ABSTRACT: This is an application for extension of a MERIT Award. A major goal of our laboratory during this grant period has been to use microneurography to advance understanding of factors that modulate reflex control of muscle sympathetic nerve activity (MSNA) in humans. Several new concepts have emerged from this research: 1) sustained stimulation of arterial baroreceptors is followed by an extended period of inhibition of MSNA in humans; 2) aortic and atrial baroreceptors contribute importantly to regulation of MSNA in humans; 3) impulses originating in muscle afferents in the leg produced different MSNA responses than impulses originating in muscle afferents in the arm; 4) beta adrenergic mechanisms facilitate increases in MSNA responses during mental stress; 5) endogenous opioids modulate cardiopulmonary baroreflex control of MSN; and 6) endurance exercise training desensitizes the muscle metaboreflex to muscle acidosis. Studies are now planned to extend this work in each of the five original areas of investigation. First, we plan to determine if the phenomenon of prolonged inhibition of MSNA by arterial baroreceptors is attenuated in hypertensive humans and if it is prevented by administration of naloxone. Second, we plan to determine if atrial cardiac baroreflex control of MSNA is impaired in patients with cardiac hypertrophy and specifically atrial disease. Third, we plan systematic studies of simultaneous recordings of arm and leg MSNA during arm and leg exercise and post-exercise circulatory arrest to test the novel concept that afferent impulses originating in leg muscles versus arm muscles trigger substantially different patterns of autonomic adjustments including MSNA responses. Fourth, we plan to determine if the phenomenon of acute beta-1 receptor antagonists modulating MSNA responses to mental stress is also observed with chronic oral administration of beta receptor antagonists and if this phenomenon is specific for antagonists which readily cross the blood brain barrier. We also plan to determine if endogenous opioid blockade with naloxone augments MSNA responses to mental stress. Fifth, studies are planned to determine if two arm endurance exercise training blunts the MSNA responses to arm cycling. These studies which will employ the same general experimental approaches and methods in the original application should further advance our understanding of the factors which modulate MSNA in humans.