application) The activation of cardiac sympathetic afferents during ischemia is responsible for conveying cardiac nociception and initiating neural reflexes which lead to hemodynamic alterations and arrhythmias. """"""""Silent"""""""" afferents (afferents exhibiting no spontaneous activity and unresponsive to physiological stimuli) are known to play a critical role in nociception, however it remains uncertain whether the heart is innervated by silent cardiac sympathetic afferents. Furthermore, the role of many ischemic metabolites in activation of ischemia-sensitive cardiac sympathetic afferents remains to be established. The following hypotheses will be tested: 1. the heart is innervated by a population of silent sympathetic afferents which function primarily as nociceptors; and 2. myocardial ischemia increases protons and amphipathic lipid metabolites (palmitylcarnitine and lysophosphatidylcholine) concentrations in the myocardial interstitial fluid which contribute to the activation of cardiac sympathetic afferents. The investigator proposes to initially demonstrate the presence of silent cardiac afferents utilizing a stimulating electrode as a search stimulus. The investigator will then determine the responses of silent cardiac sympathetic afferents to cardiac distension, myocardial ischemia, and algesic chemicals. In addition, the investigator plans to use cardiac microdialysis to document the production of protons/lactic acid and amphipathic lipid metabolites in the myocardial interstitial fluid during ischemia. Finally, the investigator will record single-unit activity of afferents to evaluate the role of protons and amphipathic lipid metabolites in the activation of ischemia-sensitive cardiac afferents by buffering the pH of the afferent's receptive field and inhibiting the activity of carnitine acyltransferase-I, respectively. The proposed research will provide insights into the neural encoding mechanism of cardiac nociception and mechanisms of activation of cardiac nociceptors during ischemia. Such information may also suggest alternate interventions designed to treat intractable angina pectoris and to limit potentially dangerous cardiac reflexes.
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