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J Appl Physiol 91: 351-356, 2001;
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Vol. 91, Issue 1, 351-356, July 2001

Effects of Pseudomonas aeruginosa endotoxin on vasodilation in the intact spinotrapezius muscle

Hideyuki Suzuki1,3, Hiroyuki Ikezaki1,3, Rinku Chandiwala1,3, Dennis Hong1,3, and Israel Rubinstein1,2,3

Departments of 1 Medicine and 2 Pharmaceutics and Pharmacodynamics, University of Illinois at Chicago, and 3 Veterans Affairs Chicago Health Care System West Side Division, Chicago, Illinois 60612


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The purpose of this study was to determine whether short-term exposure to clinically relevant concentrations of Pseudomonas aeruginosa lipopolysaccharide (LPS) impairs vasoreactivity of resistance arterioles in the intact spinotrapezius muscle microcirculation and, if so, to determine the mechanisms mediating this response. Using intravital microscopy, we found that 60-min suffusion of P. aeruginosa LPS (0.03-3.0 µg/ml) on the in situ hamster spinotrapezius muscle elicited an immediate, profound, and prolonged concentration-dependent vasodilation (P < 0.05). This response was reversible once suffusion of P. aeruginosa LPS was stopped. Pretreatment with NG-nitro-L-arginine methyl ester (10.0 µM), a nonselective nitric oxide (NO) synthase inhibitor, but not NG-nitro-D-arginine methyl ester, abrogated P. aeruginosa LPS-induced vasodilation and elicited a small, albeit significant, vasoconstriction. Indomethacin had no significant effects on P. aeruginosa LPS-induced responses. P. aeruginosa LPS had no significant effects on acetylcholine- and nitroglycerin-induced vasodilation in the spinotrapezius muscle. Collectively, these data indicate that short-term exposure to clinically relevant concentrations of P. aeruginosa LPS evokes an immediate, potent, prolonged, and reversible NO-dependent, prostaglandin-independent vasodilation in skeletal muscles in vivo. We suggest this response could play an important role in the pathophysiology of the profound vasomotor dysfunction observed in the peripheral circulation of patients with P. aeruginosa sepsis syndrome.

gram-negative sepsis; skeletal muscle; microcirculation; vasomotor tone; nitric oxide; NG- nitro-L-arginine methyl ester; hamster; lipopolysaccharide


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

DESPITE RECENT ADVANCES IN therapeutics and medical technology, gram-negative bacterial sepsis syndrome remains a major cause of morbidity and mortality among hospitalized patients in the United States (5, 6, 31). This condition is also associated with substantial medical expense, which accentuates its socioeconomic impact on the community (6). Hence, there is an urgent need to develop new therapies for gram-negative bacterial sepsis syndrome using rational drug design that is based on the proposed mechanisms underlying its pathophysiology.

To this end, Pseudomonas aeruginosa is an important opportunistic gram-negative bacterium often associated with sepsis syndrome and poor outcome, particularly among patients with impaired immune responses and hospitalized patients (3, 5, 6, 31). P. aeruginosa sepsis syndrome is characterized by profound vasodilation in skeletal muscles, which harbor the largest proportion of resistance arterioles in the peripheral circulation (4, 8, 13, 22, 29, 32, 38, 48), that leads to intractable hypotension (1, 2, 9, 12, 28). A growing body of experimental evidence suggests that P. aeruginosa lipopolysaccharide (LPS), a macromolecular glycolipid component of bacterial wall (11, 18, 35), plays an important role in the pathophysiology of this response (2, 9, 11, 12, 18). However, the mechanisms underlying the deleterious effects of clinically relevant concentrations of P. aeruginosa LPS on resistance arterioles in skeletal muscles in vivo are uncertain (10, 21, 32, 35, 41).

Hence, the purpose of this study was to begin to address this issue by determining whether short-term exposure to clinically relevant concentrations of P. aeruginosa LPS impairs vasoreactivity of resistance arterioles in the intact hamster spinotrapezius muscle and, if so, to determine the mechanisms mediating this response.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

General Methods

Preparation of animals. The intact hamster peripheral microcirculation was used in these studies. This model is used by us and other investigators to elucidate mechanisms underlying the host inflammatory response to injury, such as evoked by P. aeruginosa and LPS, in vivo (7, 14-16, 23-25, 29, 33, 36, 37, 39, 42-46). Adult male golden Syrian hamsters (n = 40) weighing 132 ± 3 g were anesthetized with pentobarbital sodium (6 mg/100 g body wt ip). A tracheostomy was performed to facilitate spontaneous breathing. A femoral vein was cannulated to inject supplemental anesthesia during the experiment (2-4 mg · 100 g body wt-1 · h-1). A femoral artery was cannulated to monitor mean arterial pressure and heart rate, which did not change significantly during the course of the experiments (102 ± 4 mmHg and 312 ± 3 beats/min at the start and 98 ± 2 mmHg and 316 ± 4 beats/min at the conclusion of the experiments, respectively; P > 0.5). Body temperature was monitored during the experiments and maintained constant (37-38°C) using a heating pad.

The right spinotrapezius muscle was prepared for intravital microvascular observation as previously described in our laboratory and reports in the literature (13, 19, 26, 27, 42). Briefly, a median skin incision was made along the spine and the loose connective tissue beneath the skin was cut away to expose the muscle surface. The animal was placed on its left side, and the lateral side of the right spinotrapezius muscle was carefully pulled out with blunt dissection. The muscle was spread, ventral surface up, over a plastic baseplate, and its edge fixed in the horizontal position using a silk thread. Care was taken to maintain a physiological length of the muscle during the procedure. An upper plastic chamber was placed above the muscle and contained the suffusate. The chamber was connected via a three-way valve to a reservoir that allowed continuous suffusion of the muscle with warm (37-38°C) bicarbonate buffer [composition (in mM): 131.9 NaCl, 2.95 KCl, 1.48 CaCl2, 0.76 MgCl2, and 11.87 NaHCO3] bubbled continuously with 95% N2-5% CO2 (pH 7.4). The chamber was connected via a three-way valve to an infusion pump that allowed controlled administration of P. aeruginosa LPS and drugs into the suffusate.

Determination of arteriolar diameter. The spinotrapezius muscle microcirculation was transilluminated with a fiber-optic light source (Nikon) and viewed through a Nikon microscope using a water-immersion lens (×4) and a ×10 eyepiece. The image was projected through the microscope and into a closed-circuit television system consisting of low-light camera (WV-1500, Panasonic), monitor (TR-124 MA, Panasonic), and videotape recorder (AG-1230, Panasonic). The luminal diameter of second-order arterioles (baseline diameter, 52 ± 1 µm; see below), which regulate vascular resistance in the spinotrapezius muscle (13, 19, 26, 27, 42), was measured from the video display of the microscope image using a videomicrometer (VIA 100, Boeckeler Instruments, Tucson, AZ) as previously described in our laboratory (42). This system was calibrated against a precision line-width standard. In each animal, the same arteriolar segment was used to measure changes in diameter during the experiment.

Experimental Protocols

Effects of P. aeruginosa LPS on arteriolar diameter. The purpose of these studies was to determine the effects of short-term suffusion of P. aeruginosa LPS on arteriolar diameter in the in situ spinotrapezius muscle. After bicarbonate buffer was suffused for 45 min (equilibration period), increasing concentrations of P. aeruginosa LPS (0.03, 0.3, and 3.0 µg/ml) were suffused for 60 min each in a random order. Arteriolar diameter was measured before, every minute during the first 15 min of suffusion, and every 5 min for the next 90 min. At least 45 min elapsed between subsequent suffusions of P. aeruginosa LPS. Baseline arteriolar diameter was 52 ± 1 µm at the beginning and 51 ± 2 µm at the conclusion of these experiments. In preliminary studies, we determined that repeated suffusions of 0.03, 0.3, and 3.0 µg/ml P. aeruginosa LPS were associated with reproducible increases in arteriolar diameter from baseline: 9 ± 1 and 10 ± 2% (0.03 µg/ml), 19 ± 2 and 17 ± 3% (0.3 µg/ml), and 26 ± 2 and 28 ± 1% (3.0 µg/ml). In addition, suffusion of saline (vehicle) for the entire duration of the experiment had no significant effects on arteriolar diameter (1 ± 1 and 1 ± 2% and the start and conclusion of the experiment, respectively). The concentrations of P. aeruginosa LPS used in these studies are based on preliminary studies and previous reports in the literature (10, 18, 21, 32, 35, 41).

Effects of an NO synthase inhibitor on P. aeruginosa LPS-induced vasodilation. On the basis of the results of the experiments outlined above, we next determined whether pharmacologic inhibition of nitric oxide (NO) synthase attenuates P. aeruginosa LPS-induced vasodilation in the in situ spinotrapezius muscle. After the equilibration period, P. aeruginosa LPS (0.3 µg/ml) was suffused for 60 min. Once arteriolar diameter returned to baseline, NG-nitro-L-arginine methyl ester (L-NAME), an NO inhibitor (30, 34), or NG-nitro-D-arginine methyl ester (D-NAME), its inactive enantiomer (each, 10.0 µM), was suffused for 30 min before and during repeated suffusion of P. aeruginosa LPS (0.3 µg/ml) for 60 min. Arteriolar diameter was determined during each intervention as outlined above. Baseline arteriolar diameter was 51 ± 1 µm at the beginning and 52 ± 1 µm at the conclusion of these experiments. In preliminary studies, we determined that repeated suffusions of L-NAME and D-NAME (each, 10.0 µM) for 90 min had no significant effects on arteriolar diameter (1 ± 2 and 1 ± 1% for L-NAME and 1 ± 1 and 1 ± 1% for D-NAME). The concentrations of L-NAME and D-NAME used in these studies are based on previous studies in our laboratory and reports in the literature (1, 12, 16, 23, 25, 36, 40, 42, 45, 47). The former has been shown to attenuate NO-dependent vasodilation in the in situ peripheral microcirculation of hamsters (23, 40).

Effects of indomethacin on P. aeruginosa LPS-induced vasodilation. Suzuki et al. (42) showed that vasodilation elicited by suffusion of Escherichia coli LPS on the in situ hamster spinotrapezius muscle is mediated by prostaglandins. Similar observations were reported in other species and vascular beds (20, 47). The purpose of these studies was to determine whether prostaglandins modulate the vasorelaxant effects of P. aeruginosa LPS in this microvascular bed. After the equilibration period, indomethacin (10 mg/kg) was administered intravenously over 30 min using an infusion pump followed by suffusion of P. aeruginosa LPS (0.3 µg/ml) on the spinotrapezius muscle for 60 min. Arteriolar diameter was determined during each intervention. Baseline arteriolar diameter was 51 ± 2 µm at the beginning and 51 ± 1 µm at the conclusion of these experiments. In preliminary studies, we determined that intravenous infusion of indomethacin (10 mg/kg) had no significant effects on arteriolar diameter and systemic arterial pressure (1 ± 1% before and 1 ± 1% after, and 101 ± 4 mmHg before and 97 ± 3 mmHg after infusion, respectively). The concentration of indomethacin used in these studies is based on previous studies in our laboratory and a report in the literature and has been shown to inhibit cyclooxygenase in hamsters (14, 37, 42).

Effects of P. aeruginosa LPS on acetylcholine- and nitroglycerin-induced vasodilation. The purpose of these studies was to determine whether P. aeruginosa LPS modulates vascular smooth muscle responsiveness to endogenous and exogenous NO in the in situ spinotrapezius muscle (1, 12, 16, 28, 48). After the equilibration period, acetylcholine (10.0 µM), a receptor- and endothelium-dependent vasodilator, or nitroglycerin (10.0 µM), an NO donor that elicits endothelium-independent vasodilation, was suffused for 7 min. Once arteriolar diameter returned to baseline, P. aeruginosa LPS (0.3 µg/ml) was suffused for 60 min. Once arteriolar diameter returned to baseline (see below), suffusion of acetylcholine (10.0 µM) or nitroglycerin (10.0 µM) was repeated as outlined above. Arteriolar diameter was determined during each intervention. Baseline arteriolar diameter was 52 ± 1 µm at the beginning and 52 ± 1 µm at the conclusion of these experiments. In preliminary studies, we determined that repeated suffusions of acetylcholine and nitroglycerin (each, 10.0 µM) for 7 min each were associated with reproducible increases in arteriolar diameter. The concentrations of acetylcholine and nitroglycerin used in these studies are based on previous studies in our laboratory and reports in the literature (16 23, 36, 39, 45).

Drugs

P. aeruginosa LPS (serotype 10), L-NAME, D-NAME, indomethacin, and acetylcholine were obtained from Sigma Chemical (St. Louis, MO). Nitroglycerin was obtained from American Regent Laboratories (Shirley, NY). Indomethacin was dissolved in Na2CO3 and diluted in saline to the desired concentration on the day of the experiment. P. aeruginosa LPS and all other drugs were dissolved in saline to the desired concentrations on the day of the experiment.

Data and Statistical Analyses

When a compound was suffused over the spinotrapezius muscle, we determined the maximal steady-state change in arteriolar diameter and used this value as the response to that compound. Arteriolar diameter was expressed as the ratio of experimental to control diameter, with control diameter normalized to 100%, to account for intra- and interanimal variability as previously described in our laboratory (16, 23, 39, 40, 42). Data are expressed as means ± SE except for body weight and arteriolar diameter, which were expressed as means ± SD because they characterize the entire sample group and are not compared with another group. Differences between variables were assessed by two-way analysis of variance and the Newman-Keuls multiple-range test. A P value of <0.05 was considered statistically significant; n is given as the number of experiments with each experiment representing a separate animal.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of P. aeruginosa LPS on Arteriolar Diameter

Suffusion of P. aeruginosa LPS for 60 min elicited a significant, immediate, concentration-dependent increase in arteriolar diameter from baseline in the in situ spinotrapezius muscle (Fig. 1; each group, n = 4 animals; P < 0.05). This response was observed within 5 min after the start of suffusion, lasted 10 min after suffusion was stopped, and returned to baseline within 10 min thereafter (Fig. 2; n = 4 animals; P < 0.05).


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  		Fig. 1.   Effects of 60-min suffusion of Pseudomonas aeruginosa lipopolysaccharide (LPS) on arteriolar diameter in the in situ hamster spinotrapezius muscle. Values are means ± SE; each group, n = 4 animals. *P < 0.05 compared with baseline. dagger P < 0.05 compared with 0.03 µg/ml P. aeruginosa LPS. ¶P < 0.05 compared with 0.3 µg/ml P. aeruginosa LPS.



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  		Fig. 2.   Time course of changes in arteriolar diameter in the in situ hamster spinotrapezius muscle during 60-min suffusion of P. aeruginosa LPS (0.3 µg/ml). Values are means ± SE; n = 4 animals. Arrows, duration of suffusion. *P < 0.05 compared with baseline.

Effects of a NO Synthase Inhibitor on P. aeruginosa LPS-Induced Vasodilation

Suffusion of L-NAME, but not D-NAME (each, 10.0 µM), on the in situ spinotrapezius muscle abrogated P. aeruginosa LPS (0.3 µg/ml)-induced vasodilation and unmasked a small, albeit significant, and transient vasoconstriction (7 ± 1% decrease from baseline; Fig. 3; each group, n = 4 animals; P < 0.05). Arteriolar diameter returned to baseline within 15 min after suffusion of L-NAME and P. aeruginosa LPS was stopped (Fig. 3).


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  		Fig. 3.   Effects of 60-min suffusion of P. aeruginosa LPS on arteriolar diameter in the in situ hamster spinotrapezius muscle in the absence and presence of NG-nitro-L-arginine methyl ester (L-NAME; 10.0 µM) or NG-nitro-D-arginine methyl ester (D-NAME; 10.0 µM). Values are means ± SE; each group, n = 4 animals. *P < 0.05 compared with baseline. dagger P < 0.05 compared with P. aeruginosa LPS alone.

Effects of Indomethacin on P. aeruginosa LPS-Induced Vasodilation

Pretreatment with indomethacin (10 mg/kg iv) had no significant effects on P. aeruginosa LPS (0.3 µg/ml)-induced vasodilation (Fig. 4; each group, n = 4 animals).


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  		Fig. 4.   Effects of 60-min suffusion of P. aeruginosa LPS on arteriolar diameter in the in situ hamster spinotrapezius muscle in the absence (open bar) and presence (solid bar) of indomethacin (10 mg/kg iv). Values are means ± SE; each group, n = 4 animals. *P < 0.05 compared with baseline.

Effects of P. aeruginosa LPS on Acetylcholine- and Nitroglycerin-induced Vasodilation

Suffusion of P. aeruginosa LPS (0.3 µg/ml) on the in situ spinotrapezius muscle for 60 min had no significant effects on acetylcholine (10.0 µM)- and nitroglycerin (10.0 µM)-induced vasodilation in this microvascular bed (Fig. 5; each group, n = 4 animals).


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  		Fig. 5.   Effects of 7-min suffusion of acetylcholine and nitroglycerin on arteriolar diameter in the in situ hamster spinotrapezius muscle before (open bars) and after (solid bars) 60-min suffusion of P. aeruginosa LPS (0.3 µg/ml). Values are means ± SE; each group, n = 4 animals. *P < 0.05 compared with baseline.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

There are three new findings of this study. First, we found that short-term suffusion of P. aeruginosa LPS, at concentrations detected in patients with sepsis syndrome (10, 21, 32, 35, 41), on the intact hamster spinotrapezius muscle is associated with an immediate, potent, and prolonged concentration-dependent vasodilation. This response is reversible because arteriolar diameter returned to baseline once suffusion of P. aeruginosa LPS was stopped. The magnitude of the vasodilation was substantial because it corresponds to ~70% reduction in peripheral vascular resistance, a value consistently observed in patients with sepsis syndrome (22, 31, 32, 38). Conceivably, the deleterious effects of P. aeruginosa LPS on vasomotor tone in skeletal muscles could underlie the intractable hypotension observed in patients with P. aeruginosa sepsis syndrome because the largest proportion of resistance arterioles that regulate peripheral vascular resistance is present in these muscles (4, 8, 13, 22, 28, 32, 38, 42).

Second, pharmacological inhibition of NO synthase abrogated P. aeruginosa LPS-induced vasodilation and elicited slight, albeit significant, and transient vasoconstriction. Conceivably, inhibition of NO synthase could have shifted the balance of local vasoregulatory mechanisms in the spinotrapezius muscle microcirculation from vasodilation to vasoconstriction. This process was not mediated through local elaboration of vasoconstrictor prostaglandins because indomethacin, at a concentration previously shown to inhibit cyclooxygenase in hamsters (14, 37, 42), had no significant effects on P. aeruginosa LPS-induced responses.

Last, vasodilation elicited by P. aeruginosa LPS was not related to nonspecific effects on the contractile apparatus in intact spinotrapezius muscle microvessels because the magnitude of vasodilation elicited by suffusion of acetylcholine, an endothelium- and NO-dependent vasodilator, and nitroglycerin, an NO donor, on the spinotrapezius muscle was similar before and after suffusion of P. aeruginosa LPS. Collectively, these data suggest that short-term suffusion of clinically relevant concentrations of P. aeruginosa LPS on the intact hamster spinotrapezius muscle resistance arterioles evokes immediate, potent, and prolonged NO-dependent, prostaglandin-independent vasodilation.

Current concepts suggest that elaboration of NO and/or an NO-containing compound(s) is amplified during gram-negative sepsis syndrome presumably through upregulation of inducible NO synthase (1, 2, 5, 12, 17, 30, 34, 43, 47). The increase in NO output evokes profound, long-lasting vasodilation in the peripheral microcirculation that promotes intractable hypotension (30, 31, 34). Booke et al. (2) showed that S-ethylisothiourea, a non-amino acid inhibitor of NO synthase, reverses vasodilation elicited by live P. aeruginosa in conscious sheep. Inducible NO synthase may have mediated P. aeruginosa LPS-induced vasodilation in the intact hamster spinotrapezius muscle observed in this study. However, the short-term (60 min) duration of exposure coupled with maximal vasodilation observed already within 10 min after the start of P. aeruginosa LPS suffusion do not support this contention. Alternatively, P. aeruginosa LPS may amplify the activity of constitutively expressed isoforms of NO synthase, including inducible NO synthase, in spinotrapezius muscle resistance arterioles by activating tyrosine kinases and/or increasing the availability of enzyme cofactors in target cells (17, 25, 30, 34, 43). Clearly, additional studies using biochemical tools, isoform-selective NO synthase inhibitors, and inducible NO synthase knockout mice are warranted to support or refute this hypothesis.

The observation that exposure to P. aeruginosa LPS elicits immediate, potent, and prolonged vasodilation in the spinotrapezius muscle contrasts with that evoked by E. coli LPS, a bacterium commonly associated with sepsis syndrome in humans (5, 10, 32, 35), in the same preparation (42). Previous work from our laboratory showed that 60-min suffusion of E. coli LPS on the intact hamster spinotrapezius muscle elicits an immediate biphasic vasomotor response consisting of an initial vasoconstriction followed by profound and prolonged vasodilation (42). The former was mediated by angiotensin II, a potent vasoconstrictor peptide, and the latter by reactive oxygen species and vasodilator prostaglandins. Importantly, pharmacological inhibition of NO synthase had no significant effects on E. coli LPS-induced responses. In addition, the deleterious effects of E. coli LPS on vasomotor tone were mediated by proteases released from perivascular mast cells. Taken together, these data suggest that gram-negative bacterial LPS elicits an immediate, profound, and prolonged vasomotor dysfunction in skeletal muscles that is bacterium specific and involves activation of distinct target cells and metabolic pathways in the microcirculation. Although the mechanisms underlying the disparate vasomotor response to P. aeruginosa LPS and E. coli LPS in the intact skeletal muscle microcirculation are uncertain, they may account, in part, for the more severe cardiovascular dysfunction and higher mortality rate observed after exposure to P. aeruginosa LPS than to E. coli LPS in a canine model of septic shock and the relatively poor outcome of patients with P. aeruginosa sepsis syndrome (3, 9, 11, 18, 22). To this end, these data may have important implications for the development of new drugs to treat gram-negative sepsis syndrome by targeting specific metabolic pathways activated by distinct gram-negative pathogens, such as P. aeruginosa and E. coli, in the skeletal muscle microcirculation (31, 34, 42).

In summary, we found that short-term exposure to clinically relevant concentrations of P. aeruginosa LPS evokes an immediate, potent, prolonged, and reversible NO-dependent, prostaglandin-independent vasodilation in the intact hamster spinotrapezius muscle. We suggest this response could play an important role in the pathophysiology of the profound vasomotor dysfunction observed in the peripheral circulation of patients with P. aeruginosa sepsis syndrome.


    ACKNOWLEDGEMENTS

This study was supported, in part, by National Institute of Dental Research (NIDR) Grant DE-10347 and by American Heart Association of Metropolitan Chicago Grant-in-Aid. I. Rubinstein is a recipient of NIDR Research Career Development Award DE-00386 and a University of Illinois Scholar Award.


    FOOTNOTES

Address for reprint requests and other correspondence: I. Rubinstein, Dept. of Medicine (M/C 787), Univ. of Illinois at Chicago, 840 South Wood St., Chicago, IL 60612-7323 (E-mail: IRubinst{at}uic.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.

Received 8 August 2000; accepted in final form 2 March 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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J APPL PHYSIOL 91(1):351-356
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