Hypertension and heart failure increase risk for ventricular arrhythmias and sudden cardiac death. Autonomic dysregulation and sympathetic hyperactivity accompany these diseases and trigger lethal arrhythmias. Interventions that target the central nervous system to inhibit sympathetic outflow have not been effective in prolonging life in patients, whereas interventions that target the periphery (beta blockers, ganglionectomy) decrease arrhythmias and prolong life. We hypothesize that central nervous system activity is amplified by post- ganglionic neurons in cardiovascular disease to enhance cardiac sympathetic transmission which contributes to pathology. During the previous period of support, we showed that noradrenergic sympathetic neurons have excitatory cholinergic collateral projections. Preliminary data indicate that hypertension causes a significant increase in cardiac sympathetic neuron activity. Additional data indicate that cholinergic collateral transmission is required for the development of hyperactivity in cardiac sympathetic neurons, and that increased collateral transmission is involved. In Aim 1 we will determine if hypertension increases sympathetic neuron activity generally, or if the increased activity is limited to cardiac neurons, and if collateral signaling is required. In Aim 2 we will investigate the mechanisms by which cholinergic collateral transmission is elevated in hypertension. New data from multiple labs implicate satellite glial cells as important regulators of sympathetic neuronal activity. In Aim 3 we will determine if activation of satellite glial cells in sympathetic ganglia plays a role in sympathetic hyperactivity in disease. We have assembled a team of accomplished experts, key animal models, and powerful genetic tools to accomplish these studies. We expect that novel insights and targets for therapeutic intervention will come from the studies described here, and that this work with have implications for treatment of the many diseases characterized by high sympathetic activation.