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     

Regional analysis of brain opiate receptors in rats with hereditary hypothalamic diabetes insipidus.

The regional distribution of stereospecific ³H-dihydromorphine binding sites in Brattleboro rats with hereditary hypothalamic diabetes insipidus was studied. Control animals were homozygous normal Brattleboro rats and rats heterozygous for the vasopressin deficiency. Scatchard plots of ³H-dihydromorphine binding in a washed membrane preparation showed that rats with diabetes insipidus exhibited higher receptor concentrations in all assayed areas of the cerebral hemispheres. In the diencephalon, receptor concentrations were lower in diabetes insipidus rats. The results point to the existence of interactions between brain opioid systems and neurohypophyseal peptides.     

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.     

Prevalence of diabetes mellitus in individuals heterozygous and homozygous for sickle cell anemia

Colorimetric determinations of glycosylated Hb were carried out in a sample (n = 97) of sickle cell anemia patients, and in an age- and sex-matched group of individuals (n = 45) heterozygous for sickle cell anemia, from the Eastern Province of Saudi Arabia. A statistically significant increase in the value of glycosylated Hb was found in sickle cell trait (HbAS) group, when compared with those of sickle cell anemia (HbSS) and normal (HbAA) groups. Since glycosylated Hb is considered a valid indicator of long-term blood glucose, and assuming normal red blood cell survival in HbAS carriers, the increased value of glycosylated Hb may suggest that there exists a higher incidence of undiagnosed diabetes mellitus in individuals with heterozygous inheritance for sickle cell hemoglobin than homozygous sickle cell patients and normal individuals. The mechanism underlying this observation remains to be defined.     

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.     

Oxytocin action: lipid metabolism in adipocytes from homozygous diabetes insipidus rats (Brattleboro strain)

Oxytocin, like insulin, stimulates glucose oxidation in normal rat adipocytes. Fat cells from homozygous Brattleboro rats that exhibit diabetes insipidus (HoDI animals) and that have a normal number of oxytocin receptors, however, are unable to respond to oxytocin in terms of glucose oxidation. We now report that in adipocytes from HoDI animals that are responsive to insulin, oxytocin was also unable to stimulate lipogenesis. In contrast, oxytocin like insulin was able to inhibit epinephrine-stimulated lipolysis in adipocytes from HoDI animals. Thus, in HoDI adipocytes, the results indicate that the receptor-effector system is only partially defective.     

Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene.

Mutations in the X-chromosomal V2 receptor gene are known to cause nephrogenic diabetes insipidus (NDI). Besides the X-linked form, an autosomal mode of inheritance has been described. Recently, mutations in the autosomal gene coding for water-channel aquaporin 2 (AQP2) of the renal collecting duct were reported in an NDI patient. In the present study, missense mutations and a single nucleotide deletion in the aquaporin 2 gene of three NDI patients from consanguineous matings are described. Expression studies in Xenopus oocytes showed that the missense AQP2 proteins are nonfunctional. These results prove that mutations in the AQP2 gene cause autosomal recessive NDI.     

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.     

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     

Immunohistochemical localization of human pituitary glycopeptide (HPGP)-like immunoreactivity in the hypothalamus and pituitary of normal and homozygous diabetes insipidus (Brattleboro) rats

Sections of the hypothalami and pituitary glands of normal (Sprague-Dawley) and homozygous diabetes insipidus (Brattleboro) rats were stained with antiserum to a human pituitary glycopeptide (HPGP) by using the immunohistochemical peroxidase-antiperoxidase method at the light microscopic level. Our results show in normal rats that immunoreactive HPGP was localized in the perikarya of the magnocellular neurons of the hypothalamus, in the posterior pituitary, and in the nerve fibers distributed in the median eminence (ME) and in the areas between the supraoptic nuclei (SON), paraventricular nuclei (PVN), and median eminence and also in the suprachiasmatic nuclei (SCN), a part of the parvocellular system. In the Brattleboro rats, however, no staining was found either in the hypothalami or pituitary glands. The present data strongly support our previous hypothesis that HPGP, a 39 residue glycopeptide isolated from human neurohypophysis, may be part of the precursor of arginine-vasopressin and its neurophysin II (Pro-NP-AVP).     

The genetic conditions in heterozygous and homozygous populations of Drosophila. II. X-ray induced lethals in a homozygous and a heterozygous population

Strains of Drosophila melanogaster were made isogenic for their second chromosomes by means of the marker strain LCy/Pm. One of these strains was used as a founder for a homozygous experimental population (W). All other strains were mixed and established a heterozygous population (LKW). Both populations were free of lethals in the beginning with respect to their second chromosomes. After they had been exposed to an X-ray irradiation of 7000 r they contained about 26 per cent newly induced lethal chromosomes. Whereas in the heterozygous population the lethal frequency decreased rather fast to 10 per cent, that of the homozygous population remained rather constant at 25 per cent during a period of 135 days. After a year of continuation, however, both populations reached the same lethal frequency of about 10 per cent. Allelism tests carried out after 10 generations revealed that there was a highly heterotic lethal factor in the homozygous population. After excluding this heterotic lethal from the calculations, the lethal frequencies of the two populations remained significantly different. It was assumed that the relative mean fitness of lethal heterozygotes was generally higher in the homo-than in the heterozygous populations. The results indicate that homozygous populations are much more capable of incorporation new mutations than heterozygous.     

Platelet aggregation and ATP secretion in whole blood of normal cats and cats homozygous and heterozygous for Chediak-Higashi syndrome

A rapid and simple technique using the Whole Blood Lumi-Aggregometer was used to study storage pool disease in Chediak-Higashi homozygote and heterozygote cats. Feline Chedlak-Higashi platelets aggregated after the addition of both ADP and collagen. During platelet aggregation, ATP secretion was assayed; the whole blood aggregometer is effective in detecting decreased levels of secretable ATP in homozygote cats. No storage pool deficiency was found in heterozygote cats. However, upon analysis of impedance tracings, a decreased platelet aggregation response was seen in both homozygote and heterozygote cats. These results suggest that prolonged bleeding times in Chediak-Higashi cats may involve a mechanism in addition to a dense granule deficiency.