In physiology, aldosterone escape is a term that has been used to refer to two distinct phenomena involving aldosterone that are exactly opposite each other: In patients with hyperaldosteronism, chronic exposure to excess aldosterone does not cause edema as might be expected. Aldosterone initially results in an increase in Na+ reabsorption in these patients through stimulation of ENaC channels in principal cells of the renal collecting tubules. Increased ENaC channels situated in the apical membranes of the principal cells allow for more Na+ reabsorption, which may cause a transient increase in fluid reabsorption as well. However, within a few days, Na+ reabsorption returns to normal as evidenced by normal urinary Na+ levels in these patients. This return to normal is induced by volume expansion, as escape typically occurs in humans after a weight gain of approximately 3 kg. The exact mechanism(s) underpinning aldosterone escape are an active subject of research, though several mechanisms have been proposed. Proposed mechanisms for this phenomenon do not include a reduced sensitivity of mineralocorticoid receptors to aldosterone, because low serum potassium is often seen in these patients, which is the direct result of aldosterone-induced expression of ENaC channels. Furthermore, electrolyte homeostasis is maintained in these patients, which excludes the possibility that other Na+ transporters elsewhere in the kidney are being shut down. If, in fact, other transporters such as the Na+-H+ antiporter in the proximal tubule or the Na+/K+/2Cl− symporter in the thick ascending loop of Henle were being blocked, other electrolyte disturbances would be expected, such as seen during use of diuretics. One mechanism proposed by ES Prakash suggests that pressure natriuresis underpins aldosterone escape, as Starling force backflow of Na+ and water into the tubules thus favors Na+ excretion. Experiments isolating the perfusion pressures seen by glomerular capillaries from heightened systemic pressures due to hyperaldosteronism have shown that Na+ excretion remains minimal until the kidney is exposed to heightened perfusion pressures. These experiments brought about the proposition that initially high perfusion pressures due to increased Na+ and water reabsorption in a high aldosterone state actually causes "backflow" of Na+ and water into the tubules. Normally, Na+ and water are reabsorbed from the tubules and dumped into the renal interstitium. From there, Starling forces dictate the gradient for movement of water and Na+ into the peritubular capillaries. Because hydrostatic pressures in the tubules, interstitium and peritubular capillaries are normally equivalent, oncotic pressures govern flow. Typically, oncotic pressures are higher in the peritubular capillaries, because protein composition in the interstitium is negligible; therefore, Na+ and water leave the interstitial space and enter the capillaries. However, hyperadosteronism raises pressures in the peritubular capillaries. When hydrostatic pressures are raised in the peritubular capillaries, Starling forces begin to favor "backflow" of Na+ and water from the interstitium into the tubules—thus, increasing Na+ excretion. This is a proposed mechanism of aldosterone escape for how patients with increased levels of aldosterone are able to maintain Na+ balance and avoid an edematous state. Another mechanism proposed by RW Schrier suggests that aldosterone involves synergistic processes. In addition to increasing renal perfusion pressure, the resultant volume expansion decreases proximal sodium reabsorption and increases sodium delivery to the distal nephron sites of mineralocorticoid action. This increased delivery of sodium overrides the enhanced aldosterone sodium reabsorption at the site of mineralocorticoid action. Moreover, volume expansion, secondary to the action of aldosterone, increases levels of plasma natriuretic hormone and therefore its inhibitory effect on sodium reabsorption in the collecting duct. Together, these events contribute to normal aldosterone escape and the prevention of edema. Others have suggested the involvement of decreased abundance of the thiazide-sensitive sodium-chloride cotransporter which mediates sodium reabsorption in the distal tubule.