Disorders of the Posterior Pituitary

Osmotic Regulation

The rate of secretion of vasopressin from the paraventricular and supraoptic nuclei is influenced by several physiologic variables, including plasma osmolality and intravascular volume, as well as nausea and a number of pharmacologic agents. The major osmotically active constituents of blood are sodium, chloride, and glucose (with insulin deficiency). Normal blood osmolality ranges between 280 and 290 mOsm/kg H ₂ O.

The work of Verney first demonstrated the relationship of increased vasopressin release in response to increasing plasma osmolality, as altered by infusion of sodium chloride or sucrose. At that time, it was postulated that there existed intracranial sensors sensitive to changes in plasma osmolality. Multiple researchers have subsequently confirmed that plasma vasopressin concentration increases in response to increasing plasma tonicity, with the location of the osmosensor, likely to be within the circumventricular organ, neuronal nuclei surrounding the third ventricle, which lacks. a blood-brain barrier. The organ vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO), areas of the preoptic hypothalamus outside the blood-brain barrier, are likely sites of both osmosensing, because lesions of the OVLT result in impaired vasopressin secretion and hypernatremia. Also the site of action of angiotensin II, infused intracerebrally or peripherally, to produce vasopressin secretion and antidiuresis resides within the OVLT.

The pattern of secretion of vasopressin into blood has been characterized extensively in normal individuals and in those with abnormalities in water homeostasis. Normally, at a serum osmolality of less than 280 mOsm/kg, plasma vasopressin concentration is at or below 1 pg/mL, the lower limit of detection of most radioimmunoassays. Above 283 mOsm/kg—the normal threshold for vasopressin release—plasma vasopressin concentration increases in proportion to plasma osmolality, up to a maximum concentration of about 20 pg/mL at a blood osmolality of approximately 320 mOsm/kg ( Fig. 12.5 ). The osmosensor can detect as little as a 1% change in blood osmolality. Plasma concentrations in excess of 5 pg/mL are also found with nausea, hypotension, hypovolemia, and insulin-induced hypoglycemia, but further increments in urine concentration do not occur, because peak antidiuretic effect is achieved at 5 pg/mL. The rate of increase of plasma vasopressin concentration, and thus the sensitivity of the osmosensor, exhibits substantial (as much as 10-fold) interindividual variation as plasma osmolality increases. The set-point for vasopressin secretion varies in a single individual, in relation to changes in volume status and hormonal environment (e.g., pregnancy ) or glucocorticoid status. After the seventh week of gestation, osmotic thresholds for both vasopressin release and thirst are reduced by approximately 10 mOsm/kg (see Fig. 12.5 ), such that normal blood osmolality, during pregnancy, is approximately 273 mOsm/ kg (serum sodium 135 mEq/L). Similarly, thresholds for vasopressin release and thirst during the luteal phase of the menstrual cycle are approximately 5 mOsm/kg lower than those in the follicular phase. Human chorionic gonadotropin, during pregnancy, and luteinizing hormone, during the second half of the menstrual cycle, may contribute to these changes in osmotic thresholds.

The sensation of thirst, a more integrated cortical activity, is determined by other anatomically distinct hypothalamic neurons, with afferents involving the ventromedial nucleus, and subfornical organ. The activation of the thirst mechanism is probably mediated by angiotensin II. Whether the osmosensor for thirst and vasopressin release are the same is not certain, although this is suggested by lesions in the anteroventral region of the third ventricle that abolish both thirst sensation and vasopressin release. It makes physiologic sense that the threshold for thirst (293 mOsm/kg) is approximately 10 mOsm/kg higher than that for vasopressin release (see Fig. 12.5 ). Otherwise, during the development of hyperosmolality, the initial activation of thirst and water ingestion would result in polyuria, without activation of vasopressin release, causing a persistent diuretic state. Immediately after water ingestion, before a change in blood osmolality or volume, vasopressin concentration falls and thirst ceases. The degree of suppression is directly related to the coldness and volume of the ingested fluid. Water that bypasses the pharynx does not have this effect. The effect is probably mediated by chemoreceptors present in the oropharynx that project to the subfornical organ, which results in decreased thirst and vasopressin release. This “presystemic” regulation of thirst and vasopressin secretion, before osmolality changes, guards against both the rapid overdrinking of fluids after prior intense thirst, and reversal of antidiuresis with the onset of water ingestion.

As noted earlier, water balance is regulated in two ways: (1) vasopressin secretion stimulates water reabsorption by the kidney, thereby reducing future water loss, and (2) thirst stimulates water ingestion, thereby restoring previous water loss. Ideally, these two systems work in parallel to efficiently regulate extracellular fluid tonicity ( Fig. 12.6 ); however, each system by itself can maintain plasma osmolality in the near-normal range. For example, in the absence of vasopressin secretion but with free access to water, thirst drives water ingestion up to the 5 to 10 L/m ² of urine output seen with vasopressin deficiency. Conversely, an intact vasopressin secretory system can compensate for some degree of disordered thirst regulation. When both vasopressin secretion and thirst are compromised, however, by either disease or iatrogenic means, there is great risk of the occurrence of life-threatening abnormalities in plasma osmolality.

Nonosmotic Regulation

Separate from osmotic regulation, vasopressin has been shown to be secreted in response to alterations in intravascular volume. Afferent baroreceptor pathways arising from the right and left atria and the aortic arch (carotid sinus) are stimulated by increasing intravascular volume and stretch of vessel walls, and they send signals through the vagus and glossopharyngeal nerves, respectively, to the brain stem nucleus tractus solitarius. Noradrenergic fibers from the nucleus tractus solitarius synapse on the hypothalamic paraventricular nucleus and the supraoptic nucleus and, on stimulation, inhibit vasopressin secretion.

The pattern of vasopressin secretion in response to volume, as opposed to osmotic stimuli, is markedly different ( Fig. 12.7 ). Although minor changes in plasma osmolality above 280 mOsm/kg evoke linear increases in plasma vasopressin, substantial alteration in intravascular volume is required for alteration in vasopressin output. No change in vasopressin secretion is seen until blood volume decreases by approximately 8%. With intravascular volume deficits exceeding 8%, vasopressin concentration increases exponentially. Furthermore, osmotic and hemodynamic stimuli can interact in a mutually synergistic fashion, so that the response to either stimulus may be enhanced by the concomitant presence of the other (see Fig. 12.7 ). When blood volume or blood pressure decreases by approximately 25%, vasopressin concentrations are evident of 20- to 30-fold above normal, and vastly exceeding those required for maximal antidiuresis. Mice with deletion of the V1a vasopressin receptor gene, Avpr1 , indicate that vasopressin acting through this receptor is required to maintain normal blood pressure, even at low concentrations of blood vasopressin.

Nausea, as evoked by apomorphine, motion sickness, or vasovagal reactions, is a very potent stimulus for vasopressin secretion. This effect is likely mediated by afferents from the area postrema of the brain stem and may result in vasopressin concentrations two to three orders of magnitude above basal levels. Nicotine is also a strong stimulus for vasopressin release. These pathways probably do not involve osmotic or hemodynamic sensor systems, because blockade of the emetic stimulus, with dopamine or opioid antagonists, does not alter the vasopressin response to hypernatremia or hypovolemia.

Vasopressin secretion is inhibited by glucocorticoids; because of this, loss of negative regulation of vasopressin secretion occurs in the setting of primary or secondary glucocorticoid insufficiency. The insertion of aquaporin-2 (AQP2) in the renal luminal membrane is stimulated by nitric oxide. Glucocorticoids inhibit nitric oxide synthase, thereby providing a mechanism by which they may facilitate free water clearance, by inhibiting nitric oxide-induced insertion of AQP2 into the luminal membrane. The effects of cortisol loss of both enhancing hypothalamic vasopressin production and directly impairing free water excretion are important considerations in the evaluation of the patient with hyponatremia, as is subsequently discussed.

Vasopressin Receptors

Vasopressin, released from the posterior pituitary and the median eminence, affects the function of several tissue types by binding to members of a family of G protein–coupled cell surface receptors, which subsequently transduce ligand binding into alterations of intracellular second messenger pathways. Biochemical and cell biologic studies have defined three receptor types, designated V1, V2, and V3 (or V1b). The major sites of V1 receptor expression are on vascular smooth muscle and hepatocytes, where receptor activation results in vasoconstriction and glycogenolysis, respectively. The latter activity may be augmented by stimulation of glucagon secretion from the pancreas. The V1 receptor on platelets also stimulates platelet aggregation. V1 receptor activation mobilizes intracellular calcium stores through phosphatidylinositol hydrolysis. Despite its initial characterization as a powerful pressor agent, the concentration of vasopressin needed to significantly increase blood pressure is several-fold higher than that required for maximal antidiuresis, although substantial vasoconstriction in renal and splanchnic vasculature can occur at lower concentrations. The cloning of the V1 receptor has greatly elucidated the relationship of the vasopressin (and oxytocin ) receptors and, through sensitive in situ hybridization analysis, has further localized V1 expression to the liver and the vasculature of the renal medulla, as well as to many sites within the brain, including the hippocampus, the amygdala, the hypothalamus, and the brain stem. Compared with their normal counterparts, mice genetically modified to be deficient in the V1 receptor (V1a KO) have been found to have insulin resistance, increased hepatic glucose production, decreased hepatic glycogen content, and decreased aldosterone secretion, despite a lower plasma volume, lower basal blood pressure, greater degree of lipolysis, and impaired nuclear transport of the renal tubular mineralocorticoid receptor. The V3 (or V1b) receptor is present on corticotrophs in the anterior pituitary and acts through the phosphatidylinositol pathway to increase adrenocorticotropic hormone secretion. Its binding profile for vasopressin analogues resembles more closely that of the V1 than the V2 receptor. The structure of this receptor has been determined in humans by cloning of its complementary deoxyribonucleic acid (DNA). Its structure is similar to that of the V1 and oxytocin receptors, and it is expressed in the kidney, as well as in the pituitary. Mice with deletion of the V1b (V3) receptor gene ( V1bKO ) have been created and studied. As expected, they have defective activation of the pituitary-adrenal axis, following some acute and chronic stressors. Male V1bKO mice were also found to have decreased aggression and social motivation.

Modulation of water balance occurs through the action of vasopressin on V2 receptors, located primarily in the renal collecting tubule, along with other sites in the kidney, including the thick ascending limb of the loop of Henle and periglomerular tubules. It is also present on vascular endothelial cells in some systemic vascular beds, where vasopressin stimulates vasodilation, possibly through activation of nitric oxide synthase. Vasopressin also stimulates von Willebrand factor, factor VIIIa, and tissue plasminogen activator through V2-mediated actions. Because of this, desmopressin is used to improve the prolonged bleeding times characteristic of uremia, type I von Willebrand disease, and hemophilia. The V2 receptor consists of 370 amino acids encoding seven transmembrane domains characteristic of the G protein–coupled receptors. These transmembrane domains share approximately 60% sequence identity with the V1 receptor, but substantially less with other members of this family ( Fig. 12.8 ). Unlike the V1 and V3 receptors, the V2 receptor acts through adenylate cyclase to increase intracellular cyclic adenosine monophosphate (AMP) concentration. The human V2 receptor gene is located on the long arm of the X chromosome (Xq28), at the locus associated with congenital, X-linked vasopressin-resistant diabetes insipidus. Mice in which V2R has been deleted have a similar nephrogenic diabetes insipidus phenotype.

Renal Cascade of Vasopressin Function

Vasopressin-induced increases in intracellular cyclic AMP, as mediated by the V2 receptor, triggers a complex pathway of events resulting in increased permeability of the collecting duct to water and efficient water transit across an otherwise minimally permeable epithelium ( Fig. 12.9 ). Activation of a cyclic AMP-dependent protein kinase imparts remodeling of cytoskeletal microtubules and microfilaments that culminate in the insertion of aggregates of water channels into the apical membrane. These mechanisms may involve a vesicle-associated membrane protein-2–like protein (VAMP-2), which also regulates synaptic vesicle activity in neuronal terminals, and its associated receptor syntaxin-4.

Insertion of the water channels causes an up to 100-fold increase in water permeability of the apical membrane, allowing water movement along its osmotic gradient into the hypertonic inner medullary interstitium from the tubule lumen and excretion of a concentrated urine (see Fig. 12.9 ). The molecular analysis of the water channels has revealed a family of related proteins, designated aquaporins, that differ in their sites of expression and pattern of regulation. Each protein consists of a single polypeptide chain with six membrane-spanning domains ( Fig. 12.10 ). Although functional as monomers, they form homotetramers in the plasma membrane.

AQP2 is expressed mostly within the kidney, primarily within the collecting duct. It is also expressed in the vas deferens, at least in the rat, although it is not regulated by vasopressin in this location. Studies with immunoelectron microscopy have demonstrated large amounts of AQP2 in the apical plasma membrane and subapical vesicles of the collecting duct, consistent with the “membrane shuttling” model of water channel aggregate insertion into the apical membrane after vasopressin stimulation. Studies analyzing the mechanism by which AQP2 traffics to the apical plasma membrane have demonstrated that vasopressin-induced, protein kinase A–mediated serine phosphorylation at amino acid 256 is required for its exocytosis, a process also requiring a heterotrimeric G protein of the G _i family. In response to water restriction or desmopressin infusion in humans, the content of urinary AQP2 in both soluble and membrane-bound forms has been found to increase. Mice with targeted deletion of the AQP2 gene have been made. As expected, they have nephrogenic diabetes insipidus that is unresponsive to treatment with vasopressin.

Hypercalciuria is associated with polyuria despite adequate vasopressin levels. The activation by luminal calcium, of the calcium-sensing receptor (CaSR) on the apical membranes of the collecting duct cells of the kidney, is associated with resistance to vasopressin action. The production of dilute urine when there is increased urinary concentration of calcium, has been hypothesized to be a protective mechanism to mitigate the risk of precipitation of calcium in the kidneys. Mechanisms by which the activation of the CaSR decreases AQP2 levels in the collecting duct cells include reduced synthesis of AQP2 by the generation of AQP2 targeting microribonucleic acid (miRNA), and the inactivation and degradation of AQP2 through ubiquitination and phosphorylation at serine261.

In addition to AQP2, different aquaporins appear to be involved in other aspects of renal water handling. In contrast to the apical localization of AQP2, aquaporin-3 and aquaporin-4 are expressed on the basolateral membrane of the collecting duct epithelium. They are involved in the flow of water and urea from the inside of the collecting duct cell into the extracellular renal medullary space. Mice made genetically deficient in aquaporin-4 demonstrate a mild urinary concentrating defect, whereas those with deficiency of aquaporin-3 alone, or together with aquaporin-4, demonstrate more severely impaired urinary concentrating ability. Mice made genetically deficient in aquaporin-1 demonstrate a urinary concentrating defect caused by decreased water permeability in the proximal tubule.

Anatomy and Biochemistry

Renin, which is synthesized by the renal juxtaglomerular apparatus, is a proteolytic enzyme that catalyzes the cleavage of angiotensinogen, synthesized by hepatocytes, into the decapeptide angiotensin I. Angiotensin I possesses no intrinsic vasoreactive or mineralocorticoid secretagogue activity, but is efficiently cleaved by angiotensin-converting enzyme in the lungs, as well as other peripheral sites, to generate the octapeptide angiotensin II. Angiotensin II is further metabolized to the heptapeptide angiotensin III by removal of one amino-terminal amino acid. Angiotensin II possesses greater vasopressor activity and is present in approximately a 4-fold greater amount than angiotensin III. Angiotensins II and III possess equivalent mineralocorticoid secretory activity on the adrenal glomerulosa cells.

Angiotensin II and III act through cell surface receptors (AT ₁ ) on the adrenal glomerulosa cells to activate the phospholipase C/protein kinase C pathway. This activation results in increased production of pregnenolone from cholesterol by side-chain cleavage enzyme (20,22-desmolase) and of aldosterone from corticosterone by the glomerulosa-specific corticosterone methyloxidase I and II activities (18-hydroxylation and dehydrogenation, respectively). A distinct receptor subtype for angiotensin II and III, the AT ₂ receptor, is not G protein coupled and is of unclear physiologic significance in the periphery, but may counteract AT ₁ effects by inducing natriuresis. Aldosterone, the primary and most potent endogenous mineralocorticoid released by the zona glomerulosa, acts on target tissues expressing the nuclear mineralocorticoid (or type I glucocorticoid) receptor to promote sodium absorption and potassium excretion. For control of intravascular volume, the primary target of action of aldosterone is the distal nephron. Here, aldosterone increases synthesis of apical membrane sodium channels, mitochondrial enzymes involved in adenosine triphosphate production, and components of Na ⁺ , K ⁺ adenosine triphosphatase to cause increased sodium reabsorption and potassium excretion.

Regulation of Secretion

Decreased intravascular volume as sensed by the renal juxtaglomerular apparatus results in release of renin. Increased plasma renin activity then allows increased conversion of angiotensinogen to angiotensin I, which in turn is converted peripherally to angiotensins II and III. Increased angiotensin II activity causes vasoconstriction and blood pressure elevation, whereas both angiotensins II and III stimulate aldosterone release from the zona glomerulosa and subsequent salt and water retention and potassium excretion by the distal tubule of the kidney. Conversely, expanded intravascular volume causes decreased renin output and less sodium and water resorption in the kidney, serving to decrease intravascular volume and restore homeostasis.

Changes in vascular volume are not the only regulators of the renin-angiotensin-aldosterone system. Serum potassium concentration directly modulates aldosterone release by the adrenal glomerulosa by its effects on plasma membrane potential and activation of voltage-gated calcium channels. By membrane depolarization, increased serum potassium leads to increased aldosterone synthesis, which promotes renal potassium excretion, whereas low serum potassium reduces aldosterone synthesis and decreases urinary potassium losses. Pituitary adrenocorticotropin hormone and vasopressin act through their respective receptors on the glomerulosa cells to increase acute aldosterone secretion. These effects are of short duration because long-term chronic infusions do not chronically elevate aldosterone concentrations. Direct inhibitors of aldosterone secretion, and thus promoters of natriuresis, include atrial natriuretic peptide (ANP), somatostatin, and dopamine.

Anatomy and Biochemistry

In addition to the well-defined endocrine circuit, the components of the renin-angiotensin system have been found in a wide variety of tissues, including brain, pituitary, arterial wall, heart, ovary, kidney, and adrenal, where paracrine and autocrine regulatory functions have been postulated, undergoing regulation independent of the systemic counterpart. From the standpoint of regulation of water and volume homeostasis, the brain renin-angiotensin system merits further description. It has long been known that peripherally synthesized angiotensin II could increase blood pressure by effects on the brain outside the blood-brain barrier, at sites such as the OVLT, SFO, area postrema, and median eminence, as revealed by ligand-binding studies. Over the past decade, it has become clear that the complete system for generation of angiotensin II is present within the brain. Angiotensinogen has been localized to astrocytes by both immunohistochemical peptide localization and in situ hybridization analysis of messenger RNA. In contrast, renin has been found in high concentration in nerve terminals, with enhanced release on nerve depolarization. Angiotensin-converting enzyme has been found within vascular, choroid plexus, and neuronal components of the central nervous system, most notably the SFO and many hypothalamic nuclei, sites of endogenous angiotensin II receptor expression, primarily of the AT ₁ subtype, as well as sites not expressing the angiotensin II receptor, such as the basal ganglia. The primary effector molecule, angiotensin II, has been localized specifically to neurons and subcellularly to synaptic vesicles. Two of the most significant sites include the circumventricular organs and the paraventricular nucleus of the hypothalamus. Within the paraventricular nucleus, angiotensin II immunoreactivity colocalizes with magnocellular vasopressin, whereas its receptors are within the parvocellular region of the paraventricular nucleus.

Regulation of Secretion

The forebrain angiotensin II pathway, of which the paraventricular nucleus is one component, and circumventricular organ angiotensin II pathway are important control centers for maintenance of osmotic and volume homeostasis. Increased concentration of peripheral angiotensin II, as would be expected in intravascular volume depletion, stimulates drinking behavior. This action of peripheral angiotensin II can be abolished by destruction of the OVLT or SFO, regions whose destruction has long been recognized as causing adipsia. Further effects of central angiotensin II action include augmentation of sodium appetite and stimulation of vasopressin release, all serving, as with peripheral angiotensin II, to restore intravascular volume and maintain blood pressure. The signal of hypovolemia is transduced through the vagal nerve from volume sensors to the brain stem and the region of the nucleus tractus solitarius. Efferents from these brain-stem centers project to the median preoptic nucleus and paraventricular nucleus, as does the forebrain angiotensin II pathway, where drinking and pressor effects, as well as vasopressin release, are elicited.

Separate pathways for vasopressin release mediate the response to either peripheral angiotensin II or purely osmotic stimulation of the osmosensors. The release of vasopressin in response to osmotic stimulation is not increased by peripheral angiotensin II, and pure osmotic stimulation does not increase salt appetite. Central angiotensin II, in contrast, may function as a transmitter in the osmosensing circuit, leading to vasopressin release.

Anatomy and Biochemistry

ANP was initially discovered as a component of cardiac atrial muscle that was able to induce natriuresis, a decrease in blood pressure, and an increase in hematocrit when injected into rats.

The biologically active form of ANP consists of a 28-amino-acid peptide that includes a 17-amino-acid ring structure ( Fig. 12.11 ). The primary sequence of the peptide has been conserved among mammalian species and, in addition to synthesis in cardiac atrial tissue, has been detected in brain, spinal cord, pituitary, and adrenal gland. Within the brain, ANP synthesis occurs at several critical neuroendocrine regulatory sites, including the periventricular, arcuate, anteroventral preoptic, and lateral hypothalamic nuclei. ANP is synthesized as a 151-amino-acid preprohormone and is stored as a 126-amino-acid prohormone after removal of the signal peptide sequence. Coupled with secretion of pro-ANP is its cleavage between amino acids 98 and 99 to yield the mature 28-amino-acid 99–126 fragment.

Subsequent investigation defined a second peptide from porcine brain with structural homology to ANP. This peptide, designated brain natriuretic peptide (BNP), was later found to be secreted by the heart as well, in this case, from both ventricular and atrial tissue. Human BNP consists of a 32-amino-acid processed from a larger preprohormone sharing a central ring structure with ANP (see Fig. 12.11 ), although it is less conserved between species than ANP.

A third member of this family, C-type natriuretic peptide (CNP), was also isolated from porcine brain. In brain, CNP is the most abundant member of the natriuretic peptide family. Within the hypothalamus, specific sites of synthesis largely overlap sites of ANP expression. Little CNP can be detected in plasma, and in marked contrast to ANP and BNP, CNP does not increase in plasma in the setting of cardiac failure. Outside the brain, CNP is synthesized in endothelial and vascular smooth muscle. In tissues capable of CNP gene expression, two forms of the peptide are produced, a 53-amino-acid peptide and a less abundant 22-amino-acid molecule (see Fig. 12.11 ).

Three distinct endogenous receptors exist for the natriuretic peptides. The first of these receptors isolated (natriuretic peptide receptor [NPR]-A or guanylyl cyclase [GC]-A) was cloned by virtue of its homology to sea urchin sperm guanylyl cyclase and was later found to have ANP and BNP as its normal ligands. A second guanylyl cyclase type receptor (NPR-B) has substantial homology to NPR-A; however, it binds CNP with substantially greater affinity than ANP or BNP. A third receptor (NPR-C ) does not possess guanylyl cyclase activity and probably functions to clear all three natriuretic peptides from the circulation. In situ hybridization studies using probes capable of distinguishing the different receptor types have revealed some interspecies discrepancy in distribution. The NPR-A receptor has been localized to kidney, adrenal, pituitary, brain, and heart in monkey, with NPR-B limited to adrenal, pituitary, and brain. In rat, broad tissue distribution of both NPR-A and NPR-B has been described. The NPR-C receptor has similarly been found in adrenal, heart, brain, and pituitary.

Regulation of Secretion and Action

Secretion of ANP by cardiac tissue occurs in response to increasing atrial transmural pressure, from both left and right atria. Studies using intravascular volume expansion, exercise, and hypoxia demonstrate increased plasma concentration of ANP after these stimuli in both animal and human paradigms. Also increased heart rate, especially increased atrial contractile frequency, results in increased ANP secretion. In the setting of supraventricular tachycardia, high plasma concentration of ANP, as well as suppressed concentration of vasopressin (both probably caused by an increase in atrial volume and pressure) contribute to the polyuria associated with this syndrome. Ventricular production of ANP has also been demonstrated; it is increased in states of left-sided overload associated with ventricular hypertrophy. ANP synthesized within the central nervous system varies in a volume-dependent fashion, in a manner similar to peripheral ANP, suggesting similar function.

The physiologic ramifications of increased ANP production are several. Infusion of ANP in the setting of normovolemia causes natriuresis, diuresis, and a small increase in divalent cation excretion. ANP, through the NPR-A receptor, primarily inhibits sodium reabsorption within the renal inner medullary collecting duct, but also opposes the salt-retaining effects of angiotensin II at the level of the proximal tubule. ANP similarly inhibits the actions of vasopressin and aldosterone in the renal tubules. Direct cardiovascular effects of ANP include arterial smooth muscle relaxation, both acutely and with chronic administration. In part, this effect may be mediated through opposition of angiotensin II action.

ANP modulates mineralocorticoid production in a manner that results in the reduction of intravascular volume or pressure. Although direct reduction in plasma renin activity has been described with ANP infusion, the most dramatic response to ANP occurs at the level of the adrenal glomerulosa cell. ANP inhibits aldosterone production by inhibiting action of most aldosterone secretagogues, with the most pronounced reduction being angiotensin II activity. The serum concentration of ANP at which the effects on plasma renin activity and aldosterone production occur is within the physiologic range, although the importance of this pathway in normal human physiology remains incompletely defined.

Direct injection of ANP into the central nervous system of animals has suggested an important role for ANP (or CNP) in cardiovascular and salt homeostasis. Hypotension and bradycardia have both been observed, as has inhibition of vasopressin, adrenocorticotropic hormone, and gonadotropin-releasing hormone secretion. Thus antagonistic action of ANP and angiotensin II on intravascular volume and blood pressure remain congruent between central and peripheral systems.

BNP synthesis and secretion from cardiac ventricular tissue are augmented in congestive heart failure, and, as for ANP, with hypertension, chronic renal, and chronic liver failure. BNP binds the NPR-A receptor, where it is capable of stimulating cyclic guanosine monophosphate production. Infusion of BNP inhibits aldosterone production and results in natriuresis similar to that reported for ANP. With infusion rates generating BNP concentrations 10-fold greater than baseline, reduction in blood pressure has also been found. In addition to modulating sodium homeostasis, ANP and BNP, via NPR-A receptors, stimulate the transition of white to beige fat, and therefore may be involved in thermoregulation and energy balance.

In contrast to ANP and BNP, CNP expression primarily causes activation of the NPR-B receptor. Plasma concentration of CNP does not change significantly with volume overload, and it is believed the majority of CNP action occurs in a paracrine fashion, both within the brain and vasculature. CNP synthesized within vascular endothelium acts on receptors in vascular smooth muscle to cause relaxation. CNP infusions in dogs acutely reduce blood pressure and right atrial pressure, but do not result in natriuresis, whereas, in humans, moderately supraphysiologic doses cause neither hypotension nor natriuresis. In contrast to ANP, intracerebroventricular infusion of CNP leads to a reduction in blood pressure, suggesting a role for CNP in central control of arterial pressure. CNP inhibits angiotensin II–stimulated vasopressin secretion but stimulates thirst. The overall importance of the CNP central pathways in modulation of water balance in humans remains to be defined.