Abstract

Neural mechanisms have been implicated in the generation of cardiac arrhythmias and also have the potential for triggering coronary vasospasm. The heart contains an elaborate neural network that includes sympathetic nerves, intrinsic cardiac ganglia and sensory nerves. This proposal is based on the recent discovery that sensory neurons can have efferent functions mediated by tachykinins (TKs) and calcitonin gene-related peptide (CGRP) that are released from their peripheral processes. The PI will evaluate the hypothesis that TKs have direct effects on coronary flow and affect the function of cardiac ganglia by stimulating postjunctional TK receptors on cholinergic neurons. The problem will be addressed at cellular, isolated organ and whole animal levels using the guinea pig. The PI will also test the hypothesis that local effects of the TKs and/or CGRP contribute to cardiac and coronary responses evoked by ischemia and reperfusion.
Six specific aims have been defined to address the hypotheses.
Aim 1. Use isolated hearts to identify the responses mediated by specific types of TK receptor and autoradiographic methods to localize and quantify these receptors.
Aim 2. Determine the importance of TK receptor types, nitric oxide, cholinergic neurons and noncholinergic mechanisms to responses evoked by SP and NKA in isolated hearts.
Aim 3. Identify and characterize responses to endogenous TKs in the isolated heart model.
Aim 4. Determine effects of exogenous and endogenous TKs on intracardiac neurons and intraganglionic transmission in vitro using microelectrode recording techniques.
Aim 5. Determine effects of exogenous and endogenous TKs on cholinergic neurons in cardiac ganglia in vivo.
Aim 6. Use selective TK and CGRP antagonists to identify cardiac and coronary effects of endogenous sensory neuropeptides in isolated hearts and anesthetized guinea pigs during ischemia and reperfusion. This line of investigation could ultimately establish sensory neuron peptide receptors as targets for therapy of specific cardiac arrhythmias and coronary vasospasm.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054633-02
Application #
2735264
Study Section
Special Emphasis Panel (ZRG4-PHRA (03))
Project Start
1997-07-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
East Tennessee State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Johnson City
State
TN
Country
United States
Zip Code
37614

  Publications

Hoover, Donald B; Tompkins, John D; Parsons, Rodney L (2009) Differential activation of guinea pig intrinsic cardiac neurons by the PAC1 agonists maxadilan and pituitary adenylate cyclase-activating polypeptide 27 (PACAP27). J Pharmacol Exp Ther 331:197-203
Hancock, John C; Hoover, Donald B (2008) Capsaicin-evoked bradycardia in anesthetized guinea pigs is mediated by endogenous tachykinins. Regul Pept 147:19-24
Tompkins, John D; Ardell, Jeffrey L; Hoover, Donald B et al. (2007) Neurally released pituitary adenylate cyclase-activating polypeptide enhances guinea pig intrinsic cardiac neurone excitability. J Physiol 582:87-93
Mabe, Abigail M; Hoard, Jennifer L; Duffourc, Michelle M et al. (2006) Localization of cholinergic innervation and neurturin receptors in adult mouse heart and expression of the neurturin gene. Cell Tissue Res 326:57-67
Parsons, Rodney L; Locknar, Sarah A; Young, Beth A et al. (2006) Presence and co-localization of vasoactive intestinal polypeptide with neuronal nitric oxide synthase in cells and nerve fibers within guinea pig intrinsic cardiac ganglia and cardiac tissue. Cell Tissue Res 323:197-209
Harrison, Theresa A; Perry, Kristi M; Hoover, Donald B (2005) Regional cardiac ganglia projections in the guinea pig heart studied by postmortem DiI tracing. Anat Rec A Discov Mol Cell Evol Biol 285:758-70
Zhang, Lili; Hancock, John C; Hoover, Donald B (2005) Tachykinin agonists modulate cholinergic neurotransmission at guinea-pig intracardiac Ganglia. J Pharmacol Sci 99:228-38
Chang, Yingzi; Lawson, Lisa J; Hancock, John C et al. (2005) Pituitary adenylate cyclase-activating polypeptide: localization and differential influence on isolated hearts from rats and guinea pigs. Regul Pept 129:139-46
Katori, Tatsuo; Hoover, Donald B; Ardell, Jeffrey L et al. (2005) Calcitonin gene-related peptide in vivo positive inotropy is attributable to regional sympatho-stimulation and is blunted in congestive heart failure. Circ Res 96:234-43
Harrison, Theresa A; Hoover, Donald B; King, Michael S (2004) Distinct regional distributions of NK1 and NK3 neurokinin receptor immunoreactivity in rat brainstem gustatory centers. Brain Res Bull 63:7-17

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