**Animal Models of Central Diabetes Insipidus: Oxytocin and Low-Sodium Diets as Complementary Treatments and Low-Sodium Diets as Complementary Treatments**

**Animal Models of Central Diabetes Insipidus: Oxytocin** 

DOI: 10.5772/intechopen.69538

Antonio Bernal, Javier Mahía and Amadeo Puerto

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

Antonio Bernal, Javier Mahía and Amadeo

http://dx.doi.org/10.5772/intechopen.69538

#### **Abstract**

Puerto

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68 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

Human central diabetes insipidus (CDI) is a neurobiological syndrome characterized by the presence of hypotonic polyuria, hypernatremia, and polydipsia. CDI can be acquired (aCDI) as the result of brain damage to magnocellular neurosecretory cells or fibers that constitute the hypothalamic-neurohypophyseal system or can be caused by genetic disorders (hereditary CDI). aCDI can be experimentally induced by various surgical interventions, including neurohypophysectomy, pituitary stalk compression (PSC), hypophysectomy, and hypothalamic mediobasal lesions. CDI has been associated with a deficient production of arginine vasopressin (AVP) (the antidiuretic hormone secreted by magnocellular system), while more recently, aCDI animal studies also suggest the possible involvement of oxytocin (OT) (a natriuretic-promoting hormone secreted by neurosecretory systems) and other factors related to serum fluid concentration. Both humans and animals with aCDI may benefit from the combined administration of AVP and OT and, importantly, from a low-sodium diet. Moreover, increased OT levels are observed in Brattleboro rats (with mutated AVP gene), which may explain the regulatory hydromineral capacity shown by these animals after hydromineral challenges. In short, the symptoms shown by the different CDI animal models suggest the involvement of additional factors besides the absence of AVP, which appear to depend on the particular neurobiological systems affected in each case.

**Keywords:** central diabetes insipidus, hypophysectomy, neurohypophysectomy, pituitary stalk compression, mediobasal hypothalamic lesion, arginine vasopressin, oxytocin, hypernatremia, low-sodium diet

### **1. Introduction**

The term diabetes refers to a wide variety of syndromes, including diabetes insipidus (DI), which share in common the copious production of urine (polyuria). DI is characterized by the

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excretion of abundant diluted, "tasteless" urine and was first described by Willis in the seventeenth century. The incidence of this disorder is around 1:25,000 cases, with no statistically significant differences between males and females.

In general, two main DI types can be distinguished: one that is related to deficient secretion of the antidiuretic hormone arginine vasopressin (AVP), which is better documented and referred to as central, neurogenic, neurohypophyseal, or hypothalamic DI, and another characterized by renal insensitivity to the antidiuretic effect of AVP, designated nephrogenic DI [1–5].

This chapter starts with a description of the general characteristics of central diabetes insipidus (CDI), including its symptoms, the brain systems involved, and the etiologies of acquired and hereditary CDI. We then review the main animal models of acquired (neurohypophysectomy, pituitary stalk compression (PSC), hypophysectomy, and hypothalamic mediobasal lesions) and hereditary (Brattleboro rats) CDI. Finally, data from animal and human studies are discussed in relation to the therapeutic usefulness of oxytocin and a lowsodium diet.

and human genes for OT-neurophysin I and AVP-neurophysin II are both on chromosome 20,

(A) Arginine Vasopressin

(B) Oxytocin

Cys -Tyr -Phe-Gln -Asn -Cys -Pro.Arg -Gly -NH2

Cys -Tyr -Ile -Gln -Asn -Cys -Pro-Leu -Gly -NH2

**Figure 1.** Chemical structure of (A) AVP and (B) OT. AVP is formed by amino acids cysteine-tyrosine-phenylalanine-

. In both cases, a ring of amino acids 1–6 is formed by a disulfide bond.

Animal Models of Central Diabetes Insipidus: Oxytocin and Low-Sodium Diets as...

http://dx.doi.org/10.5772/intechopen.69538

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and OT by cysteine-tyrosine-isoleucine-glutamine-asparagine-

Both hormones are synthesized in the perikarya of the magnocellular neurons of hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). There is a predominance of AVPproducing cells in the SON, while oxytocinergic cells are confined to the rostral and dorsal nucleus region. For its part, the magnocellular PVN possesses a similar number of oxytocinergic and vasopressinergic neurons; its anteromedial portion contains mostly OT neurons, whereas its anterolateral portion contains an inner part with AVP neurons, surrounded by a ring of OT neurons. Less densely packed groups of AVP and OT neurons are found in posterior PVN. The axons of this complex (magnocellular PVN and SON) pass through the inner part of the median eminence, forming the neurohypophyseal stalk, and terminate in the neurohypophysis. Axonal swellings have been identified near fenestrated capillaries in both the median eminence and neurohypophysis, permitting access of these neurohormones to the

Hyperosmolality, hypernatremia, and hypovolemia (isotonic loss of fluid and electrolytes) are the main triggers of AVP and OT secretion [7, 11, 12]. After AVP is released into the blood, it acts by binding to AVP receptor 2 (AVPR2) on the basal surface of renal collecting tubule cells, triggering an intracellular signaling cascade. This concludes with activation of a cyclic adenosine monophosphate kinase pathway, increasing the production and insertion of aquaporin-II (AQP2) channels into the cell membrane. This in turn leads to passive water resorption from the lumen of the nephron into the cells of the collecting duct along an osmotic gradient [12–15]. The consequent excretion of concentrated urine is a survival mechanism for prolonged starvation periods. Conversely, diluted urine is excreted in the absence of AVP [8]. The neurohormone OT is especially involved in the excretion of body sodium or natriuresis [11, 16–20]. This secretion appears to be stimulated by increases in the glomerular filtration rate [21] and reductions in tubular sodium reabsorption [22]. These effects are mediated by actions on OT receptors present in the kidney and also, indirectly, by cardiac secretion of

separated by only 12 kb of intergenic sequences [9].

glutamine-asparagine-cysteine-proline-arginine-glycine-NH2

cysteine-proline-leucine-glycine-NH2

bloodstream [10].
