mixture within a water-jacketed Plexiglas container) and subsequently into the femoral artery. Perfusate exited the oxygenator with a PO2 of 500-600 Torr. Perfusate was returned to the reservoir on exiting the femoral vein and recirculated. Temperature of the preparation was maintained at 37°C by using a heating tape (Thermolyne) within the perfusion box.
Perfusate. The perfusate consisted of Krebs-Henseleit bicarbonate buffer solution with bovine erythrocytes (hematocrit ~40%). Bovine erythrocytes were obtained from local slaughterhouses and underwent a series of washes in saline and in Krebs-Henseleit bicarbonate buffer solution before use in experiments. The perfusate contained bovine serum albumin (4 g/100 ml), bovine insulin (100 µU/ml), glucose (5.0 mM), and pyruvate (0.15 mM). All chemicals used in perfusate preparation were purchased from Sigma-Aldrich.
Experimental design. After the arterial and venous catheters were secured, total inflow to the hindlimb was gradually increased to 8-9 ml/min. This inflow resulted in skeletal muscle flows similar to those reported for hindlimb muscles in conscious rats at rest (6, 7). Total inflow was maintained at this level for the duration of an experiment. Inflow was determined by timed collection of venous effluent. Perfusion pressure was monitored at a manifold port within the perfusion system immediately proximal to the femoral arterial catheter. The pressure transducer was situated at the same level as the animal and was connected to a blood pressure analyzer (Digi-Med). A constant-flow, variable-pressure approach was therefore utilized in this study.
Perfusion pressure and flows were determined during an experiment under control conditions and at peak effect of vasodilating agents. Vasodilators used were the endothelium-dependent agent acetylcholine (ACh; Ref. 18) and the endothelium-independent agent sodium nitroprusside (SNP; Ref. 18). Stock solutions of ACh (1.10 × 102 M) and SNP (2.68 × 102 M) were
infused, by using an infusion pump (Harvard Apparatus), into the
perfusate via a manifold port within the perfusion system immediately
proximal to the femoral arterial catheter. Vasodilators were infused at
the relatively low rate of 9 ml/h (0.15 ml/min; 1-2% of total
inflow to the hindlimb) to avoid alterations in perfusion pressure. ACh
and SNP stock solution concentrations and infusion rate utilized were
based on results of preliminary experiments (data not shown). ACh and
SNP concentrations in femoral arterial perfusate were calculated as the
quotient of their rate of infusion (mol/min) and total inflow to the
hindlimb (ml/min; Ref. 4). Perfusion pressure was
monitored continuously, and at peak effect of ACh or SNP (i.e., peak
decrease in perfusion pressure), regional flows were determined by
using radiolabeled microspheres (see Determination of regional
flows).
During an experiment, regional flows were determined at four time
points: control, at peak effect of ACh (ACh I), at peak effect of ACh
after infusion of an endothelial inhibitor (ACh II), and at peak effect
of SNP. In series I, the endothelial inhibitor used was
NG-nitro-L-arginine methyl ester
(L-NAME), an inhibitor of EDNO formation (18).
L-NAME was in a stock solution of 27 mg/ml isotonic saline
and was infused at a rate of 3 ml/h (0.05 ml/min) over a 20-min period
between ACh I and ACh II. This resulted in administration of 884 ± 35 mg L-NAME/kg of hindlimb mass. In series
II, the endothelial inhibitor used was indomethacin, an inhibitor
of the formation of vasodilatory prostaglandins (18).
Indomethacin was in a stock solution of 0.36 mg/ml ethanol and was
infused at a rate of 3 ml/h (0.05 ml/min) over 20 min between ACh I and
ACh II. This resulted in administration of 12.9 ± 0.5 mg
indomethacin/kg of hindlimb mass. In series III, both
L-NAME and indomethacin were infused during back-to-back
20-min infusion periods. This resulted in administration of 798 ± 28 and 10.6 ± 0.4 mg/kg of hindlimb mass for L-NAME
and indomethacin, respectively. Effects of vehicles were determined in
separate series of experiments in which either saline or ethanol was
infused between ACh I and ACh II. All vasoactive agents were purchased
from Sigma-Aldrich.
Determination of regional flows.
Regional flow determinations were made at the experimental time points
detailed above, as described previously (7, 16). Briefly,
radiolabeled (46Sc, 85Sr, 113Sn,
141Ce) microspheres (15-µm diameter; New England Nuclear)
were infused into the perfusate via manifold ports within the perfusion
system immediately proximal to the femoral arterial catheter. At the conclusion of an experiment, all muscles and other tissues (i.e., fat,
bones, foot) of the hindlimb were dissected, weighed, and counted in a
gamma counter (Packard). Flows to individual muscles and
tissues were calculated as follows
![Flow (muscle) = [counts/min (muscle)/counts/min(total)]](/content/vol94/issue5/fulltext/1777/img001.gif)
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Statistical analysis.
All data are presented as means ± SE. Vascular conductance,
rather than resistance, was used as an expression of vasomotor function
because of its linear relationship with flow (13). Conductance was calculated as the quotient of flow
(ml · min1 · 100 g1) and perfusion pressure (mmHg). In addition to
examination of data for individual muscles and tissues, muscles and
other tissues were combined into groups for analysis. The
high-oxidative muscle group included soleus, plantaris, red
gastrocnemius, red tibialis anterior, tibialis posterior, and peroneal
muscles. These muscles are classified as high oxidative because they
are composed of 
50% SO + FOG muscle fibers (2, 8).
The low-oxidative muscle group included white gastrocnemius, mixed
gastrocnemius, white tibialis anterior, extensor digitorum longus,
flexor digitorum longus, and flexor hallicus longus muscles. These
muscles are classified as low oxidative because they are composed of
<50% SO + FOG fibers (2, 8). The other tissues
group included fat, tibia and fibula, and foot. Data for muscles and
tissues of the upper leg, although necessarily included in all flow
calculations, are not presented because animal-to-animal variability in
femoral arterial catheter placement precluded reliable determination of regional flows in this portion of the hindlimb.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Vehicle series.
Data obtained from experiments in which vehicles for L-NAME
(saline; n = 5) and indomethacin (ethanol;
n = 5) were infused between ACh I and ACh II are
presented in Fig. 1 for three
representative muscles. Total inflows for the saline and ethanol series
were 8.9 ± 0.1 and 9.0 ± 0.1 ml/min, respectively. ACh
concentration established was 1.84 ± 0.01 × 104 M for the saline series and 1.84 ± 0.02 × 104 M for the ethanol series. Figure 1 (left)
shows that ACh induced an increase in conductance in the soleus muscle
that was similar in magnitude before and after saline infusion.
Similarly, it is apparent in Fig. 1 (right) that ethanol
infusion did not alter the ACh-induced increase in conductance in the
soleus muscle. For both vehicles, increases in conductance induced by
ACh in the red gastrocnemius muscle were of borderline significance
(0.05 < P < 0.10). ACh administration did not
increase conductance in the white gastrocnemius muscle.
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Series I (L-NAME).
Perfusion conditions for rats of series I
(L-NAME; n = 9) are presented in Table
1. Concentrations of ACh and SNP
established were 1.86 ± 0.02 × 104 and
4.54 ± 0.04 × 104 M, respectively, and
resulted in decreases in perfusion pressure (Table 1).
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Series II (indomethacin).
Perfusion conditions for rats of series II (indomethacin;
n = 8) are presented in Table 1. Concentrations of ACh
and SNP established were 1.92 ± 0.01 × 104
and 4.69 ± 0.03 × 104 M, respectively, and
resulted in decreases in perfusion pressure (Table 1).
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Series III (L-NAME + indomethacin).
Perfusion conditions for rats of series III
(L-NAME + indomethacin; n = 7) are
presented in Table 1. Concentrations of ACh and SNP established were
1.97 ± 0.01 × 104 and 4.81 ± 0.03 × 104 M, respectively, and resulted in decreases in
perfusion pressure (Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The key new finding of this study was that endothelium-dependent dilation, as reflected by increased conductance in response to ACh, was only exhibited by vasculature in high-oxidative skeletal muscle. This endothelium-dependent vasodilation appeared to be primarily due to nitric oxide formation. Furthermore, vasculature in high-oxidative muscle exhibited dilation in response to an endothelium-independent agent, SNP, that acts via the same pathway in vascular smooth muscle as EDNO. Vasculature in low-oxidative muscle, on the other hand, did not exhibit dilation in response to either agent. It appears that vessels in high-oxidative, but not low-oxidative, skeletal muscle contain the intracellular signaling pathways required to both generate and respond to nitric oxide. These findings are consistent with, and may contribute to the mechanistic basis for, the well-established finding that blood flows during exercise to high-oxidative muscles are severalfold greater than those to low-oxidative muscles (cf. Ref. 12).
Experimental preparation. Vasodilatory responses in a number of skeletal muscles of differing fiber type composition were determined by using the isolated perfused rat hindlimb preparation. Those vasodilatory responses reflected the integrated response of conduit- and resistance-type vessels of an entire vascular bed. This experimental preparation permitted determination of muscle-specific flows at peak vasodilatory response via continuous monitoring of perfusion pressure. It also allowed local (i.e., hindlimb) delivery of vasodilatory agents, establishing agent concentrations similar to those used in isolated vessel studies (5, 10, 11, 17, 22), as well as local delivery of endothelial inhibitors. Vasodilatory responses induced by ACh were reproducible, as illustrated by experiments of the vehicle series (see Fig. 1). Additional advantages of this experimental preparation are that the perfused mass is primarily skeletal muscle (~80%; Ref. 7) and that vasculature is free of neural and humoral influences.
A potential limitation of our experimental preparation was that a constant-flow approach was used. Thus, when flow to certain muscles and tissues increased, it did so at the expense of flow to other muscles and tissues. Our data indicate that flow was diverted from nonmuscle tissues (i.e., fat, bone, foot) during ACh and SNP administration. The need to monitor vascular responses to ACh and SNP with perfusion pressure necessitated the use of a constant-flow, variable-pressure approach.Endothelium-dependent vasodilatory responses. Our finding that vasculature in high-oxidative, but not low-oxidative, skeletal muscle exhibited endothelium-dependent dilation is consistent with findings of Hirai et al. (8). These investigators determined muscle-specific blood flows in rats during treadmill running, before and after inhibition of EDNO formation with L-NAME. They found that the reduction in blood flow to various hindlimb muscles during exercise with L-NAME treatment was related to high-oxidative (i.e., SO + FOG) muscle fiber content. Our findings also resemble those of Woodman and co-workers (21), who recently reported that infusion of ACh into the femoral artery increased blood flow to the highly oxidative soleus muscle but not the low-oxidative white gastrocnemius muscle section, of anesthetized rats.
Our findings extend those of Hirai and co-workers (8) in two ways. First, the treadmill running intensity utilized in their study was relatively mild (60-70% maximal O2 consumption). Thus it is unlikely that recruitment of low-oxidative muscle, with the attendant increase in blood flow, occurred (cf. Ref. 12). Consequences of inhibition of EDNO formation in vasculature of low-oxidative muscle are likely only to be revealed when its blood flow is increased by more intense exercise, which would be expected to recruit this type of skeletal muscle. Our preparation permitted examination of responses in low-oxidative muscle via administration of ACh throughout the hindlimb; nonetheless, endothelium-dependent vasodilation was not exhibited by this type of skeletal muscle. Although delivery of ACh to low-oxidative muscle, by virtue of lower flow, was somewhat less than that to high-oxidative muscle, stimulation of its vascular endothelium by ACh likely occurred. ACh-induced vasodilation in high-oxidative muscle exaggerated the difference in conductance between high- and low-oxidative muscle groups present under control conditions (~50% greater in high-oxidative muscle). Second, to permit locomotion on the treadmill, Hirai et al. restricted their dose of systemically administered L-NAME to 30 mg/kg. Our experimental preparation, by allowing local delivery of vasoactive agents, permitted much higher doses of L-NAME (800-900 mg/kg) to be used, ensuring more complete inhibition of EDNO formation. Thus our findings in series I and III constitute strong evidence that endothelium-dependent vasodilation induced by ACh in high-oxidative muscle is primarily mediated by nitric oxide. Further evidence that nitric oxide is the primary endothelium-derived vasodilator in high-oxidative skeletal muscle came from experiments of series II. Indomethacin, an inhibitor of cyclooxygenase and, therefore, of vasodilatory prostaglandin formation in the endothelium was without effect on ACh-induced dilation of vasculature in high-oxidative muscle. Our experimental preparation permitted administration of doses of indomethacin in excess of those previously used. Wilson and Kapoor (20), in a study of exercise-induced hyperemia in forearm muscle, used an indomethacin dose of ~3 mg/kg. This dose abolished release of vasodilatory prostaglandins in the forearm. It is therefore likely that inhibition of endothelial cyclooxygenase was achieved with our doses of 10-15 mg/kg. Although some studies have demonstrated a role for prostaglandins in dilation of the skeletal muscle vasculature (10, 11, 20), many investigations have failed to do so. Prostaglandins appear to play a more prominent role in vascular control in other bodily regions (e.g., renal; Ref. 1). We must concede, however, that endothelium-derived prostaglandins may play a vasodilatory role in skeletal muscle, a role that cannot be deduced by using indomethacin. In support of this possibility, experiments using cultured endothelial cells have shown that when vasodilatory prostaglandin formation is inhibited with indomethacin, EDNO formation increases (3). Increased EDNO formation may compensate for a lack of prostaglandin production. A similar interaction between EDNO and prostaglandin formation may have occurred in experiments of series II. Our finding that vasculature in high-oxidative skeletal muscle demonstrated significant endothelium-dependent dilation is also consistent with findings from studies by Delp et al. (5) and Wunsch et al. (22). They reported that arterioles isolated from the soleus muscle exhibited robust dilation to ACh. Thesse investigataors found, however, that arterioles from the superficial gastrocnemius (a low-oxidative muscle) also exhibited dilation, albeit lesser in magnitude, in response to ACh. We consistently failed to observe a vasodilatory response to ACh in this muscle section in situ. This difference between studies is difficult to reconcile, but it may involve differences in the experimental conditions under which vascular responses were determined (i.e., in situ vs. in vitro) and/or in vascular response determined (i.e, mass flow vs. isolated vessel diameter). Regarding the latter possibility, arterial vessels in low-oxidative skeletal muscle may also have exhibited endothelium-dependent vasodilation in situ, but by virtue of their lesser abundance in low-oxidative muscle (cf. Ref. 15), the radiolabeled-microsphere technique that we employed in this study was unable to detect dilation of a relatively small number of arterial vessels. In more highly vascularized high-oxidative muscle (cf. Ref. 15), dilation of a greater number of vessels appeared to result in a detectable increase in bulk flow.Endothelium-independent vasodilatory responses. Our findings indicate that vasculature in high-oxidative skeletal muscle is not only capable of nitric oxide formation in its endothelium but also of responding to nitric oxide. The ability of vascular smooth muscle to respond to nitric oxide was reflected by the dilatory response to SNP, a nitric oxide donor. Low-oxidative muscle, on the other hand, did not exhibit vasodilation in response to SNP. These findings are at odds with those of McCurdy and co-workers (17), who reported that arterioles isolated from the superficial gastrocnemius exhibited maximal dilatory responses to SNP equal to those of arterioles from the soleus muscle. Again, differences in experimental conditions and/or vascular response measured may account for these differing findings, as elaborated on above.
Perspectives. The finding that endothelium-dependent dilation was only exhibited by vasculature in high-oxidative skeletal muscle is consistent with data obtained during exercise in vivo. Blood flows to high-oxidative muscles are several times greater than those to low-oxidative muscles, even during high-intensity treadmill running that is known to recruit the latter (cf. Ref. 12). Our data, obtained using the pharmacological agent ACh in situ, reflect potential for endothelium-dependent vasodilation. Whether this vasodilatory potential in high-oxidative skeletal muscle is utilized during exercise is uncertain. Increased blood flow and, consequently, increased shear stress on the vascular endothelium in high-oxidative muscle during exercise would nonetheless be predicted to engage endothelium-dependent dilation during acute exercise.
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ACKNOWLEDGEMENTS |
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The technical assistance of Molly Edmonds, Sue Hageman, Lisa Lloyd, and Mike Zbreski is gratefully acknowledged. This research could not have been conducted without the cooperation of the staffs at Alta Vista (Kansas) Locker, Burlingame (Kansas) Locker and Meat Market, and Clay Center (Kansas) Locker, who graciously provided bovine blood.
This work was supported by National Heart, Lung, and Blood Institute Grant HL-57226 and American Heart Association, Kansas Affiliate, Grant AHA-KS-98-GB-25.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. M. McAllister, Dept. of Anatomy and Physiology, Kansas State University, 228 Coles Hall, Manhattan, KS (E-mail: mcallist{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.
First published January 17, 2003;10.1152/japplphysiol.00901.2002
Received 9 October 2002; accepted in final form 11 December 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 R. M. McAllister, I. Albarracin, J. L. Jasperse, and E. M. Price Thyroid status and endothelium-dependent vasodilation in skeletal muscle Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R284 - R291. [Abstract] [Full Text] [PDF]
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 I. Momken, P. Lechene, R. Ventura-Clapier, and V. Veksler Voluntary physical activity alterations in endothelial nitric oxide synthase knockout mice Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H914 - H920. [Abstract] [Full Text] [PDF]
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P. S. Clifford and Y. Hellsten Vasodilatory mechanisms in contracting skeletal muscle J Appl Physiol, July 1, 2004; 97(1): 393 - 403. [Abstract] [Full Text] [PDF]
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P. McDonough, B. J. Behnke, T. I. Musch, and D. C. Poole Effects of chronic heart failure in rats on the recovery of microvascular PO2 after contractions in muscles of opposing fibre type Exp Physiol, July 1, 2004; 89(4): 473 - 485. [Abstract] [Full Text] [PDF]
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 B.J Behnke, M.D Delp, P McDonough, S.A Spier, D.C Poole, and T.I Musch Effects of chronic heart failure on microvascular oxygen exchange dynamics in muscles of contrasting fiber type Cardiovasc Res, February 1, 2004; 61(2): 325 - 332. [Abstract] [Full Text] [PDF]
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T. I. Musch, K. E. Eklund, K. S. Hageman, and D. C. Poole Altered regional blood flow responses to submaximal exercise in older rats J Appl Physiol, January 1, 2004; 96(1): 81 - 88. [Abstract] [Full Text] [PDF]
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