The effects of elevated circulating prolactin in rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain)

Administration of ovine or rat PRL to animals, including man, has resulted in decreased urine volume and increased urine osmolality. Contamination of PRL preparations with vasopressin is the most likely explanation for the apparent antidiuretic effect. In this study, diabetes insipidus rats lacking vasopressin(homozygous Brattleboro rats) had extra anterior pituitary glands implanted under the kidney capsule, resulting in hyperprolactinemia. The urine of such rats was not more concentrated than that of unoperated littermates or sham-operated littermates with diabetes insipidus. In fact, hyperprolactinemic male rats produced even less concentrated urine than control rats. Furthermore, the hyperprolactinemic rats responded to exogenous vasopressin in a manner similar to normoprolactinemic rats. These studies provide strong evidence against an antidiuretic action of PRL in mammals.     

Neurophysin biosynthesis in normal rats and in rats with hereditary diabetes insipidus.

When [35S]cysteine was injected adjacent to the supraoptic nucleus (SON) in rats, it was rapidly incorporated into proteins in the SON. The [35S]cysteine-labeled proteins extracted from the SON were separated by isoelectric focusing on polyacrylamide gels. Twenty minutes after the injection of [35S]cysteine, two major labeled peaks (pI = 5.4 and 6.1) were found in the SON of normal rats; Brattleboro rats had only one major labeled peak (pI = 5.4). One hour after the injection, four major radioactive peaks were found in the SON of normal animals (pI = 5.1, 5.4, 5.6, and 6.1). Animals with diabetes insipidus had only two major labeled proteins (pI = 5.1 AND 5.4). Twenty-four hours after normal rats were injected with [35S]cysteine, all of the labeled peaks described above, except for the one with pI = 5.1, had decreased markedly in size and a small amount of labeled protein with pI about 4.8 was present in the SON. After 24 hr the posterior pituitary of normal animals contained two [35S]cysteine-labeled proteins with pI = 4.6 AND 4.8. The pituitaries of Brattleboro rats had only the pI = 4.6 labeled protein. These pulse-chase data, with data we have presented elsewhere, indicate that the vasopressin- and oxytocin-neurophysins are synthesized as parts of separate precursors (pI = 6.1 and 5.4, respectively). These precursors are converted into at least two intermediates (pI = 5.6 and 5.1) which, in turn, yield the vasopressin-neurophysin (pI = 4.8) and the oxytocin-neurophysin (pI = 4.6).     

Atrial natriuretic peptides in brain nuclei of rats with inherited diabetes insipidus (Brattleboro rats)

The concentration of atrial natriuretic peptides (ANF) was measured radioimmunologically in 18 selected microdissected brain areas of rats with inherited diabetes insipidus (Brattleboro rats) and their control rats (Long-Evans rats). In 7 brain areas known to be involved in the regulation of fluid homeostasis or blood pressure (subfornical organ, organum vasculosum lamina terminalis, periventricular preoptic nucleus, perifornical nucleus, nucleus of the solitary tract, tegmentum pontis, arcuate nucleus) ANF concentration was significantly changed. After restoration of antidiuresis with the V2 receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP) ANF levels of Brattleboro rats adapted at least partly to those of the control rats in all brain areas except the subfornical organ. Furthermore, ANF was then significantly changed in the supraoptic and paraventricular nuclei of DDAVP-treated diabetes insipidus rats. These data show that the central ANF system is sensitive for changes in electrolyte and fluid homeostasis.     

Water and electrolyte balance in adrenalectomized rats with diabetes insipidus (Brattleboro strain) given antidiuretic hormone

Vasopressin [antidiuretic hormone (ADH) as pitressin tannate in oil] was injected daily into male Brattleboro rats with hypothalamic diabetes insipidus before and after adrenalectomy. Body weight increased after ADH treatment. Urine volume, water intake, and excretion of osmotically free water fell as urinary osmolarity increased; all stabilized after 5–6 days. Total solute, sodium, calcium, and magnesium excretory rates also diminished. After adrenalectomy, body weight, food and water intakes, and urine volumes were reduced compared with those of sham-operated ADH-injected animals. The proportion of the dietary intakes of sodium, potassium, calcium, magnesium, and chloride appearing in the urine all increased initially after adrenalectomy. Seven days after operation, plasma sodium concentration and muscle sodium content were reduced; plasma potassium concentration and muscle water content were also higher than in sham-operated animals. The pattern of adrenal insufficiency observed in these ADH-injected rats was similar to that previously found in adrenalectomized normal, but not diabetic, rats. Vasopressin clearly influeces some of the characteristic features of adrenalectomized animals.     

Blunted pressure natriuresis in the Brattleboro diabetes insipidus rat

Antidiuretic hormone is known to stimulate the renal synthesis of prostaglandins. These autacoids, in turn, modulate the pressure natriuresis phenomenon. Accordingly, the present study was done to test the hypothesis that, in the absence of antidiuretic hormone and antidiuretic hormone-dependent prostaglandin synthesis, the pressure natriuresis response is blunted. Experiments were performed on Brattleboro diabetes insipidus rats (n = 7) and Long Evans control rats (n = 14). A change in perfusion pressure in the Long Evans rats from 89.3 +/- 1.0 to 108.7 +/- 1.1 mm Hg (p less than 0.05) was associated with significant increases in the fractional excretion of sodium (1.1 +/- 0.2 to 2.3 +/- 0.3%) and the urinary prostaglandin excretion (32.6 +/- 6.8 to 56.6 +/- 10.0 pg/min). In contrast, a similar change in perfusion pressure in the diabetes insipidus rat from 88.6 +/- 1.4 to 106.2 +/- 1.5 mm Hg (p less than 0.05) resulted in no significant increases in either sodium or prostaglandin excretions. Treatment of a third group of diabetes insipidus rats (n = 9) with 1-desamino-8-D-arginine vasopressin (1 microgram/day) restored the natriuretic response to increases in renal perfusion pressure. Treated diabetes insipidus and Long Evans control rats had comparable natriuretic responses to increases in renal perfusion pressure. Untreated diabetes insipidus rats, on the other hand, had blunted responses. In summary, the pressure natriuresis response in diabetes insipidus rats is blunted compared with Long Evans control rats. We conclude that antidiuretic hormone is necessary for the complete expression of the pressure natriuresis response.     

Vasopressin and oxytocin content of microdissected hypothalamic areas in rats with hereditary diabetes insipidus.

Vasopressin was virtually absent from 5 microdissected hypothalamic areas and from the posterior pituitary glands of homozygous Brattleboro rats. The oxytocin concentration was normal in all these areas except for the arcuate nucleus, where it was absent. These results support the concept that Brattleboro rats have a specific defect in biosynthesis of vasopressin. The significance of the absence of oxytocin from the arcuate nucleus in these rats remains to be determined.     

The effects of vasopressin on pituitary oxytocin content and plasma renin activity in rats with hypothalamic diabetes insipidus (Brattleboro strain)

Drinking, urine flow and osmolarity, plasma renin activity (PRA), and pituitary oxytocin have been studied in male and female Brattleboro rats, homozygous [with diabetes insipidus (DI)] and heterozygous (non-DI) for the phenotype of hypothalamic diabetes insipidus. The polydipsia and polyuria as well as the extreme hypotonicity of the urine was confirmed for male and female DI rats: urine to plasma osmolar ratios averaged 0.5 in DI and 5.0 in non-DI. Under similar conditions female DI rats concentrated the urine slightly more than males. PRAs were higher in DI than in non-DI rats, a difference especially noticeable in male animals. Pituitary oxytocin content was much reduced in male and female DI rats compared with equivalent non-DIs. In male DI rats, vasopressin (1.0 U/rat/day for 7 days) produced a profound fall in PRA and an increased pituitary oxytocin content as well as inducing the formation of an hypertonic urine with renal reabsorption of osmotically free water. In female DI rats, graded does of vasopressin (0.1, 0.25, 0.5 or 1.0 U/rat/day for 8 days) all reduced the pituitary oxytocin concent to the same degree, while the reduction in fluid turnover and the marginal increases in PRA were roughly proportional to the dose employed. Female DI rats were less sensitive to vasopressin than male DI animals as judged by the urinary osmolarity achieved for a given dose of hormone.