The aims were to study effects of iterative exposures to moderate elevations of local intravascular pressure on arterial/arteriolar stiffness and plasma levels of vasoactive substances. Pressures in the vasculature of an arm were increased by 150mmHg in healthy men (n = 11) before and after a 5-wk regimen, during which the vasculature in one arm was exposed to fifteen 40-min sessions of moderately increased transmural pressure (+65 to +105 mmHg). This vascular pressure training and the pressuredistension determinations were conducted by exposing the subjects' arm versus remaining part of the body to differential ambient pressure. During the pressure-distension determinations, venous samples were simultaneously obtained from pressurized and unpressurized vessels. Pressure training reduced arterial pressure distension by 40 ± 23% and pressure-induced flow by 33 ± 30% (P < 0.01), but only in the pressure-trained arm, suggesting local adaptive mechanisms. The distending pressure-diameter and distending pressure-flow curves, with training-induced increments in pressure thresholds and reductions in response gains, suggest that the increased precapillary stiffness was attributable to increased contractility and structural remodeling of the walls. Acute vascular pressure provocation induced local release of angiotensin-II (ANG II) and endothelin-1 (ET-1) (P < 0.05), suggesting that these vasoconstrictors limited the pressure distension. Pressure training increased basal levels of ET-1 and induced local pressure release of matrix metalloproteinase 7 (P < 0.05), suggesting involvement of these substances in vascular remodeling. The findings are compatible with the notion that local intravascular pressure load acts as a prime mover in the development of primary hypertension.