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

We seek to identify potential novel treatments and preventions of cardiovascular diseases by evaluating naturally occurring neuroprotective mechanisms in hibernating hamsters. In these animals, the nucleus tractus solitarius, an area of the brain that is critical for the moment-to- moment regulation of blood pressure, continues to regulate blood pressure and appropriately distribute blood flow to organs under conditions that would be life-threatening to humans. Our evaluation of suspected adaptive mechanisms related to neuronal excitability and the production of mitochondrial uncoupling proteins will reveal possible targets for developing novel drugs designed to protect the brain, including brainstem regions that regulate blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091763-02
Application #
7851352
Study Section
Special Emphasis Panel (ZRG1-CVS-B (50))
Program Officer
Wong, Renee P
Project Start
2009-09-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$368,889
Indirect Cost
Name
University of California Davis
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Sekizawa, Shin-Ichi; Horwitz, Barbara A; Horowitz, John M et al. (2013) Protection of signal processing at low temperature in baroreceptive neurons in the nucleus tractus solitarius of Syrian hamsters, a hibernating species. Am J Physiol Regul Integr Comp Physiol 305:R1153-62
Horwitz, Barbara A; Chau, Sat M; Hamilton, Jock S et al. (2013) Temporal relationships of blood pressure, heart rate, baroreflex function, and body temperature change over a hibernation bout in Syrian hamsters. Am J Physiol Regul Integr Comp Physiol 305:R759-68
Sekizawa, Shin-Ichi; Horowitz, John M; Horwitz, Barbara A et al. (2012) Realignment of signal processing within a sensory brainstem nucleus as brain temperature declines in the Syrian hamster, a hibernating species. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 198:267-82
Carey, Hannah V; Martin, Sandra L; Horwitz, Barbara A et al. (2012) Elucidating nature's solutions to heart, lung, and blood diseases and sleep disorders. Circ Res 110:915-21