A central component of the feedback system for long-term control of arterial pressure is the pressure-natriuresis mechanism, whereby increases in renal perfusion pressure lead to decreases in sodium reabsorption and increases in sodium excretion. The specific intrarenal mechanism for the decrease in tubular reabsorption in response to increases in renal perfusion pressure appears to be related to increases in hemodynamic factors such as medullary blood flow and renal interstitial hydrostatic pressure (RIHP), and renal autocoids such as nitric oxide, prostaglandins, kinins, and angiotensin II. Increases in renal perfusion pressure are associated with significant increases in RIHP, nitric oxide, prostaglandin E2, and kinins, and decreases in angiotensin II. The mechanism whereby RIHP increases in the absence of discernible changes in whole kidney renal blood flow and peritubular capillary hydrostatic and/or oncotic pressures may be related to increases in renal medullary flow as a result of nitric oxide-induced reductions in renal medullary vascular resistance. Several lines of investigation support an important quantitative role for RIHP in mediating pressure natriuresis. Preventing RIHP from increasing in response to increases in renal perfusion pressure markedly attenuates pressure natriuresis. Furthermore, direct increases in RIHP, comparable to increases measured in response to increases in renal perfusion pressure, have been shown to significantly decrease tubular reabsorption of sodium in the proximal tubule and increase sodium excretion. The exact mechanism whereby RIHP influences tubular reabsorption is unknown, but may be related to alterations in tight junctional permeability to sodium in proximal tubules, redistribution of apical sodium transporters, and/or release of renal autacoids such as prostaglandin E2.