Renal effects of cyclic AMP in normal and congenital diabetes insipidus rats

The administration of dibutyryl cyclic AMP to normal rats undergoing water diuresis and to rats with congenital diabetes insipidus resulted in a rise in the excretion of Na⁺ and K⁺. A reduction in free water clearance was also observed in the normal rat, but this could not be entirely attributed to the effect of the nucleotide alone. Infusion of cyclic AMP to Brattleboro rats led to a modest rise in urine osmolality and a fall in urine flow, free water clearance and solute excretion, all of which could be explained on the basis of a fall in GFR. From the present experiments, it may be concluded that at the doses used neither cyclic AMP nor its dibutyryl derivative mimic the effects of ADH on water reabsorption by the kidney in vivo.     

Renal effect of acute hypobaric pressure breathing in normal and diabetes insipidus rats

The role of blood volume regulatory mechanisms located in the low pressure system in the control of urinary excretion was studied using hypobaric pressure breathing in normal and diabetes insipidus (Brattleboro strain with a congenital lack of vasopressin) rats. Rats were placed in an altitude simulator chamber for 4 h. A pump maintained pressure reduced to 701, 577 and 472 mbar simulating respectively altitude of 3,000, 4,500 and 6,000 m. In normal rats, hypobaric breathing induced an increase in urine flow, urinary urea and K+ excretion and urinary pH but did not significantly modify creatinine and Na+ excretion. In diabetes insipidus rats, hypobaric breathing produced oliguria and an decrease in urea, creatinine, Na+, K+, Cl- urinary excretions. Since acute hypobaric pressure breathing induced opposed effects in normal and Brattleboro rats, it is suggested that this kind of experimental procedure which increases intrathoracic blood volume elicits a diuretic response through an inhibition of vasopressin release. These experiments confirm the main role of vasopressin in the control of central blood volume.     

Plasma ADH in normal Long-Evans rats and in Long-Evans rats heterozygous and homozygous for hypothalamic diabetes insipidus.

A radioimmunoassay for the measurement of arginine-vasopressin (AVP) in rat plasma is described. By precipitating plasma proteins with acetone prior to the assay, a blanc value of zero was obtained for plasma of rats with hypothalamic diabetes insipidus (DI). Under $\text{ad lib}$. water intake as well as after 48 hrs of dehydration, AVP concentrations in plasma of rats heterozygous for DI were by roughly 50 % lower than in plasma of normal control rats. In plasma of DI rats no AVP was measurable 24 hrs after withdrawal of water. These data support the notion that DI rats do not produce any AVP and that the heterozygous animals have partial ADH deficiency. - In normal and heterozygous rats, AVP concentrations in plasma obtained at 5 p.m. were lower than in plasma collected at 10 a.m. This might indicate a diurnal fluctuation of plasma AVP concentrations in the rat.     

Microtubular number in the tractus hypophyseus of newborn normal rats and newborn rats with congenital diabetes insipidus

Summary Evidence has already been adduced suggesting that an increase in microtubular number occurs in the tractus hypophyseus of rats stressed by the administration of hypertonic saline, and of rats with congenital diabetes insipidus (CDI). Since the tractus hypophyseus in these animals shows high secretory activity, it seems likely that the microtubular increase reflects the participation of microtubules in axoplasmic transport. To exclude, however, a congenital microtubular abnormality in CDI, affected newborn rats were examined. In these, the microtubular number was normal, thus suggesting that the increase in microtubular number seen in adult animals was not a congenital morphological abnormality. However, by 4 days of age there was a slight but statistically significant increase in microtubular number in affected rats, a change probably attributable to increased secretory activity.This project was supported by the Medical Research Council     

Vasopressin and ethanol preference. II. Altered preference in two strains of diabetes insipidus rats and nephrogenic diabetes insipidus mice

In the first paper of this series, the influence of a single gene (di) for vasopressin deficiency on ethanol intake in rats was demonstrated. We studied preference for concentrations of ethanol between 2.2 and 10 percent versus tap water in Brattleboro rats homozygous for diabetes insipidus (di/di), heterozygous (di/+) or normal (+/+). The di/di rats, totally lacking in vasopressin, had greatly reduced preference scores for all concentrations of ethanol. Their intake of ethanol (g/day) was higher than heterozygotes or normals, but only when 2.2 percent ethanol was offered as a choice. Treatment with vasopressin or related peptides restored ethanol drinking to normal but also corrected water balance. In the experiments reported here, Roman High Avoidance (RHA) rats of three genotypes (+/+, di/+, and di/di) were also tested for ethanol intake and preference with similar but not identical results. Thus, the effects of the di gene are independent of the genetic background on which it is placed to at least some extent. Chlorothiazide, a drug unrelated to vasopressin, also normalized ethanol drinking and corrected water balance in di/di rats. In nephrogenic diabetes insipidus mice, there was a strong negative correlation between severity of polydipsia and preference for ethanol. Thus, no paradigm tested was effective in dissociating polydipsia from reduced ethanol preference and increased ethanol intake. While these results cannot exclude a possible regulatory role for endogenous vasopressin in ethanol preference drinking, they more strongly suggest that reduced preference for ethanol and increased ethanol intake are epiphenomena secondary to a polydipsic state.     

Effects of diabetes insipidus mutations on neurophysin folding and function

Mechanisms underlying the pathogenicity of diabetes insipidus mutations were probed by studying their effects on the properties of bovine oxytocin-related neurophysin. The mutations G17V, DeltaE47, G57S, G57R, and C67STOP were each shown to have structural consequences that would diminish the conformational stability and folding efficiency of the precursors in which they were incorporated, and factors contributing to the origins of these property changes were identified. Effects of the mutations on dimerization of the folded proteins were similarly analyzed. The projected relative impact of the above mutations on precursor folding properties qualitatively parallels the reported relative severity of their effects on the biological handling of the human vasopressin precursor, but quantitative differences between thermodynamic effects and biological impact are noted and explored. The sole mutation for which no clear thermodynamic basis was found for its pathogenicity was 87STOP, suggesting that the region of the precursor deleted by this mutation plays a role in targeting independent from effects on folding, or participates in stabilizing interactions unique to the human vasopressin precursor.     

Natriuretic effect of atrial natriuretic peptide in diabetes insipidus rats

Washout of the solute concentration gradient in the renal medullary interstitium has been suggested to play a role in mediating the natriuretic response to atrial natriuretic peptide (ANP). The purpose of this study was to determine the effects of ANP 8-33 on sodium excretion in Brattleboro diabetes insipidus (DI) rats, in which medullary tonicity is known to be decreased as compared to Long-Evans (LE) control rats. Basal urine osmolality (Uosm) was significantly lower in DI rats as compared to LE rats (123 +/- 6 vs 673 +/- 38 mOsm/kg). Infusion of ANP 8-33 at a rate of 4 micrograms/kg/hr for 60 min resulted in a significantly greater increase in UnaV (delta 6.1 +/- 1.2 vs delta 2.9 +/- 0.7 microEq/min) and urine flow (delta 40 +/- 12 vs delta 8 +/- 7 microliter/min) in the LE rats than in the DI rats. The greater natriuresis occurred in the LE rats despite no significant change in Uosm. Fractional lithium reabsorption (an indicator of proximal sodium reabsorption) decreased similarly in both groups. Infusion of ANP had no effect on mean arterial pressure in LE and DI groups. In summary, infusion of ANP in the DI rat resulted in a significant natriuresis, albeit less than in LE rats. The natriuresis in the LE rats occurred despite no significant change in Uosm. These data suggest that mechanisms other than medullary washout are responsible for the natriuretic effects of ANP.     

Prenatal exposure to ethanol causes partial diabetes insipidus in adult rats

Chronic consumption of ethanol in adult rats and humans leads to reduced AVP-producing neurons, and prenatal ethanol (PE) exposure has been reported to cause changes in the morphology of AVP-producing cells in the suprachiasmatic nucleus of young rats. The present studies further characterize the effects of PE exposure on AVP in the young adult rat, its hypothalamic synthesis, pituitary storage, and osmotically stimulated release. Pregnant rats were fed a liquid diet with 35% of the calories from ethanol or a control liquid diet for days 7-22 of pregnancy. Water consumption and urine excretion rate were measured in the offspring at 60-68 days of age. Subsequently, the offspring were infused with 5% NaCl at 0.05 ml.kg(-1).min(-1) with plasma samples taken before and at three 40-min intervals during infusion for measurement of AVP and osmolality. Urine output and water intake were approximately 20% greater in PE-exposed rats than in rats with no PE exposure, and female rats had a greater water intake than males. The relationship between plasma osmolality and AVP in PE-exposed rats was parallel to, but shifted to the right of, the control rats, indicating an increase in osmotic threshold for AVP release. Pituitary AVP was reduced by 13% and hypothalamic AVP mRNA content was reduced by 35% in PE-exposed rats. Our data suggest that PE exposure can cause a permanent condition of a mild partial central diabetes insipidus.     

The juxtaglomerular apparatus of rats with hereditary hypothalamic diabetes insipidus

Summary The juxtaglomerular apparatus (JGA) of rats with hereditary hypothalamic diabetes insipidus (DI) was studied. Plasma concentration of renin and angiotensin II, as well as serum sodium concentration and serum osmolality of DI rats are elevated. The morphological examination reveals no characteristic alteration of the epitheloid cells. The results show that the epitheloid cells are sufficiently adapted for the higher release of renin.Supported by the Deutsche Forschungsgemeinschaft SFB 90 Heidelberg. The expert technical assistance of Mrs. Marlis Kopp is gratefully acknowledged     

Dissociation of cold-water swin and morphine analgesia in Brattleboro rats with diabetes insipidus

The present study examined whether vasopressin mediated the analgesic response to morphine and cold-water stress by comparing the analgesic responses of homozygous Brattleboro rats with diabetes insipidus with those of normal rats of the same strain of similar weight. Brattleboro rats exhibited hypersensitive responses to foot shock which were brought back to within normal limits by systemic administration of arginine vasopressin and desamino-D-arginine vasopressin. While Brattleboro rats failed to display an analgesic response to cold-water swim stress, they displayed a normal analgesic response to morphine. These results provide further evidence for dissociation of pain-inhibitory mechanisms into opioid and non-opioid components, and suggests that vasopressin might be involved in the elucidation of the latter component.