Project 1: Autonomic Determinants of Ortliostatic Tolerance David Robertson, IVI.D., Project Leader Maintenance of upright posture is a challenge for the autonomic nervous system. Even mild perturbation of autonomic control mechanisms can alter orthostatic tolerance. When one or more determinants of orthostatic intolerance is impaired, orthostatic intolerance or syncope can supervene. Project 1 focuses on one such determinant which escaped detection until it was discovered during studies earlier in this PPG project. The effect was a surprisingly large pressor response elicited by oral ingestion of 16 oz of water. The systolic pressor effect averaged ~40 mm Hg in patients with baroreflex impairment but some had smaller responses and a few had increases greater than 100 mm Hg. These remarkable pressor effects were not predicted by classical physiology, but have been subsequently replicated and their magnitude confirmed by multiple investigators. We have termed this the osmopressor response (OPR). it seems to signal an important but heretofore unrecognized mechanism at work in human cardiovascular regulation. We have made progress in understanding the physiological basis of water's pressor effect, and hypothesize that the osmopressor response (OPR) is an important autonomic determinant of orthostatic tolerance in human subjects. The goal of Project 1 is to elucidate mechanisms underlying OPR function, to identify OPR's potential role in normal and pathological conditions, and to find ways to harness it to benefit human health. Project Specific Aims are: (1-2) To elucidate the structure and function of the osmopressor response (OPR) (3) To identify the role of the OPR in health and disease (4) To harness the OPR mechanism to benefit health RELEVANCE (See instructions): Control of blood pressure is important for health. We recently discovered an unexpected way that the body uses water drinking to control blood pressure. It is a powerful effect in some but not all people. If we can understand how this works and find new drugs that can affect it, we might be able through simple and inexpensive measures to prevent high and low blood pressure, and help prevent people from passing out.