PROJECT SUMMARY There are currently ~6.5 million men and women in the United States with heart failure. By 2030, that number is predicted to climb to over 8.5 million and direct heart failure-related health care costs are predicted to command $53.1 billion. Heart failure patients commonly exhibit exaggerated levels of sympathetic nervous system activity at rest and during exercise compared to healthy subjects. An exaggerated increase in sympathetic nervous system activity during exercise (i.e., sympatho-excitation) is a direct contributor to exercise intolerance and lack of functional independence which is the main reason that heart failure patients seek medical care. A neural reflex that is activated by mechanical and metabolic signals within contracting skeletal muscles contributes importantly to the increase in sympathetic nervous system activity that occurs during exercise. In heart failure patients, the activation of this reflex, termed the exercise pressor reflex, is exaggerated which underlies mechanistically the exercise-induced sympatho-excitation. Currently, there are no therapies that are designed specifically to reduce the activation of the exercise pressor reflex in heart failure patients which reflects our current limited understanding of the mechanisms that contribute to its exaggeration. We will use male and female rats with surgically-induced heart failure (post-myocardial infarction model) to study the mechanistic bases and possible therapeutic targets of the exaggerated exercise pressor reflex. In Aim 1, we will investigate the role played by endoperoxide (EP) 4 receptors, which are stimulated by prostaglandins produced within skeletal muscles, in evoking the exercise pressor reflex in heart failure. In Aim 2, we will investigate the role played by mechanically activated piezo2 channels in evoking the exercise pressor reflex in heart failure. In Aim 3, we will investigate whether peripheral δ-opioid receptor stimulation reduces the exercise pressor reflex in heart failure. We will investigate these aims using a complementary blend of whole animal and molecular level approaches so that our findings are integrative and translational. Collectively, our experiments may identity three possible targets (EP4 receptors, piezo2 channels, and δ-opioid receptors) for therapies aimed at 1) mitigating the sympatho-excitation that occurs during exercise and 2) increasing exercise tolerance, functional independence, and overall quality of life in heart failure patients.