Both inhibitory (vagal afferent) and excitatory (sympathetic or spinal afferent) reflexes are manifested during myocardial ischemia and reperfusion. Cardiac sympathetic afferent stimulation leads to symptoms of angina pectoris and potentially life threatening hemodynamic adjustments, including hypertension and arrhythmias that can exacerbate ischemia and infarction. During the last four cycles of this grant we have identified a number of chemical mediators released during ischemia that play an important role in activating ischemically sensitive cardiac spinal nerve endings to evoke reflex hypertension. These include bradykinin (BK), reactive oxygen species, protons, cyclooxygenase metabolites, serotonin (5HT), histamine, and most recently thromboxane A2 and endothelin. In the last funding cycle we observed that thromboxane and endothelin activate cardiac afferents during myocardial ischemia and reflexly elevates blood pressure. However, it is clear that other mediators signal these nerve endings since inhibition of the action or synthesis of a metabolite does not fully eliminate afferent activation during ischemia. In addition, we have identified roles for glutamate and nitric oxide in the rostral ventral lateral medulla (rVLM), which processes cardiac spinal afferent information, and, in turn, regulate sympathetic outflow. The current proposal further examines interactions between previously identified and new chemical mediators, including adenosine 5'- triphosphate (ATP) and opioids during myocardial ischemia, which act independently and interactively with other mediators to stimulate ventricular nerve endings. Thus, we have begun to investigate mechanisms of inhibitory chemical mediators in the heart that appear to modulate cardiac sympathetic afferent excitability during ischemia. With respect to central neural processing we are capitalizing on our previous observation that the external lateral parabrachial nucleus (elPBN) is activated by cardiac sympathetic afferent stimulation, to evaluate its role in processing input from the heart. This grant proposal thus proposes five sets of hypotheses designed to extend our past and preliminary studies of mechanisms of activation of cardiac afferents by 1) ATP, 2) opioid system, 3) interactions between excitatory and inhibitory peripheral chemical signals;and CNS processing of the cardiac afferents involving 4) excitation by glutamate and modulation by GABA through GABAB and GABAA receptors in elPBN neurons and 5) their projections to the rVLM. We will use combined whole animal reflex, cellular electrophysiological, microdialysis/HPLC measurement and pharmacological approaches in the proposed investigations. Additional knowledge derived from these studies will allow a better understanding of the mechanisms underlying the genesis of angina pectoris and reflex activation of the cardiovascular system during myocardial ischemia and reperfusion.

Public Health Relevance

Myocardial ischemia is associated with both chest pain and cardiovascular reflex responses originating from the heart. Cardiac afferents stimulation during myocardial ischemia can lead to morbidity and mortality. Ischemia and reperfusion of the heart produce many mediators that may activate sympathetic afferent endings resulting in an increase in blood pressure. Regions in the brain are responsible for the integration of input from the heart. The current application will provide important new information on both mediators and mechanism of action in the brain during myocardial ischemia and its elevated blood pressure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Lathrop, David A
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University of California Irvine
Internal Medicine/Medicine
Schools of Medicine
United States
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Fu, Liang-Wu; Longhurst, John C (2013) Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia. Am J Physiol Heart Circ Physiol 305:H76-85
Fu, Liang-Wu; Guo, Zhi-Ling; Longhurst, John C (2012) Ionotropic glutamate receptors in the external lateral parabrachial nucleus participate in processing cardiac sympathoexcitatory reflexes. Am J Physiol Heart Circ Physiol 302:H1444-53
Fu, Liang-Wu; Guo, Zhi-Ling; Longhurst, John C (2010) Endogenous endothelin stimulates cardiac sympathetic afferents during ischaemia. J Physiol 588:2473-86
Fu, Liang-Wu; Longhurst, John C (2010) Bradykinin and thromboxane A2 reciprocally interact to synergistically stimulate cardiac spinal afferents during myocardial ischemia. Am J Physiol Heart Circ Physiol 298:H235-44
Fu, Liang-Wu; Longhurst, John C (2010) A new function for ATP: activating cardiac sympathetic afferents during myocardial ischemia. Am J Physiol Heart Circ Physiol 299:H1762-71
Guo, Zhi-Ling; Tjen-A-Looi, Stephanie C; Fu, Liang-Wu et al. (2009) Nitric oxide in rostral ventrolateral medulla regulates cardiac-sympathetic reflexes: role of synthase isoforms. Am J Physiol Heart Circ Physiol 297:H1478-86
Fu, Liang-Wu; Longhurst, John C (2009) Regulation of cardiac afferent excitability in ischemia. Handb Exp Pharmacol :185-225
Fu, Liang-Wu; Guo, Zhi-Ling; Longhurst, John C (2008) Undiscovered role of endogenous thromboxane A2 in activation of cardiac sympathetic afferents during ischaemia. J Physiol 586:3287-300
Fu, Liang-Wu; Phan, Andrew; Longhurst, John C (2008) Myocardial ischemia-mediated excitatory reflexes: a new function for thromboxane A2? Am J Physiol Heart Circ Physiol 295:H2530-40
Guo, Zhi-Ling; Longhurst, John C (2007) Expression of c-Fos in arcuate nucleus induced by electroacupuncture: relations to neurons containing opioids and glutamate. Brain Res 1166:65-76

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