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Blood pressure stability may be jeopardized in astronauts experiencing orthostatic stress. There is disagreement about cardiovascular and endocrine stress responses that emerge when a critical (presyncopal) state is reached. We studied hemodynamic and neurohormonal changes as induced by an orthostatic stress paradigm (head-up tilt combined with lower body negative pressure) that leads to a syncopal endpoint. From supine control to presyncope, heart rate increased by 78% and thoracic impedance by 12%. There was a 49% fall in stroke volume index, 19% in mean arterial blood pressure, 14% in total peripheral resistance index and 11% in plasma volume. Plasma norepinephrine rose by 107, epinephrine by 491, plasma renin activity by 167, and cortisol by 25%. Hemodynamic and hormonal changes of clearly different magnitude emerge in presyncope as compared to supine rest. Additional studies are warranted to reveal the exact time course of orthostatic changes up to syncopal levels.