The long-range goal of the PI is to better understand the mechanisms that regulate the autonomic responses during exercise in normal subjects and in patients with heart failure (HF). It is known that sympathetic nervous system activity is increased with exercise in normal subjects and is increased in HF subjects at rest and in response to exercise. Heightened peripheral sympathetic nerve activity and the resultant increased neurovascular levels of norepinephrine (NE) evoke vasoconstriction. In this proposal, we will measure interstitial concentrations of NE with the microdialysis method. Interstitial concentrations of NE provide an outstanding index of NE concentrations at the neurovascular junction. The proposed experiments are based on recently published studies from our laboratory as well as pilot data that have been gathered over the past year. The first and second specific aims are to examine the mechanisms for the rise in interstitial NE (NEi) and adenosine triphosphate (ATPi) in exercising muscle. We will examine if enhanced NEi is due to: 1) activation of the sympathetic nerves; 2) an ATP mediated increase in NE release; and/or 3) an ATP mediated inhibition of neuronal re-uptake of NE (uptake 1). Our data suggests that ATPi concentrations in skeletal muscle rise with muscle contraction. We hypothesize that elevated ATP increases NEi by activation of P2X receptors on the sympathetic efferent nerves, and/or by inhibition of uptake 1. The third and fourth specific aims are to examine why NEi and ATPi are higher in skeletal muscle of rats with congestive heart failure (myocardial infarctions model). We will examine if higher levels of NEi in HF rats are due to: 1) an increase in NE release by sympathetic nerve; 2) an impairment of uptake 1; 3) an inhibition of uptake 1 by elevated ATP; or 4) to activation of sympathetic nerve terminal P2X receptors by ATP. The fifth specific aim is to determine if interstitial NE and ATP change as a function of time after the myocardial infarct that induces HF. These experiments will examine ATP and NE at rest, during muscle contraction, and during muscle stretch. A key feature of this proposal is that microdialysis techniques will be used to: 1) determine NEi and ATPi; and 2) deliver specific substances to the interstitial space. Our laboratory has substantial expertise with these methods. To the best of our knowledge, experiments such as these have never been performed in a HF model. Completion of these studies in this proposal will provide a systematic evaluation of circulatory regulation during exercise in an important cardiovascular disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075533-01A1
Application #
6820937
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Varghese, Jamie
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$285,236
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Xing, Jihong; Lu, Jian; Li, Jianhua (2009) Angiotensin II inhibits GABAergic synaptic transmission in dorsolateral periaqueductal gray neurons. Neurosci Lett 455:8-13
Xing, Jihong; Gao, Zhaohui; Lu, Jian et al. (2008) Femoral artery occlusion augments TRPV1-mediated sympathetic responsiveness. Am J Physiol Heart Circ Physiol 295:H1262-H1269
Xing, Jihong; Sinoway, Lawrence; Li, Jianhua (2008) Differential responses of sensory neurones innervating glycolytic and oxidative muscle to protons and capsaicin. J Physiol 586:3245-52
Gao, Zhaohui; Koba, Satoshi; Sinoway, Lawrence et al. (2008) 20-HETE increases renal sympathetic nerve activity via activation of chemically and mechanically sensitive muscle afferents. J Physiol 586:2581-91
Li, Jianhua; Gao, Zhaohui; Kehoe, Valerie et al. (2008) Interstitial adenosine triphosphate modulates muscle afferent nerve-mediated pressor reflex. Muscle Nerve 38:972-7
Xing, Jihong; Li, De-Pei; Li, Jianhua (2008) Role of GABA receptors in nitric oxide inhibition of dorsolateral periaqueductal gray neurons. Neuropharmacology 54:734-44

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