Autonomic dysreflexia (AD) is a potentially life-threatening consequence of cervical and high thoracic (above T6) spinal cord injury (SCI) characterized by abruptly high elevations in blood pressure in response to noxious stimuli below the injury level. 1,2 In addition to the potential morbidity caused by acute rise in blood pressure, recurrent AD over a longer period has been associated with changes in vascular structure that lead to CVD 3,4and impaired immune function, 5 which are both leading causes of mortality in persons with SCI. 6 While peripheral arteriolar vasoconstriction (VC) is documented to be pronounced during AD,7,8 The pathophysiological mechanisms of this VC are not well defined. A few proposed mechanisms include: 1) increase in neuronal release of norepinephrine (NE) and co-transmitters (CT); 2) post-junctional alpha-receptor hypersensitivity; 3) impaired reuptake of NE and/or 4) increases in circulating catecholamines (Epinephrine > NE) from adrenal stimulation.2,9 None of these mechanisms has been fully proven or is widely accepted. Furthermore, there are no known effective preventative or targeted treatment of the underlying pathophysiology of the AD, as the mechanisms are unknown. Current clinical care of AD with pharmacologic therapies is not without potential for significant side effects. Pharmacologic treatment includes short acting anti- hypertensives (e.g.; nitroglycerin and nifedipine), which can cause systemic hypotension. There is no known treatment targeting the underlying arteriolar vasoconstriction mechanisms of AD since they are unknown. Elucidating the underlying pathophysiology will facilitate the development of targeted treatment(s) to attenuate AD without significant adverse side effects. Our proposal aims to take the next step in elucidating the underlying pathophysiology of VC during AD. We aim to test one of the proposed mechanisms using a novel non-invasive technique never before used in studies testing VC pathology during AD. Specifically we will test following hypotheses: 1) Blockade of pre-synaptic neural release of NE and CT will abolish cutaneous VC during AD and 2) blockade of post synaptic alpha adrenergic receptors will decrease but not fully abolish VC during AD. Arterioles of the skin are easily accessible to test these hypotheses. We will use a novel and non- invasive technique of local iontophoretic delivery of pharmacologic agents combined with skin blood flow monitoring by laser Doppler flowmetry (LDF) and mean blood pressure (MAP) monitoring to define the underlying pathophysiology.10 Specific AIM 1 will compare the impact of a sympathetic neuronal blocking agent (bretylium = BT; blocks release of NE and co-transmitters from sympathetic noradrenergic nerves)) on cutaneous vascular conductance (CVC=LDF/MAP) during an AD episode at BT treated and control (CON) sites on a forearm and posterior calf. CVC will be compared at baseline = BL at normotension then every 20 seconds during AD stimulate...