The Role of Vasopressin V2 Receptor in Drug-Induced Hyponatremia

Hyponatremia is frequently encountered in clinical practice and usually induced by renal water retention. Many medications are considered to be among the various causes of hyponatremia, because they either stimulate the release of arginine vasopressin (AVP) or potentiate its action in the kidney. Antidepressants, anticonvulsants, antipsychotics, diuretics, and cytotoxic agents are the major causes of drug-induced hyponatremia. However, studies addressing the potential of these drugs to increase AVP release from the posterior pituitary gland or enhance urine concentration through intrarenal mechanisms are lacking. We previously showed that in the absence of AVP, sertraline, carbamazepine, haloperidol, and cyclophosphamide each increased vasopressin V2 receptor (V2R) mRNA and aquaporin-2 (AQP2) protein and mRNA expression in primary cultured inner medullary collecting duct cells. The upregulation of AQP2 was blocked by the V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors. These findings led us to conclude that the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the main mechanism of drug-induced hyponatremia. Previous studies have also shown that the V2R has a role in chlorpropamide-induced hyponatremia. Several other agents, including metformin and statins, have been found to induce antidiuresis and AQP2 upregulation through various V2R-independent pathways in animal experiments but are not associated with hyponatremia despite being frequently used clinically. In brief, drug-induced hyponatremia can be largely explained by AQP2 upregulation from V2R-cAMP-PKA signaling in the absence of AVP stimulation. This paper reviews the central and nephrogenic mechanisms of drug-induced hyponatremia and discusses the importance of the canonical pathway of AQP2 upregulation in drug-induced NSIAD.

Comprehensive Genomic Characterization of A Case of Granular Cell Tumor of the Posterior Pituitary Gland: A Case Report

Granular cell tumors of the pituitary belong to a rare family of neoplasms, arising from the posterior pituitary gland. Although considered benign, they may cause significant morbidity and residual disease after resection can lead to poor clinical outcomes. Currently, there is no known medical therapy for any posterior pituitary gland tumor, in part due to sparse molecular characterization of these lesions. We report data from whole exome sequencing of a case of granular cell tumor of the pituitary, performed under an institutional review board approved protocol. A 77 year-old female underwent resection of an incidentally diagnosed pituitary mass that was causing radiographic compression of the optic nerves with a subclinical temporal field defect and central hypothyroidism. The pathology of the resected specimen demonstrated a granular cell tumor of the posterior pituitary gland. Whole-exome sequencing revealed mutations predicted to be deleterious in key oncogenes, SETD2 and PAX8, both of which have been described in other cancers and could potentially be amenable to targeted therapies with existing approved drugs, including immune checkpoint inhibitors and histone deacetylase inhibitors, respectively. To our knowledge, this is the first comprehensive genomic characterization of granular cell tumor of the posterior pituitary gland. We report mutations in oncogenes predicted to be deleterious and reported in other cancers with potential for therapeutic targeting with existing pharmacologic agents. These data provide new insights into the molecular pathogenesis of GCT of the pituitary and may warrant further investigation.

Oestrogen-Dependent Oxytocin Dynamics in the Hypothalamus of Female Rats

Oxytocin (OXT) is produced in the hypothalamic nuclei and is secreted into systemic circulation from the posterior pituitary gland (PP). In the central nervous system, OXT regulates behaviours including maternal and feeding behaviours. Our aim was to evaluate whether oestrogen regulates hypothalamic OXT dynamics. Herein, we provide the first evidence that OXT dynamics in the hypothalamus vary with sex and that oestrogen may modulate dynamic changes in OXT levels, using OXT-mRFP1 transgenic rats. The fluorescence intensity of OXT-mRFP1 in the hypothalamic nuclei and PP was most strongly expressed during the oestrus stage in female rats and decreased significantly in ovariectomised rats. Oestrogen replacement caused significant increases in the fluorescent intensities in the hypothalamic nuclei and PP in a dose-dependent manner. This was also demonstrated in feeding behaviour and hypothalamic Fos neurons using immunohistochemistry. Hypothalamic OXT expression was oestrogen dependent and could be enhanced centrally by the administration of oestrogen.

Disorders of the posterior pituitary gland

The posterior pituitary produces arginine vasopressin, which has a key role in fluid homeostasis, and oxytocin, which stimulates uterine contraction during birth and ejection of milk during lactation. Cranial diabetes insipidus is the passage of large volumes of dilute urine due to vasopressin deficient synthesis and/or release. The most common cause is lesions of the neurohypophysis or the hypothalamic median eminence damaging the magnocellular neurons. MRI of the neurohypophysis is required to delineate the cause. Mild polyuria can be managed simply by ensuring adequate fluid intake; treatment with the long-acting vasopressin analogue, desmopressin is used for more severe cases. The syndrome of inappropriate antidiuresis is diagnosed when there is hyponatraemia with hypotonic plasma, inappropriate urine osmolality, and urinary sodium more than 20 mmol/litre, together with no evidence of volume overload or hypovolaemia, and normal renal, adrenal, and thyroid function.

Transient Central Diabetes Insipidus after Discontinuation of Vasopressin

Central diabetes insipidus (CDI) is an uncommon condition resulting from lack of vasopressin secretion from the posterior pituitary gland typically caused by some form of destruction of the gland. Here we present a case of transient CDI after discontinuation of vasopressin used for septic shock without evidence of overt pituitary damage. Serum sodium concentration peaked at 160 mmol/L in the setting of polyuria within days of vasopressin discontinuation without identified alternative etiologies. Sodium levels and urine output normalized with administration of desmopressin with continued stability after desmopressin was discontinued. This is one of few reported cases of diabetes insipidus occurring after discontinuation of vasopressin and the rapid and profound response to desmopressin in this case proves a central etiology. This case allows for speculation into predisposing risk factors for this phenomenon including preexisting neurological disease.

Lillian Mary Pickford. 14 August 1902—14 August 2002

Mary Pickford was an experimental physiologist who carried out pioneering work on the actions of the hormones (oxytocin and vasopressin [ syn. antidiuretic hormone, ADH]) secreted by the posterior pituitary gland, which is part of the brain. She provided understanding of how the secretion of these hormones is controlled to regulate body fluid composition, specifically the maintenance, through actions on the kidneys, of normal osmolarity and Na + concentration, and hence blood volume and pressure. Using the water-loaded dog model she showed that vasopressin is the only hormone that regulates the excretion of water, by stimulating the kidneys to concentrate urine; she found that oxytocin could stimulate excretion of Na + . She showed that acetylcholine is an excitatory neurotransmitter in the hypothalamus, stimulating the neurons that produce vasopressin to secrete—the first evidence for acetylcholine action in the brain. The principles that Mary established have been extensively confirmed; hence, she was important in the establishment of the concepts and discipline of neuroendocrinology, which is about the bidirectional interactions between hormones and the brain. Using human and animal models, in her later work Mary focused on possible roles of interactions between female sex hormones and vasodilating actions of oxytocin in the perimenopausal problem of ‘hot flashes’ (or ‘hot flushes’) experienced by many women. She faced, but overcame, entrenched gender prejudice during her career; she was the first woman to be elected to the Pharmacological Society, and the first woman appointed to a chair in the Edinburgh Medical School.