Prolonged periods of recumbancy, as well as long space missions, induce orthostatic intolerance. Deconditioning of several biloogical functions may contribute to such orthostatic intolerance. The present studies concerns deconditioning of the pressure resistance of peripheral blood following prolonged bedrest (BR). In the upright body position longitudinally oriented blood vessels are aligned with the gravitational force field, resulting in substantial intravascular pressure gradients along the vessels. The question was whether blood vessels of the lower body need the regular increments of local intravascular pressures, associated with habitually assuming erect posture, to maintain their pressure resistance. Several series of experiments were conducted in healthy test subjects to investigate the in vivo pressure distension in arteries, arterioles and veins in the arm or the leg. Each subject was positioned either seated or supine in a hyperbaric chamber with either one arm or a lower leg protruding through a hole in the chamber door. Increased pressure in the vessels of the arm/leg was accomplished by increasing chamber pressure. Vessel diameter and flow were measured using Doppler ultrasonography. Measurements were conducted before and after 5 weeks of sustained horizontal BR. Before BR, distensibility was considerably larger in the arteries, arterioles and veins of the arm than in the corresponding vessels of the leg. BR increased vascular distensibility, especially in the arteries and arterioles of the leg, an effect that could be counteracted by intermittently (3 x 40 min/week) increasing local transmural pressure by exposing a lower leg to subatmospheric pressure of 90 mmHg. It thus appears the pressure resistance of arteries, arterioles and veins adapts to meet the demands imposed by the local pressure acting on the vessel wall. The mechanisms governing such local adaptation of vascular wall stiffness are largely unknown. In separate experiments we have found that intravascular pressure provocations induce local release of the vasoconstrictor endothelin-1 (ET-1). After BR, pressure-induced local release of ET-1 was more pronounced in the lower leg that had intermittently been exposed to transmural pressure increments than in the control leg. Thus, decreased local production/release of vasoconstrictors, including ET-1, may be one mechanism underlying the BR-induced increase in leg vessel distensibility.