: Patients with myocardial ischemia typically experience angina pectoris. Activation of cardiac sympathetic afferents during ischemia is responsible for conveying cardiac nociception and initiating cardiovascular reflexes, which lead to hemodynamic alterations and arrhythmias. However, the mechanisms of activation of cardiac nociceptors are not fully understood. Endothelin-l (ET-1) and cyclooxygenase-2 products are produced early during myocardial ischemia. but their contributions to activation of cardiac nociceptors during ischemia remain uncertain. Therefore, we propose to test the following novel hypotheses: 1. Myocardial interstitial prostaglandins are increased during ischemia due to stimulation of the cyclooxygenase-2 pathway, which plays a significant role in activation of cardiac sympathetic afferents during ischemia. 2. Production of ET-1 in myocardial interstitium is increased during ischemia; an increased cardiac interstitial ET- 1 level elicits generation of prostaglandins through cyclooxygenase-2. 3. ET- 1 selectively stimulates ischemically sensitive cardiac afferents through activation of ETA, but not ETB, receptors; the stimulating effect of ET-l on ischemically sensitive cardiac afferents is mediated by prostaglandins due to activation of cyclooxygenase-2. 4. Endogenously produced ET- 1 during myocardial ischemia contributes to ischemic stimulation of cardiac sympathetic afferents. The techniques of cardiac microdialysis and single-unit recording of cardiac sympathetic afferents will be used to explore the mechanisms of generation of prostaglandins and ET-1 during myocardial ischemia, and to study the role of ET-1 and cyclooxygenase-2 in ischemic stimulation of cardiac sympathetic afferents. These studies are important prerequisites for the understanding of the pathophysiological role of ET-1 and prostaglandins in activation of cardiac nociceptors and elaborating the perception of chest pain in patients with myocardial ischemia. Such information could also suggest alternate interventions designed to treat intractable angina pectoris and to limit potentially detrimental cardiovascular reflexes in patients with coronary artery disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Lathrop, David A
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Pennsylvania State University
Schools of Medicine
United States
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Li, De-Pei; Chen, Shao-Rui; Pan, Hui-Lin (2010) Adenosine inhibits paraventricular pre-sympathetic neurons through ATP-dependent potassium channels. J Neurochem 113:530-42
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Chen, Qian; Pan, Hui-Lin (2007) Signaling mechanisms of angiotensin II-induced attenuation of GABAergic input to hypothalamic presympathetic neurons. J Neurophysiol 97:3279-87
Zahner, Matthew R; Li, De-Pei; Pan, Hui-Lin (2007) Benzodiazepine inhibits hypothalamic presympathetic neurons by potentiation of GABAergic synaptic input. Neuropharmacology 52:467-75
Li, De-Pei; Pan, Hui-Lin (2007) Glutamatergic inputs in the hypothalamic paraventricular nucleus maintain sympathetic vasomotor tone in hypertension. Hypertension 49:916-25
Yang, Q; Chen, S-R; Li, D-P et al. (2007) Kv1.1/1.2 channels are downstream effectors of nitric oxide on synaptic GABA release to preautonomic neurons in the paraventricular nucleus. Neuroscience 149:315-27
Li, De-Pei; Pan, Hui-Lin (2007) Role of gamma-aminobutyric acid (GABA)A and GABAB receptors in paraventricular nucleus in control of sympathetic vasomotor tone in hypertension. J Pharmacol Exp Ther 320:615-26
Wu, Zi-Zhen; Pan, Hui-Lin (2007) Role of TRPV1 and intracellular Ca2+ in excitation of cardiac sensory neurons by bradykinin. Am J Physiol Regul Integr Comp Physiol 293:R276-83
Chen, Q; Pan, H-L (2006) Regulation of synaptic input to hypothalamic presympathetic neurons by GABA(B) receptors. Neuroscience 142:595-606

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