In the US, congestive heart failure (HF) is a common and lethal disease with 500,000 patients being diagnosed, and with ~300,000 deaths each year. Sympathoexcitation plays a prominent role in disease progression. It is known that sympathoexcitation is inversely related to disease prognosis. Sympathetic nervous activity (SNA) is increased with exercise in normal subjects and is increased in HF patients at rest and in response to exercise. These exaggerated SNA responses are well correlated with morbidity and mortality in HF patients. The long-term goals of the PI are to better understand the mechanisms that regulate the autonomic nervous system during exercise in HF. The mechano- and metabo-sensitive muscle afferents contribute to regulation of SNA in HF. The receptors that stimulate those muscle afferents have yet to be precisely identified and characterized. Over the last several years our research efforts have focused on the roles played by purinergic P2X receptors, capsaicin receptors (TRPV1) and acid sensing ion channels in evoking abnormal SNA responses to muscle contraction in HF. The data indicate that abnormalities in those receptors in primary afferent neurons may initiate the development of an exaggerated muscle reflex in HF. While our laboratory and others have collected substantial evidence showing alternations in muscle afferent-mediated response in this disease, little is known regarding the underlying receptor mechanisms of primary afferent neurons. Prostaglandins and adenosine are important by-products in active muscles and engaged in the abnormal reflex response in HF.
Specific Aim #1 of this proposal is to examine contributions of prostaglandin to exaggerated muscle reflex in HF. We hypothesize that prostaglandins facilitate responses of P2X receptors in the dorsal root ganglion (DRG) neurons of HF rats.
Specific Aim #2 of this proposal is to determine contributions of adenosine to blunted muscle metaboreflex in HF. We hypothesize that adenosine inhibits TRPV1 responses of DRG neurons to a greater degree in HF as compared with controls. The proposed experiments are based on recently published work from our laboratory as well as pilot data that have been gathered and will be performed on dissociated DRG cells using whole cell patch-clamp methods. Completion of these studies will provide an evaluation of muscle afferent-mediated circulatory responses in HF patients at the cellular level. These studies will lay the groundwork for future experiments to examine novel therapeutics to treat exercise intolerance in this disease.

Public Health Relevance

Congestive heart failure is a common and lethal disease in the U.S. The proposed studies in this grant are to examine the role of primary muscle afferent neurons in mediating abnormal sympathetic nerve responses in heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090720-02
Application #
7851305
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Lathrop, David A
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$387,750
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
Xing, Jihong; Li, Jianhua (2017) TRPA1 Function in Skeletal Muscle Sensory Neurons Following Femoral Artery Occlusion. Cell Physiol Biochem 42:2307-2317
Xing, Jihong; Li, Jianhua (2017) Proteinase-Activated Receptor-2 Sensitivity of Amplified TRPA1 Activity in Skeletal Muscle Afferent Nerves and Exercise Pressor Reflex in Rats with Femoral Artery Occlusion. Cell Physiol Biochem 44:163-171
Xing, Jihong; Li, Jianhua (2016) The Role Played by Adenosine in Modulating Reflex Sympathetic and Pressor Responses Evoked by Stimulation of TRPV1 in Muscle Afferents. Cell Physiol Biochem 40:39-48
Xing, Jihong; Li, Jianhua (2016) Bradykinin Contributes to Sympathetic and Pressor Responses Evoked by Activation of Skeletal Muscle Afferents P2X in Heart Failure. Cell Physiol Biochem 39:2101-2109
Xing, Jihong; Lu, Jian; Li, Jianhua (2015) ASIC3 contributes to the blunted muscle metaboreflex in heart failure. Med Sci Sports Exerc 47:257-63
Xing, Jihong; Lu, Jian; Li, Jianhua (2014) Role of angiotensin-(1-7) and Mas-R-nNOS pathways in amplified neuronal activity of dorsolateral periaqueductal gray after chronic heart failure. Neurosci Lett 563:6-11
Li, Jianhua; Xing, Jihong; Lu, Jian (2014) Nerve Growth Factor, Muscle Afferent Receptors and Autonomic Responsiveness with Femoral Artery Occlusion. J Mod Physiol Res 1:1-18
Gao, Wei; Li, Jianhua (2013) Femoral Artery Occlusion Increases Muscle Pressor Reflex and Expression of Hypoxia-Inducible Factor-1? in Sensory Neurons. J Cardiovasc Dis 1:34-40
Xing, Jihong; Lu, Jian; Li, Jianhua (2013) Augmented P2X response and immunolabeling in dorsal root ganglion neurons innervating skeletal muscle following femoral artery occlusion. J Neurophysiol 109:2161-8
Lu, Jian; Xing, Jihong; Li, Jianhua (2013) Bradykinin B2 receptor contributes to the exaggerated muscle mechanoreflex in rats with femoral artery occlusion. Am J Physiol Heart Circ Physiol 304:H1166-74

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