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Editorials |
Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
Correspondence: Dr. Sei Sasaki, Department of Nephrology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8519, Japan. Phone: 81-3-5803-5212; Fax: 81-3-5803-0132; E-mail: ssasaki.kid{at}tmd.ac.jp
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The understanding of water permeability along the collecting ducts at a molecular level has substantially advanced since the discoveries of the vasopressin type 2 receptor (V2R) and aquaporin-2 water channel (AQP2).3,4 Binding of vasopressin to V2R located at the basolateral membrane of collecting duct cells activates adenylate cyclase, which in turn increases cAMP levels and stimulates protein kinase A. Subsequent protein kinase A–mediated phosphorylation of AQP2 itself triggers trafficking of AQP2 from storage vesicles to the apical membrane (short-term regulation). Increased intracellular cAMP also enhances the transcription of AQP2 through a pathway mediated by a cAMP-responsive element, increasing the abundance of AQP2 (long-term regulation). Vasopressin as well increases the expression of AQP3 on the basolateral membrane of collecting ducts. This evidence clearly tells us that circulating vasopressin and V2R and AQP2/AQP3 in collecting duct cells are key players in urine concentration.5,6
What about oxytocin? Does it contribute to urine-concentrating ability? Recognition of the antidiuretic effect of oxytocin goes back to the early 1960s with clinical observations showing that systemic infusion of high-dosage oxytocin in obstetric patients causes antidiuresis, indicating vasopressin-like effects.7,8 Later studies in Brattleboro rats (congenital vasopressin-deficient rats) clearly show that exogenously administered oxytocin also has an antidiuretic effect. Oxytocin at low physiologic dosages increases the water permeability of medullary collecting ducts in Brattleboro rats through the V2 receptor but not the oxytocin receptor.9
Li et al.10 in this issue of JASN now show in Brattleboro rats that chronic minipump infusion of oxytocin stimulates apical localization of AQP2 (short-term regulation) and increases the protein abundance of AQP2 and AQP3 in the inner medulla of the kidney (long-term regulation), with the effects again mediated by V2 receptor, not by the oxytocin receptor. This study thus seems to complete the story: Oxytocin binds to V2R, regulates AQP2 and AQP3 in short- and long-term settings, and ultimately facilitates water permeability of the collecting duct.
What are the implications of this antidiuretic effect by oxytocin? Two issues of clinical relevance are immediately apparent. First, oxytocin infusions are not infrequently used to induce labor toward the end of pregnancy; however, because rates of infusion are low and transient, antidiuresis is mild and water intoxication unlikely. In relatively more rare clinical situations, such as when evacuating the products of conception in cases of missed or incomplete abortion or stimulating myometrial conceptions in instances of uterine atony during the early puerperium, larger infusions of oxytocin can be administered for a longer period and may cause antidiuresis, resulting in water intoxication.7,8 In these settings, harmful events can be prevented if physicians are aware of the antidiuretic action of oxytocin and restrict infusions of water. Limiting the volume of electrolyte-free fluid is essential. In this regard, the recent clinical availability of nonpeptide V2R antagonists is good news.11 Water retention resulting in acute symptomatic hyponatremia as a result of oxytocin infusion probably can be reversed with V2R antagonists while the oxytocin receptor-mediated uterine contraction persists.
Second, oxytocin may be a good candidate to explain the presence of unknown antidiuretic substances in syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In patients with SIADH, plasma vasopressin levels are usually inappropriately high compared with plasma osmolality, but vasopressin levels are below the limits of RIA detection in a certain portion of the patients (as much as 10 to 20%).12 The existence of other antidiuretic substances in plasma has been postulated. Oxytocin may fit this profile nicely. A few studies have shown elevated levels of plasma oxytocin in patients with small-cell lung cancer; however, these increments were usually accompanied by concomitant increases in vasopressin.13 At present, no report has suggested that oxytocin alone produces SIADH in clinical cases, but this may be attributable to the lack of a reliable RIA for oxytocin in clinical settings. Related to this topic, the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is caused by a gain-of-function mutation of V2R. In this disease, endogenous vasopressin is completely suppressed while antidiuresis persists.14 The symptoms of disease start from childhood, but similar mutations seem to explain some sporadic episodes of SIADH in adults.15
How should we differentiate oxytocin-induced SIADH from NSIAD? Oxytocin-induced SIADH will respond to V2R antagonists as illustrated by Li et al.10, whereas patients with NSIAD are unable to respond to V2R antagonists.15 Clinicians would thus be well advised to note that oxytocin has antidiuretic activity and contributes to hyponatremia in certain clinical settings and that V2R antagonists may be useful in the differential diagnosis and treatment of inappropriate antidiuresis.
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Footnotes |
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See related article, "Molecular Mechanisms of Antidiuretic Effect of Oxytocin," on pages 225–232.
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