AJP - Heart Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 293: H1190-H1195, 2007. First published April 20, 2007; doi:10.1152/ajpheart.00231.2007
0363-6135/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/2/H1190    most recent
00231.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Xing, J.
Right arrow Articles by Li, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xing, J.
Right arrow Articles by Li, J.

Interstitial norepinephrine concentrations in skeletal muscle of ischemic heart failure

Jihong Xing, Satoshi Koba, Valerie Kehoe, Zhaohui Gao, Kristen Rice, Nicholas King, Lawrence Sinoway, and Jianhua Li

Penn State Heart and Vascular Institute, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania

Submitted 22 February 2007 ; accepted in final form 17 April 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
During exercise, sympathetic nerve responses are accentuated in heart failure (HF), and this enhances norepinephrine (NE) release and evokes vasoconstriction. Two key pathophysiological responses could contribute to the greater NE release: 1) increased sympathetic nerve discharge and 2) increased NE in the neurovascular junction for a given level of sympathetic discharge. In this report, we focus on the second of these two general issues and test the following hypotheses: 1) in HF for a given level of sympathetic nerve stimulation, NE concentration in the interstitium (an index of neurovascular NE) would be greater, and 2) the greater interstitial NE concentration would be linked to reduced NE uptake. Studies were performed in rats 8–10 wk after induction of myocardial infarction (MI). Interstitial NE samples were collected from microdialysis probes inserted into the hindlimb muscle. Dialysate concentration of NE was determined by the HPLC method. First, interstitial NE concentration increased during electrical stimulation of the lumbar sympathetic nerves in eight control rats. An increase in interstitial NE concentration was significantly greater in 10 rats with severe MI. Additionally, an NE uptake-1 inhibitor (desipramine, 1 µM) was injected into the arterial blood supply of the muscle in six control and eight MI rats. Desipramine increased interstitial NE concentration by 24% in control and by only 3% (P < 0.05 vs. control) in MI rats. In conclusion, given levels of electrical stimulation of the lumbar sympathetic nerve lead to higher interstitial NE concentration in HF. This effect is due, in part, to reduced NE uptake-1 in HF.

nervous system; sympathetic; exercise; blood flow

THE CAUSES OF EXERCISE LIMITATION in heart failure (HF) are poorly understood. However, it appears that reduced blood flow to active muscle may contribute to this response (14, 23, 29, 30). The causes of blood flow limitation may be due more to exaggerated sympathetic activation than to reductions in the intrinsic ability of the peripheral vasculature to dilate (23, 24). When the sympathetic nervous system is engaged, norepinephrine (NE) is released from the neurovascular junction, evoking vasoconstriction within a given vascular bed (15, 22). However, the determinants of the neurovascular concentrations of NE in skeletal muscle during exercise in congestive HF have received little attention. In this investigation, we utilized the microdialysis method to measure interstitial NE concentration in the hindlimb muscle after electrical stimulation of the lumbar sympathetic nerve in rats with myocardial infarction (MI) and in control animals. Interstitial NE was used as a surrogate of neurovascular NE. We hypothesized that interstitial NE concentration for a given level of electrical stimulation of the sympathetic nerves would be augmented in HF.

Furthermore, since NE uptake-1 represents the major pathway by which released NE is metabolized and interstitial NE concentration is regulated (11), we hypothesized that NE uptake-1 would be impaired in the skeletal muscle of MI rats. To test this hypothesis, an NE uptake-1 inhibitor, desipramine, was infused into the arterial blood supply of the hindlimb muscle in rats with MI and in control animals.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
All procedures were approved by the Animal Care Committee of this institution.

Coronary Artery Ligation

Male Sprague-Dawley rats (150–180 g body wt) were anesthetized by inhalation of isoflurane-oxygen (2–5% isoflurane in 100% oxygen), intubated, and artificially ventilated. A left thoracotomy between the fourth and fifth ribs exposed the left ventricular (LV) wall. The left coronary artery was ligated. Experiments were performed 8–10 wk after coronary artery ligation. Age- and body weight-matched rats that did not undergo the surgery served as controls.

A transthoracic echocardiogram was performed 1–2 wk before the experiments. The rats were anesthetized by inhalation of isoflurane-oxygen. The transducer was positioned on the left anterior chest, and LV dimensions were measured (Table 1). The fractional shortening (FS) was determined by echocardiographic measurements. On the basis of FS data, the animals were considered control with FS > 40% (n = 14), mild HF with 30% < FS < 40% (n = 6), and severe HF with FS < 30% (n = 18).


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

  		Table 1. General and echocardiographic measurements

 
Experimental Preparation

The rats were anesthetized by inhalation of isoflurane-oxygen. An endotracheal tube was inserted into the trachea and attached to a ventilator. Polyethylene catheters were inserted into the common carotid artery and external jugular vein for measurement of arterial blood pressure and for drug administration, respectively. The lumbar sympathetic trunk at L3–L5 was carefully dissected from other connective tissues. A piece of laboratory film was placed under the isolated nerves. A bipolar electrode was then placed between the nerves and the film to deliver electrical stimulation and embedded in a silicone gel. Once the gel hardened, silicone rubber was fixed to the surrounding tissue with a glue containing {alpha}-cyanoacrylate. Lumbar sympathetic nerve activity at L3–L5 mainly reflects the component of nerve activity that regulates the vasculatures of the hindlimb muscles (9). The femoral artery and arterial collaterals were isolated. A catheter was inserted into the popliteal artery through the femoral artery for the injection of drugs into the arterial blood supply of the hindlimb muscles. The animals were ventilated, and tidal CO2 was monitored and maintained within normal ranges, as previously described (16, 17). Body temperature was maintained at 37.5–38.5°C by a heating pad and external heat lamps, and fluid balance was stabilized by a continuous infusion of saline.

Decerebration was performed as previously described (9, 16, 17). Once this procedure was completed, anesthesia was removed from the inhaled mixture. The triceps surae muscle was isolated, and the calcaneal bone of the hindlimb was cut. The Achilles tendon was connected to a force transducer for monitoring muscle tension during experiments. The pelvis was stabilized in a spinal unit, and the knee joints were secured by clamping the patellar tendon to a spinal unit.

Microdialysis

The skin directly over the triceps surae muscles of both legs was dissected away, and four microdialysis probes were inserted into the muscle of each leg. Briefly, the probes were inserted into the muscle via a cannula in the direction parallel to muscle fiber orientation. After insertion, the microdialysis probes were attached to a perfusion pump and perfused at a rate of 2.5 µl/min with Ringer solution.

The semipermeable fibers with a molecular weight cutoff of 30,000 (0.20 mm ID, 0.22 mm OD; Spectrum Laboratories, Laguna, CA) were used to construct the microdialysis probes. Each end of a single fiber was inserted ~1 cm into a hollow polyamide tube (0.25 mm ID, 0.36 mm OD) and glued. The length of the probe fibers was 2.0 cm. The dialysate was collected in 250-µl microcentrifuge tubes and immediately sealed (to prevent evaporation) and stored at –80°C.

The concentrations of dialysate NE in each of the dialysis probes were measured using HPLC methods. Because the dialysate samples were ultraclean, purification was not required before analysis.

Experimental Protocols

After the microdialysis probes were inserted, a 60-min equilibration period was allowed. During this period, resting dialysate samples were collected every 20 min. The experimental intervention was then performed. Samples were collected during each 10-min intervention. A 60-min rest period was allowed between each intervention. Dialysate was collected before, during, and after each intervention. Baseline muscle tension was adjusted to and maintained at 0.1 kg during experiments to minimize the difference in the tension-induced NE response among experimental groups (16).

Study 1: electrical stimulation of lumbar sympathetic nerves in large-MI, small-MI, and control rats. After control data were collected from large-MI (n = 10), small-MI (n = 6), and control (n = 8) rats, the lumbar sympathetic nerve was electrically stimulated at 1, 2, and 4 Hz (2.5 V). Each level of stimulation was sustained for 10 min, and experimental data were collected for 20 min after stimulation was completed.

Study 2: arterial injection of desipramine in large-MI and control rats. Because there was no difference in interstitial NE during sympathetic nerve stimulation between control and small-MI rats, we collected experimental data from control (n = 6) and large-MI (n = 8) rats. After control data were obtained, 0.001, 0.01, 0.1, and 1.0 µM desipramine (dissolved in Ringer solution and obtained from Sigma Chemical) was infused into the blood supply of the hindlimb muscles. Recovery data were collected for 20 min after desipramine infusion. The total volume of infused solution containing desipramine was 0.1 ml, and the duration of each infusion was 2 min.

Examination of LV End-Diastolic Pressure

On completion of each experiment, a 2-Fr micro-Millar pressure transducer catheter (Millar Instruments) was inserted into the right carotid artery and threaded into the LV for measurement of LV end-diastolic pressure (EDP).

Data Acquisition and Analyses

Mean arterial pressure (MAP) and basal muscle tension were recorded on a personal computer that used PowerLab software. Control values were determined by analysis of ≥30 s of the data immediately before the interventions. The peak change of each variable was determined by the peak response from control.

Experimental data were analyzed with one-way repeated-measures ANOVA. Tukey's post hoc analyses were utilized to determine differences between groups, as appropriate. A linear regression analysis was used to show a relationship between NE rise induced by the sympathetic stimulation and FS. Values are means ± SE. For all analyses, differences were considered significant at P < 0.05. All statistical analyses were performed using SPSS for Windows (version 13.0).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Interstitial NE stabilized 40 min after probe insertion, as previously reported (16). There were no significant differences in baseline values for muscle interstitial NE before the experiment in the control leg and in the experimental leg among healthy control (n = 14), and small-MI (n = 6), and large-MI (n = 18) rats.

NE Responses to Electrical Stimulation of Lumbar Sympathetic Nerves

Basal values for dialysate NE and responses to electrical stimulation of the lumbar sympathetic nerves in both legs of control, small-MI, and large-MI rats are shown in Table 2. Activation of the sympathetic nervous system raised muscle interstitial NE concentration in the stimulated leg, but not in the control leg. This suggests that the elevated interstitial NE concentration was not due to a systemic activation of the autonomic nervous system. Interstitial NE concentration rose as a fraction of stimulus frequency. Importantly, the rise in interstitial NE for a given level of stimulation was greater in large-MI rats than in small-MI and control rats (Fig. 1). Moreover, the magnitude of the NE response was linearly linked to the FS (Fig. 2). FS is a measurement of LV function. Baseline values for MAP before 1-, 2-, and 4-Hz stimulation and the peak response evoked by lumbar stimulations are shown in Table 3.


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

  		Table 2. Interstitial NE concentration before, during, and after electrical stimulation of lumbar sympathetic nerves in experimental and control legs

 

Figure 1
View larger version (15K):
[in this window]
[in a new window]

  		Fig. 1. Percent increases of interstitial norepinephrine (NE) concentration during electrical stimulation of lumbar sympathetic nerves in stimulated leg in control rats (n = 8) and rats with small (n = 6) and large (n = 10) myocardial infarction (MI). Interstitial NE was elevated with stimulation frequencies. Stimulation-induced rise in interstitial NE was greater in large-MI than in small-MI and control rats. *P < 0.05 vs. control. {dagger}P < 0.05 vs. control and small-MI. #P < 0.05 vs. 1 Hz.

 

Figure 2
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 2. Regression analysis showing an inverse linear relationship between NE rise induced by the sympathetic stimulation and fractional shortening, an index of left ventricular function.

 

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

  		Table 3. Baseline MAP and peak responses induced by each stimulation and during desipramine infusion

 
Effect of NE Uptake-1 Pathway on Interstitial NE Concentration

Figure 3 shows the effect of inhibition of NE uptake-1 on the interstitial NE response of both lower limbs of control and large-MI rats. Desipramine (0.001–1.0 µM) injected into the blood supply of the hindlimb muscles increased interstitial NE concentration in a dose-related fashion in the ipsilateral leg (Fig. 3), but not in the contralateral control lower limb. In control animals, 0.001, 0.01, 0.1, and 1.0 µM desipramine increased interstitial NE by 1.06 ± 2.89, 1.17 ± 1.67, 0.48 ± 2.75, and 1.01 ± 2.56% in control muscle and 1.67 ± 2.71, 7.76 ± 3.62, 9.87 ± 2.83, and 23.32 ± 3.91% (P < 0.05 vs. control muscle) in injected muscle, respectively. This suggests that the effect of desipramine was localized to the infused limb. The desipramine-induced increase in interstitial NE was less in MI than in healthy control rats (Fig. 3). Desipramine at 1.0 µM elevated interstitial NE concentration by 24% in controls and by only 3% in MI animals (P < 0.05 vs. controls). Blood pressure was unchanged by the desipramine infusions. MAP before and after desipramine infusion is shown in Table 3.


Figure 3
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 3. Increases of interstitial NE during perfusion of desipramine, an inhibitor of NE uptake-1, into muscles in healthy control (n = 6) and large-MI (n = 8) rats. Increase in interstitial NE was smaller in large-MI than in control rats. *P < 0.05 vs. control.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
A known hallmark of HF is increased sympathetic nerve activity. This induces abnormal cardiovascular regulation during exercise, including low cardiac outputs for a given level of physical exertion, as well as elevated sympathetic tones to maintain adequate blood pressure (13). Specifically, renal vasoconstriction is enhanced, and the rise in active muscle blood flow is attenuated (18, 19, 23). The reduced blood supply to the kidney leads to excessive stimulation of renin secretion and inappropriate salt and water retention (1), whereas the reduced skeletal muscle blood flow is an important contributor to exercise intolerance in the patients (28). NE is released from the neurovascular junction and evokes vasoconstriction within a given vascular bed as the sympathetic nervous system is activated (15, 22).

The results from the present study suggest that impairments in NE uptake-1 contribute importantly to interstitial NE, especially during heightened sympathoexcitation, as would be seen with physiological stress. This impairment in metabolism in HF was local. The greater rise in NE with sympathetic stimulation in HF was largely due to an impairment in NE uptake-1, since the increase in interstitial NE concentration induced by infusion of a given dose of desipramine into the arterial supply of the skeletal muscles was less in HF rats than in control animals. Interestingly, the magnitude of the rise in interstitial NE was linked to the magnitude of LV impairment. Thus we speculate that the impairment of peripheral sympathetic nerve NE uptake-1 in HF is somehow linked to the severity of LV function impairment. Furthermore, we believe that this effect, coupled with the high sympathetic tone during exercise, contributes to the heightened sympathetic vasoconstriction and blood flow limitation to skeletal muscle in HF (24). This decline in skeletal muscle blood flow likely contributes to the reduced exercise capacity in HF (14, 23, 29, 30).

Sympathetic nerve stimulation leads to the release of the vesicular contents into the synapse. The released NE can then bind to postsynaptic receptors, evoking physiological responses. NE can be 1) taken up by a variety of tissues in a "low-affinity" process termed NE uptake-2, 2) released into the circulation, a process termed spillover, and 3) taken up by the neuron in a sequestration process (NE uptake-1) (5, 7). NE uptake-1 represents the major pathway by which locally released NE is metabolized (11). NE spillover has been used as an index of NE release. However, this method has a number of limitations (2, 4, 10, 20). In this study, we have utilized microdialysis methods to measure dialysate concentrations of NE. Interstitial NE is thought to more closely reflect the NE concentration at the neurovascular junction than plasma NE or indexes of NE spillover (8).

Because collection of plasma NE samples could significantly affect baseline blood pressure and reduce blood volume in rats, we did not determine the concentrations of plasma NE together with muscle interstitial NE in the present experiment. However, previous studies have shown that, with elevated sympathetic nerve activity, plasma NE is increased (15), and the response parallels muscle interstitial NE (8). Those data suggest that NE responses may also occur in other organs in addition to active muscle.

Electrical stimulation of the lumbar sympathetic nerves has been reported to increase blood pressure (6, 26). To minimize the effect of arterial baroreflex activation on interstitial NE responses, a 2.5-V electrical stimulation was applied on the lumbar sympathetic nerves in the present experiment. An increase in MAP with such stimulation was small, and there was no difference in the MAP response between large-MI animals and controls. This suggests that application of a stimulus of this intensity to the sympathetic nerves can increase the interstitial NE response but may be insufficient to significantly augment the blood pressure response in MI rats. Additionally, impaired cardiac output should be considered to affect the blood pressure response induced by the sympathetic nerve stimulation in HF in this experiment. Because there was no difference in the blood pressure response, the rise in interstitial NE was unlikely due to activation of the arterial baroreflex.

It is possible that increased interstitial NE concentration could have caused vasoconstriction and led to a reduction in blood flow. This action attenuates the clearance of metabolites from the interstitium and contributes to accumulation of interstitial NE. Prior reports suggest that NE concentrations in active muscle are not affected by blood flow (3, 12). In addition, a reduction in blood flow can increase the concentrations of metabolic vasodilators. For instance, vasodilators released by contracting skeletal muscle cells and/or red blood cells stimulate endothelial cell pathways and induce the hyperpolarization of vascular smooth muscle (21, 25, 27). The vasodilation caused by such nonneural mechanisms can counter the sympathetic vasoconstriction effects of NE in active muscles. These peripheral blood flow responses are necessary to maintain adequate blood pressure, as well as to ensure that muscle blood supply and metabolic demand can be matched.

In conclusion, these data demonstrate that the interstitial NE response to sympathetic nerve activation is augmented in MI animals compared with a healthy control group. Reduced NE uptake-1 may play an important role in determining NE concentration in muscle sympathetic nerve terminals. These results suggest that this mechanism contributes to the exaggerated NE level at the neurovascular junction in HF, which, in turn, may alter muscle blood flow and exercise capacity in HF.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Heart, Lung, and Blood Institute Grants R01 HL-075533 (J. Li), R01 HL-078866 (J. Li), and R01 HL-060800 (L. Sinoway).


   ACKNOWLEDGMENTS
 
The authors thank Jennie Stoner for outstanding secretarial assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Li, Heart and Vascular Institute and Dept. of Medicine, H047, Pennsylvania State Univ. College of Medicine, Milton S. Hershey Medical Center, 500 Univ. Dr., Hershey, PA 17033 (e-mail: jzl10{at}psu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Dargie H. Sympathetic activity and regional blood flow in heart failure. Eur Heart J Suppl A: 39–43, 1990.
  2. Davis D, Sinoway LI, Robison J, Minotti JR, Day FP, Baily R, Zelis R. Norepinephrine kinetics during orthostatic stress in congestive heart failure. Circ Res 61: I87–I90, 1987.[Medline]
  3. Dela F, Stallknecht B, Biering-Sorensen F. An intact central nervous system is not necessary for insulin-mediated increases in leg blood flow in humans. Pflügers Arch 441: 241–250, 2000.[CrossRef][Web of Science][Medline]
  4. Eisenhofer G, Friberg P, Rundqvist B, Quyyumi AA, Lambert G, Kaye DM, Kopen IJ, Goldstein DS, Esler MD. Cardiac sympathetic nerve function in congestive heart failure. Circulation 93: 1667–1676, 1996.[Abstract/Free Full Text]
  5. Hoffman BB, Lefkowitz RL, Taylor P. Neurotransmission: the autonomic and somatic motor nervous systems. In: Goodman & Gilman's The Pharmacological Basis of Therapeutics (9th ed.), edited by Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG. New York: McGraw Hill, 1996, sect. II, chapt. 6, p. 105–139.
  6. Johnson CD, Coney AM, Marshall JM. Roles of norepinephrine and ATP in sympathetically evoked vasoconstriction in rat tail and hindlimb in vivo. Am J Physiol Heart Circ Physiol 281: H2432–H2440, 2001.[Abstract/Free Full Text]
  7. Katzung BG. Introduction to autonomic pharmacology. In: Basic & Clinical Pharmacology, edited by Katzung BG. Stamford, CT: Appleton & Lange, 1998, chapt. 6, p. 73–89.
  8. Khan MH, Sinoway LI, MacLean DA. Effects of graded LBNP on MSNA and interstitial norepinephrine. Am J Physiol Heart Circ Physiol 283: H2038–H2044, 2002.[Abstract/Free Full Text]
  9. Koba S, Gao Z, Xing J, Sinoway LI, Li J. Sympathetic responses to exercise in myocardial infarction rats: a role of central command. Am J Physiol Heart Circ Physiol 291: H2735–H2742, 2006.[Abstract/Free Full Text]
  10. Kopin IJ, Rundqvist B, Friberg P, Lenders J, Goldstein DS, Eisenhofer G. Different relationships of spillover to release of norepinephrine in human heart, kidneys, and forearm. Am J Physiol Regul Integr Comp Physiol 275: R165–R173, 1998.[Abstract/Free Full Text]
  11. Lameris TW, van Den Meiracker AH, Boomsma F, Alberts G, de Zeeuw S, Duncker DJ, Verdouw PD, Veld AJ. Catecholamine handling in the porcine heart: a microdialysis approach. Am J Physiol Heart Circ Physiol 277: H1562–H1569, 1999.[Abstract/Free Full Text]
  12. Lavoie JL, Trudeau F, Beliveau L. Effect of blood flow and muscle contraction on noradrenaline spillover in the canine gracilis muscle. Can J Physiol Pharmacol 78: 75–80, 2000.[CrossRef][Web of Science][Medline]
  13. Leimbach WN Jr, Wallin BG, Victor RG, Aylward PE, Sundlöf G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 73: 913–919, 1986.[Abstract/Free Full Text]
  14. LeJemtel TH, Maskin CS, Lucido D, Chadwick BJ. Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation 74: 245–251, 1986.[Abstract/Free Full Text]
  15. Leuenberger U, Sinoway L, Gubin S, Gaul L, Davis D, Zelis R. Effects of exercise intensity and duration on norepinephrine spillover and clearance in humans. J Appl Physiol 75: 668–674, 1993.[Abstract/Free Full Text]
  16. Li J, King N, Sinoway L. Interstitial ATP and norepinephrine concentrations in active muscle. Circulation 111: 2748–2751, 2005.[Abstract/Free Full Text]
  17. Li J, Sinoway A, Gao Z, Maile M, Pu M, Sinoway L. Muscle mechanoreflex and metaboreflex responses after myocardial infarction in rats. Circulation 110: 3049–3054, 2004.[Abstract/Free Full Text]
  18. Middlekauff HR, Nitzsche EU, Hoh CK, Hamilton MA, Fonarow GC, Hage A, Moriguchi JD. Exaggerated renal vasoconstriction during exercise in heart failure patients. Circulation 101: 784–789, 2000.[Abstract/Free Full Text]
  19. Momen A, Bower D, Boehmer J, Kunselman AR, Leuenberger UA, Sinoway LI. Renal blood flow in heart failure patients during exercise. Am J Physiol Heart Circ Physiol 287: H2834–H2839, 2004.[Abstract/Free Full Text]
  20. Paton DM. Characteristics of uptake of noradrenaline by adrenergic neurons. In: The Mechanism of Neuronal and Extraneuronal Transport of Catecholamines, edited by Paton DM. New York: Raven, 1976, p. 49–66.
  21. Rosenmeier JB, Hansen J, Gonzalez-Alonso J. Circulating ATP-induced vasodilatation overrides sympathetic vasoconstrictor activity in human skeletal muscle. J Physiol 558: 351–365, 2004.[Abstract/Free Full Text]
  22. Savard GK, Richter EA, Strange S, Kiens B, Christensen NJ, Saltin B. Norepinephrine spillover from skeletal muscle during exercise in humans: role of muscle mass. Am J Physiol Heart Circ Physiol 257: H1812–H1818, 1989.[Abstract/Free Full Text]
  23. Shoemaker JK, Naylor HL, Hogeman CS, Sinoway LI. Blood flow dynamics in heart failure. Circulation 99: 3002–3008, 1999.[Abstract/Free Full Text]
  24. Silber DH, Sutliff G, Yang QX, Smith MB, Sinoway LI, Leuenberger UA. Altered mechanisms of sympathetic activation during rhythmic forearm exercise in heart failure. J Appl Physiol 84: 1551–1559, 1998.[Abstract/Free Full Text]
  25. Thomas GD, Victor RG. Nitric oxide mediates contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle. J Physiol 506: 817–826, 1998.[Abstract/Free Full Text]
  26. Thomas GD, Zhang W, Victor RG. Impaired modulation of sympathetic vasoconstriction in contracting skeletal muscle of rats with chronic myocardial infarctions: role of oxidative stress. Circ Res 88: 816–823, 2001.[Abstract/Free Full Text]
  27. VanTeeffelen JW, Segal SS. Rapid dilation of arterioles with single contraction of hamster skeletal muscle. Am J Physiol Heart Circ Physiol 290: H119–H127, 2006.[Abstract/Free Full Text]
  28. Wilson JR, Mancini DM. Factors contributing to the exercise limitation of heart failure. J Am Coll Cardiol 22: 93A–98A, 1993.[Medline]
  29. Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 69: 1079–1087, 1984.[Abstract/Free Full Text]
  30. Zelis R, Longhurst J, Capone RJ, Mason DT. A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 50: 137–143, 1974.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
S. Koba, J. Xing, L. I. Sinoway, and J. Li
Sympathetic nerve responses to muscle contraction and stretch in ischemic heart failure
Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H311 - H321.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/2/H1190    most recent
00231.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Xing, J.
Right arrow Articles by Li, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xing, J.
Right arrow Articles by Li, J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.