Neural reflexes of cardiac origin manifested during myocardial ischemia and reperfusion can lead to hemodynamic alterations, arrhythmias, nausea, vomiting and angina. Reactive oxygen species are thought to play an important roe in local tissue injury during ischemia and reperfusion. Increased serum nicotine concentrations resulting from smoking primes neutrophils to produce oxidants. These cells may be an important source of free radicals during ischemia and particularly reperfusion. Recently we have shown that hydrogen peroxide (H2O2) and/or its metabolites, most likely hydroxyl radicals (.OH), reflexly activate the cardiovascular system through stimulation of Adelta and C fiber afferent nerve endings in abdominal visceral organs. We further have demonstrated that nicotine increases the myocardial content of PMN. We also have preliminary data demonstrating that ischemia/reperfusion of the cat's heart is associated with .OH production. The hypothesis of this proposal is that during myocardial ischemia free radicals are produced, their concentrations are enhanced by the presence of nicotine and that H2O2, and species derived from H2O2, particularly .OH, are capable of activating sympathetic and vagal afferents from the myocardium to reflexly alter heart rate, myocardial contractility and peripheral vascular resistance. Initially we will measure directly the production of .OH during ischemia and reperfusion using phenylalanine to trap .OH in the cat myocardium before and during infusion of nicotine. Secondly, H2O2 will be applied to the epicardial surface of the anterior or inferoposterior regions of myocardium to develop a dose-response curve (i.e., an H2O2 vs cardiovascular response relationship). The response to H2O2 will be determined in anesthetized cats before and after vagotomy and/or stellectomy. The importance of free reactive oxygen species will be examined using the scavenger, dimethylthiourea (DMTU), while the role of .OH will be studied with deferoxamine (DEF) to chelate iron and to inhibit the Haber-Weiss reaction. Thirdly, single unit cardiac sympathetic afferent activity will be recorded to evaluate the types of afferent nerves stimulated during regional myocardial ischemia/reperfusion in the presence and absence of nicotine, and to document the role of reactive oxygen species, using DMTU, and.OH, using DEF. which may be involved in the activation of the afferent nerve endings. We expect that our studies will demonstrate a central role for reactive oxygen species inactivating sympathetic afferent nerve endings during anterior ischemia whereas vagal afferent endings will be preferentially stimulated by these species during inferior myocardial ischemia. Furthermore, we will document reflex activation of the cardiovascular system. Nicotine will increase the production of reactive oxygen species in ischemic and particularly in reperfused myocardium. Such information will provide clinicians with a better understanding of some of the potentially dangerous cardiac reflexes and may suggest therapeutic approaches designed to limit these untoward events that can lead to angina, systemic hypertension and cardiac arrhythmias during myocardial ischemia and reperfusion.
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