Liddle syndrome, a rare genetic disorder, is characterized by hypertension due to an increase in extracellular fluid volume (ECFV) caused by activating mutations in the β or γ subunit of the epithelial Na+ channel (ENaC). These mutations result in more Na+ channels in the apical cell membrane, leading to increased Na+ reabsorption. Consequently, the renal Na+ reabsorption rate becomes inappropriately high, causing an elevation in ECFV and hypertension.

Pseudohypoaldosteronism (PHA) has two forms. The autosomal recessive form is caused by inactivating mutations in the α, β, or γ subunit of ENaC, while the autosomal dominant form is caused by an inactivating mutation in the mineralocorticoid receptor. PHA is characterized by elevated aldosterone levels, which leads to increased NaCl reabsorption despite low aldosterone levels. This results in increased Na+ excretion, reduced ECFV, hyperkalemia, and hypotension.

For individuals with expanded ECFV and elevated blood pressure, ACE inhibitors such as captopril, enalapril, and lisinopril are commonly prescribed. These drugs inhibit angiotensin-converting enzyme (ACE), which decreases fluid volume and blood pressure. By blocking the degradation of angiotensin I to angiotensin II, plasma angiotensin II levels decrease. This reduction in angiotensin II has several effects, including decreased NaCl and water reabsorption in the nephron, reduced aldosterone secretion, and systemic arteriolar dilation, resulting in lower arterial blood pressure. Additionally, ACE inhibitors increase the concentration of the vasodilator hormone bradykinin.

Water reabsorption is regulated by arginine vasopressin (AVP), the primary hormone responsible for this process in the kidneys. AVP is secreted by the posterior pituitary gland in response to increased plasma osmolality or decreased ECFV. It enhances water reabsorption in the collecting duct by increasing its permeability due to the osmotic gradient across the duct's wall. Notably, AVP has minimal impact on urinary NaCl excretion.
Liddle syndrome is a rare genetic disorder characterized by an increase in blood pressure (i.e., hypertension) secondary to an increase in ECFV. Liddle syndrome is caused by activating mutations in either the β or γ subunit of the epithelial Na+ channel (ENaC). These mutations increase the number of Na+ channels in the apical cell membrane of principal cells and thereby the amount of Na+ reabsorbed. In Liddle syndrome, the rate of renal Na+ reabsorption is inappropriately high, which leads to an increase in ECFV and hypertension. There are two different forms of pseudohypoaldosteronism (PHA) (i.e., the kidneys reabsorb NaCl as they do when aldosterone levels are low; however, in PHA, aldosterone levels are elevated). The autosomal recessive form is caused by inactivating mutations in the α, β, or γ subunit of ENaC. The cause of the autosomal dominant form is an inactivating mutation in the mineralocorticoid receptor. Pseudohypoaldosteronism is characterized by an increase in Na+ excretion, a reduction in ECFV, hyperkalemia, and hypotension. Some individuals with expanded ECFV and elevated blood pressure are treated with drugs that inhibit angiotensin-converting enzyme (ACE) (e.g., captopril, enalapril, lisinopril) and thereby lower fluid volume and blood pressure. Inhibition of ACE blocks degradation of angiotensin I to angiotensin II and thereby lowers plasma angiotensin II levels. The decline in plasma angiotensin II concentration has three effects. First, NaCl and water reabsorption by the nephron (especially the proximal tubule) falls. Second, aldosterone secretion decreases, thus reducing NaCl reabsorption in the thick ascending limb, distal tubule, and collecting duct. Third, because angiotensin is a potent vasoconstrictor, a reduction in its concentration permits the systemic arterioles to dilate and thereby lower arterial blood pressure. ACE also degrades the vasodilator hormone bradykinin; thus ACE inhibitors increase the concentration of bradykinin, a vasodilatory hormone. ACE inhibitors decrease ECFV and the arterial blood pressure by promoting renal NaCl and water excretion and by reducing total peripheral resistance.
thereby indirectly stimulate excretion of NaCl and water (see earlier discussion about ANP and BNP).
Arginine vasopressin (AVP) regulates water reabsorption. It is the most important hormone that regulates reabsorption of water in the kidneys (see ). This hormone is secreted by the posterior pituitary gland in response to an increase in plasma osmolality (1% or more) or a decrease in ECFV (>5%–10% of normal). AVP increases the permeability of the collecting duct to water. It increases reabsorption of water by the collecting duct because of the osmotic gradient that exists across the wall of the collecting duct (see
Chapter 35). AVP has little effect on urinary NaCl excretion.