The first goal is to determine the mechanisms responsible for stimulation of ventricular afferents and for activation of the reflexes they subserve during acute myocardial ischemia and following restoration of flow. Most experiments will be done in dogs. The effects of prostaglandin synthesis inhibition, blockade of bradykinin receptors (peptide antagonist), and of oxygen radical scavengers on the responses of the afferents and on the reflex responses will be investigated. Species differences in sympatho- sympathetic reflexes activated by myocardial ischemia and their dependence of differences in collateral flow and, thus, on the extent of transmural ischemia will be determine. Experiments will determine if bradykinin is release during myocardial ischemia induced by reductions in flow or by increases in demand, and its relationship to the occurrence of angina pectoris. The effects of chronic myocardial infarction on the forearm vasoconstrictor responses to venous pooling will be assessed in patients. The second goal is to determine the effect of congestive heart failure on arterial and cardiopulmonary baroreflexes, and the mechanism(s) for abnormalities detected. These experiments will be done with heart failure due to rapid ventricular pacing (systolic and diastolic ventricular dysfunction) or constrictive pericarditis (diastolic dysfunction). Recordings will be made simultaneously form arterial baroreceptors and renal sympathetic nerves during increases and decreases in arterial pressure before and after vagotomy, thus allowing us to examine afferent limb, efferent response, and input/output relationship. Single unit baroreceptor activity will be examined in normal and heart failure using isolated carotid sinus. The relationship of impaired reflex control to development of the neurohumoral excitatory state will be determined. Abnormalities of neuro-effector mechanisms in heart failure also will be determined. These studies will provide major new insights into mechanisms of reflex control during myocardial ischemia/reperfusion and heart failure.
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