**5. Concluding remarks**

was found to markedly increase their urinary osmolality [73–75], natriuresis [57, 73, 74], and water intake [69]. These preserved regulatory capacities of Brattleboro rats have been related to the presence of increased OT plasma levels [27, 40, 45, 73, 74, 76, 77], in contrast to the AVP

The OT-induced antidiuretic effect in Brattleboro rats was blocked by treatment with AVPR2 antagonist [23, 78–81] but not by OT receptor antagonist [80], suggesting that OT may act on AVPR2 of Brattleboro rats to activate the antidiuretic response [23, 24, 82]. However, OT does not appear to be the only hormone involved in the antidiuretic effects observed in Brattleboro rats. Morrissey et al. [46] reported that prolactin, an adenohypophyseal hormone that contributes to neurohormone secretion regulation [83], reduced urinary excretion volume in

OT also appears to be critical for the natriuretic capacity of Brattleboro rats. Thus, the suppression of OT secretion by neurohypox greatly diminished sodium excretion rates in Brattleboro rats; moreover, OT administration produced a substantial and sustained natriuresis in the

Besides increasing the antidiuretic and natriuretic capacity of Brattleboro rats, OT increases their urine osmolality, AQP2, glomerular filtration rate, and effective filtration fraction [21,

Other animal models have been developed in later studies. Thus, it has been found that mutations in the AQP2 gene that interfere with its cellular processing can produce autosomal recessive nephrogenic diabetes insipidus [85]. In addition, the transgenic rat TGR(ASrAOGEN)680, characterized by a transgene-producing antisense RNA against angiotensinogen in the brain and a reduced blood pressure [86], exhibits mild CDI due to a 35% reduction in plasma AVP and, unlike observations in Brattleboro rats, normal plasma sodium and osmolality [87]. With regard to the renin-angiotensin system, low-renin hypertensive animal models (e.g., transgenic TGR(mREN2)27 rat carrying the murine Ren-2 gene) have also proven useful [88].

**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.

and OT deficit of neurohypox, hypox, and MBH-lesioned animals [40, 41, 45, 49, 57].

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

Brattleboro but not control rats.

23, 74, 78–81, 84].

neurohypophysectomized animals [74].

In summary, although Brattleboro rats are considered as the prototype model of CDI, the hydromineral characteristics of these animals do not seem to be fully comparable with an acquired CDI animal model. Thus, there is an AVP secretion deficit in Brattleboro rats, but OT remains available, whereas the CDI resulting from brain damage blocks the secretion of both hormones. Moreover, the symptoms and characteristics of humans and animals with aCDI indicate the involvement of other factors besides the habitual lack of AVP, which appear to be related to the neurobiological systems affected in each animal model. For instance, natriuresis and antidiuresis are increased after salt loading in hypox animals [48, 49] but not in MBHlesioned animals [49] or humans with CDI [2].

Individualized therapies that take into account of the specific neurobiological system involved in each type of CDI are evidently desirable to improve the quality of life of these patients. However, according to the research data reviewed in this chapter, all CDI patients might benefit from a low-sodium diet and from OT administration or, possibly, the combination of low doses of AVP and OT.

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