**4. OT and low-sodium diets as complementary treatments of CDI**

At the beginning of the twentieth century, patients and animals with CDI were successfully treated with pituitary extracts (which supposedly contained both AVP and OT) (see Qureshi et al. [89] for a review). However, the observation of another oxytocic effect associated with those treatments (stimulation of uterine muscle contraction) reduced the use of pituitary extracts and of OT itself. These data, alongside the discovery of Brattleboro rats, which apparently developed all DI symptoms, including blockage by nephrectomy, focused interest on a vasopressinergic approach to CDI [90]. Thus, it was considered that AVP deficit would be solely responsible for the excretion of large volumes of diluted urine (hypotonic polyuria) and would secondarily increase serum osmolality (hyperosmolality), serum sodium concentration (hypernatremia), and water intake (polydipsia). For this reason, the first-choice treatment for CDI patients is desmopressin (1-deamino-8-d-AVP), a synthetic analog of AVP that is selective for AVPR2 and exerts an even more potent regulatory effect than that of the hormone itself.

However, many studies reviewed in this chapter appear to suggest that other hormonal components besides AVP secretion are also interrupted, including OT in acquired CDI (the most frequent form). In this line, more recent studies [91] compared the effects of OT and desmopressin administration in CDI patients, finding that both treatments had positive effects on urine flow reduction, serum sodium concentration, and osmolality, and increased urine osmolality and urinary AQP2 excretion. Other authors also reported that the administration of minute amounts of pituitrin (containing AVP and OT) appears to control and improve fluid status with minimal adverse reactions [31]. This possible therapeutic option is consistent with the synergic natriuretic effect of low doses of OT and AVP observed in CDI animal models [40, 45]. It therefore seems plausible that the combined administration in humans of lowdose AVP and OT would enhance their effects while minimizing oxytocic side effects. Hence, besides its natriuretic and antidiuretic effects [24], OT administration in patients with CDI may exert a valuable hyponatremic effect [82].

In cases in which relatively large brain lesions are responsible for CDI (MBH model), the polydipsic response cannot be understood exclusively as a secondary effect of fluid excretion, because it continues to be observed in animals whose polyuria is interrupted by nephrectomy [61]. One of the factors that may explain this hyperdipsic response is diabetic hypernatremia, which would also not be solely a consequence of hypotonic excretion, in agreement with reports that lesions in the median eminence region may affect brain circuits that control body sodium levels [66].

Some more recent animal studies have suggested that food deprivation or a low-sodium diet may be potentially useful in CDI patients, always in combination with their habitual pharmacological treatment. In fact, low-sodium diets are frequently prescribed for patients with AVPresistant or nephrogenic DI [5, 92]. These data also agree with classic studies that have indicated a relationship between diabetic polydipsia and dietary sodium. Thus, substances that increase body sodium levels were reported to exacerbate polydipsia [35, 59, 93], and, conversely, water intake was reduced in animals that were food deprived [59, 89] or on a low-sodium diet [59].
