PubMed Health⌕ Search

Biomedical subjects

G L Robertson

Publications and source records attributed to G L Robertson.

At least 19 recordsLinked to original sources
PubMed2001

Antidiuretic hormone. Normal and disordered function.

In humans and most other mammals, the antidiuretic hormone (ADH) is a nonapeptide often referred to as arginine vasopressin (AVP). It is produced by large neurons that originate in the supraoptic and paraventricular nucleus of the hypothalamus and project through the pituitary stalk to terminate on capillary plexuses scattered throughout the posterior pituitary. These plexuses drain into the systemic circulation by way of the cavernous sinus and superior vena cava.

Arginine Vasopressin↗
PubMed1999

A novel mutation (R97C) in the neurophysin moiety of prepro-vasopressin-neurophysin II associated with autosomal-dominant neurohypophyseal diabetes insipidus.

Autosomal-dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the gene encoding vasopressin-neurophysin II (AVP-NPII) on chromosome 20p13. We analyzed the AVP-NP II gene in a family with adFNDI by direct sequencing. A novel C to T transition (289C-->T in the cDNA, resulting in the substitution of Arg 97 by Cys (R97C) in the prepro-AVP-NPII precursor molecule) was identified in the gene region encoding neurophysin II in the index patient. This amino acid change is thought to result in the formation of an incorrectly folded hormone precursor, which may lead to chronic neurotoxicity and explain the dominant inheritance of the disease.

Arginine Vasopressin↗
PubMed1999

Clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation.

The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by postnatal onset of polyuria and a deficient neurosecretion of the antidiuretic hormone, arginine vasopressin (AVP). Since 1991, adFNDI has been linked to 31 different mutations of the gene that codes for the vasopressin-neurophysin II (AVP-NPII) precursor. The aims of the present study were to relate the clinical phenotype to the specific genotype and to the molecular genetic effects of the most frequently reported adFNDI mutation located at the cleavage site of the signal peptide of AVP-NPII [Ala(-1)Thr]. Genetic analysis and clinical studies of AVP secretion, urinary AVP, and urine output were performed in 16 affected and 16 unaffected family members and 11 spouses of a Danish adFNDI kindred carrying the Ala(-1)Thr mutation. Mutant complementary DNA carrying the same mutation was expressed in a neurogenic cell line (Neuro2A), and the cellular effects were studied by Western blotting, immunocytochemistry, and AVP measurements. The clinical studies showed a severe progressive deficiency of plasma and urinary AVP that manifested during childhood. The expression studies demonstrated that the Ala(- 1)Thr mutant cells produced 8-fold less AVP than wild-type cells and accumulated excessive amounts of 23-kDa NPII protein corresponding to uncleaved prepro-AVP-NPII. Furthermore, a substantial portion of the intracellular AVP-NPII precursor appeared to be colocalized with an endoplasmic reticulum antigen (Grp78). These results provide independent confirmation that this Ala(-1)Thr mutation produces adFNDI by directing the production of a mutant preprohormone that accumulates in the endoplasmic reticulum, because it cannot be cleaved from the signal peptide and transported to neurosecretory vesicles for further processing and secretion.

Adolescent↗
PubMed1998

On the mechanism of the effects of potassium restriction on blood pressure and renal sodium retention.

Dietary potassium restriction increases sodium and chloride retention, whereas potassium administration promotes both diuresis and natriuresis. In epidemiologic and clinical studies, potassium intake is inversely related to blood pressure and is lower in blacks than in whites. The present studies examined the mechanism by which potassium restriction fosters sodium conservation and the impact of race on this response. Twenty-one healthy black and white men and women ingested an isocaloric, potassium-restricted diet (20 mmol/d) containing 180 mmol/d of sodium with and without a potassium supplement (80 mmol/d) for 9 days on two occasions. Additionally, eight of these subjects ingested the same diets for 3 days followed by a water load to determine free water clearance before and during the early phase of dietary potassium restriction. During potassium restriction, mean arterial pressure (MAP) derived from 24-hour blood pressure measurements was higher (85.7 +/- 1.6 mm Hg v 82.0 +/- 1.3 mm Hg; P < 0.001), cumulative sodium excretion lower (984 +/- 59 mmol/d v 1,256 +/- 58 mmol/d; P < 0.001), and weight greater (71.1 +/- 2.1 kg v 69.3 +/- 2.2 kg; P < 0.001). Blacks displayed no greater increase in MAP, although they excreted less sodium overall and less potassium on the potassium-supplemented diet. After a water load, minimum urine osmolality (Uosm) was lower (53.0 +/- 3.0 mOsm/L v 65.6 +/- 3.5 mOsm/L; P = 0.01) and free water clearance greater (4.44 +/- 0.59 mL/min v3.72 +/- 0.58 mL/min; P = 0.009) during potassium restriction. In conclusion, in healthy, normotensive subjects, potassium restriction was associated with an increase in blood pressure and volume expansion effected by increased renal sodium and chloride retention. Potassium restriction was also associated with increased free water clearance and enhanced diluting capacity consistent with augmentation of Na+, K+:2Cl- cotransporter activity in the thick ascending limb of Henle. This mechanism may play an important role in the renal adaptation required for potassium conservation, but at the expense of sodium chloride retention and an elevation in blood pressure.

Adult↗
PubMed1997

Psychotic exacerbations and enhanced vasopressin secretion in schizophrenic patients with hyponatremia and polydipsia.

BACKGROUND: For unclear reasons, life-threatening water intoxication often coincides with acute psychosis in polydipsic schizophrenic patients with chronic hyponatremia. In contrast, most polydipsic schizophrenic patients are normonatremic and never manifest hyponatremia. To explore whether the effect of acute psychosis on water balance differs in these 2 schizophrenic subgroups, we compared their responses to drug-induced psychotic exacerbations. METHODS: Matched polydipsic schizophrenic patients with (n = 6) and without (n = 8) hyponatremia were identified based on past and current indexes of fluid intake and hydration. A transient psychotic exacerbation was induced with an infusion of the psychotomimetic methylphenidate hydrochloride (0.5 mg/kg of body weight over a 60-second period). Antidiuretic hormone levels, subjective desire for water, and factors known to influence water balance were measured at 15-minute intervals for 2 hours. RESULTS: Except for the expected differences in plasma osmolality and sodium, basal measures were similar in the 2 groups. Following methylphenidate administration, antidiuretic hormone levels increased more in the hyponatremic patients (P < .02), despite their consistently lower plasma osmolality (P < .007). No known or putative antidiuretic hormone stimulus could account for this finding. Only basal positive psychotic symptoms (P < .09) and plasma sodium (P < .18) were even marginally associated with the peak antidiuretic hormone responses, but neither factor could explain the difference in the response by the 2 groups. CONCLUSION: Psychotic exacerbations are associated with enhanced antidiuretic hormone secretion, for unknown reasons, in schizophrenic patients with hyponatremia and polydipsia, thereby placing them at increased risk of life-threatening water intoxication.

Acute Disease↗
PubMed1997

Biochemical basis of partial nephrogenic diabetes insipidus phenotypes.

Biochemical properties of mutant type 2 vasopressin receptors (V2Rs) causing a partial phenotype of nephrogenic diabetes insipidus were investigated in transiently transfected HEK 293 cells. Cell surface expression of the V2R was not altered by substituting Asp85 in the second transmembrane region by Asn as determined by saturation binding assays. Although the affinity of the mutant V2R for arginine vasopressin (AVP) was reduced only 6-fold, the response of adenylyl cyclase activity to AVP revealed a 50-fold right shift in EC50 and a decreased maximum response for the mutant V2R. These data indicated that replacement of Asp85 by Asn affected coupling of the receptor to Gs, a conclusion substantiated by a 20-fold decrease in the calculated coupling efficiency of this receptor. The Gly201Asp mutation in the second extracellular loop, also found associated with an NDI partial phenotype, decreased cell surface expression of the V2R with minor reduction in ligand-binding affinity and coupling efficiency to Gs. A pronounced difference was observed for this mutant V2R between the stimulation of adenylyl cyclase activity promoted by AVP and the V2 vasopressin receptor agonist deamino[Cys1,D-Arg8]-vasopressin, suggesting an involvement of Gly201 in the selectivity of the receptor for different ligands. These data demonstrated that while decreased ligand-binding affinity and decreased coupling to Gs are responsible for the attenuation of response to ligand in the Asp85Asn mutant V2R, cell surface expression of the V2R is the major factor reducing cellular responses to ligand for the Gly201Asp mutant V2R.

Amino Acid Substitution↗
PubMed1996

Oropharyngeal regulation of water balance in polydipsic schizophrenics.

OBJECTIVE: Disordered water balance causes substantial morbidity in a subset of schizophrenics and is the consequence of unexplained defects in the regulation of fluid intake and antidiuretic function. We aimed to determine whether oropharyngeal regulation of water balance is altered in these patients. DESIGN: A 2-hour infusion of 3% saline, followed 35 minute later by an oral water load (10 ml/kg over 3 minutes). PATIENTS: Age and sex-matched polydipsic schizophrenics with (n = 5) and without (n = 8) hyponatraemia; non-polydipsic schizophrenics (n = 6); and normal controls (n = 13). MEASUREMENTS: Plasma osmolality, sodium, AVP, and reported desire for water (expressed in cups), determined prior to, and for 30 minutes following, the water load. RESULTS: Plasma osmolality and sodium were consistently lower in the hyponatraemics (P < 0.01). Significant changes did not occur until 20 and 25 minutes, respectively, after oral water loading, and were similar across the four groups. AVP levels were consistently lower in the two polydipsic groups (P < 0.001), fell within 5 minutes after drinking and then levelled off. Neither the acute fall nor the overall pattern of the responses differed across groups. Subjective desire for water also decreased within 5 minutes of drinking, and also to a similar extent, in the four groups. Subsequent levels remained suppressed in the non-polydipsic groups, but rebounded toward baseline in the two polydipsic groups. Thus the overall patterns differed (P < 0.05). At the end of the study, ad lib intake correlated significantly with reported desire for water (r = 0.51, P < 0.002). CONCLUSIONS: The oropharyngeal regulation of water intake is disrupted in polydipsic schizophrenics with and without hyponatraemia. In contrast, the oropharyngeal regulation of AVP secretion appears preserved in the hyponatraemic subset. Previously observed elevations in plasma AVP in this subset are thus unlikely to be related to defects in oropharyngeal regulation.

Adult↗
PubMed1996

The influence of polydipsia on water excretion in hyponatremic, polydipsic, schizophrenic patients.

To determine whether polydipsia is responsible for the altered water excretion in the subset of polydipsic schizophrenic patients who develop hyponatremia, the regulation of antidiuretic function was assessed in polydipsic schizophrenic patients with hyponatremia (n = 5), polydipsic schizophrenic patients without hyponatremia (n = 5), nonpolydipsic schizophrenic patients (n = 6), and normal controls (n = 8). The severity and duration of polyuria were similar in the two polydipsic groups. After oral water loading, maximal free water clearance was similar across all four groups. Free water clearance diminished, however, at lower plasma osmolalities in the hyponatremic polydipsics (P < 0.02) and at higher plasma osmolalities in the normonatremic polydipsics (P < 0.05) relative to that in the nonpolydipsic schizophrenics and normal subjects. The increase in plasma vasopressin after osmotic stimulation with hypertonic saline was slightly, but significantly (P < 0.02), blunted in both polydipsic groups. Hyponatremia occurs in some polydipsic schizophrenics because the relationship between free water clearance to plasma osmolality/sodium is shifted to the left. Polydipsia per se is not responsible for this still unexplained shift.

Adult↗
PubMed1996

Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder characterized by progressive postnatal deficiency of arginine vasopressin as a result of mutation in the gene that encodes the hormone. To determine the extent of mutations in the coding region that produce the phenotype, we studied members of 17 unrelated kindreds with the disorder. We sequenced all 3 exons of the gene by using a rapid, direct dye-terminator method and found the causative mutation in each kindred. In four kindreds, the mutations were each identical to mutations described in other affected families. In the other 13 kindreds each mutation was unique. There were two missense mutations that altered the cleavage region of the signal peptide, seven missense mutations in exon 2, which codes for the conserved portion of the protein, one nonsense mutation in exon 2, and three nonsense mutations in exon 3. These findings, together with the clinical features of FNDI, suggest that each of the mutations exerts an effect by directing the production of a pre-prohormone that cannot be folded, processed, or degraded properly and eventually destroys vasopressinergic neurons.

Arginine Vasopressin↗
PubMed1995

Adaptive resetting of the volume control of vasopressin secretion during sustained hypovolemia.

To determine the effect of sustained hypovolemia on vasopressin secretion, we studied rats after 1-32 h of diuretic therapy. We found that an injection of furosemide (10 mg/kg) produced a transient marked increase in urine output, a moderate 7-10% reduction in blood volume, and a three- to fourfold rise in plasma vasopressin from 1.6 +/- 0.2 to 5.6 +/- 1.0 pmol/l. When the hypovolemia was maintained by repeated injections of the diuretic, plasma vasopressin remained elevated for > or = 8 h but returned almost to normal by 32 h, even though plasma electrolytes, blood pressure, hematocrit, and the other measures of hypovolemia were unchanged. At this time, pituitary vasopressin was undiminished, and plasma vasopressin rose normally or even supranormally when an acute hypovolemic or osmotic stimulus (intraperitoneal polyethylene glycol or hypertonic saline) was superimposed. However, the lines describing the relationship of log plasma vasopressin to plasma volume and plasma sodium in the rats treated with furosemide for 32 h lay to the left of the same relationships in the rats treated for 8 h or the sham-treated controls. We conclude that, in rats, the vasopressin response to sustained hypovolemia persists for > or = 8 h but is markedly diminished by 32 h. The decline in plasma vasopressin during this interval appears to be due to adaptive resetting of the volume control mechanism.

Adaptation, Physiological↗
PubMed1995

Diabetes insipidus.

Diabetes insipidus, characterized by the excretion of copious volumes of unconcentrated urine, results from a deficiency in the action of the antidiuretic hormone arginine vasopressin and can be caused by any of four fundamentally different defects, including impaired secretion (neurohypophyseal diabetes insipidus), impaired renal response (nephrogenic diabetes insipidus), excessive fluid intake (primary polydipsia), or increased metabolism of the hormone (gestational diabetes insipidus). Differentiation between their causes, pathophysiology, and treatment methods is essential for effective management and is best achieved by a combination of hormonal, clinical, and neuroradiologic observations. Understanding of the genetic forms has advanced greatly and may soon lead to improved methods of prevention, diagnosis, and treatment.

Diabetes Insipidus↗
PubMed1994

Hypodipsic hypernatremia in a dog with defective osmoregulation of antidiuretic hormone.

Hypernatremia was detected in a dog that was evaluated because of seizures. During hospitalization, the dog was fully conscious and remained hypernatremic when drinking voluntarily and when water was added to the food. Urine volume increased and urine osmolality decreased during an infusion of hypertonic saline (2.5% NaCl) solution, despite development of progressive hyperosmolality. There was no correlation between plasma antidiuretic hormone concentration and osmolality during the infusion study. The dog released antidiuretic hormone normally after nonosmotic stimulation (ie, apomorphine administration). These findings allowed a diagnosis of hypodipsic hypernatremia caused by destruction of hypothalamic osmoreceptors. At necropsy, there was hydrocephalus, atrophy of the septum pellucidum, and neuraxonal dystrophy of the cuneate nuclei. The underlying neurologic disease responsible for the CNS lesions could not be determined, but hydrocephalus may have led to pressure atrophy in the region of the hypothalamus that contains osmoreceptors.

Animals↗
PubMed1994

The effect of the nonselective opioid antagonist diprenorphine on vasopressin secretion in the rat.

Although endogenous opioids are thought to be involved in the regulation of vasopressin secretion, their precise role is unclear. We studied the effect of the potent nonselective opioid antagonist diprenorphine on the vasopressin response to osmotic (hypertonic saline, ip), hypovolemic (polyethylene glycol, ip), and hypotensive (sodium nitroprusside, sc) stimuli in male rats. We found that diprenorphine sc produced a time- and dose-dependent inhibition of the plasma vasopressin response to the hypovolemic stimulus. This inhibition was greatest 30 min after injection of the drug, but lasted for at least 4 h, was evident at doses as low as 0.0022 mumol/kg, and reached a maximum of about 85% of the stimulated control at a dose of 2.2 mumol/kg. Diprenorphine also inhibited the vasopressin response to an osmotic or a hypotensive stimulus, but the effect was less complete (approximately 50%), required 100-fold higher doses of the drug, and appeared to be bimodal. The potent kappa 1-selective opioid agonist U-50,488H also suppressed the vasopressin response to these stimuli, but the effect was not selective for hypovolemia, and the doses required (0.135-13.5 mumol/kg) were about 10- to 100-fold higher than those of diprenorphine. We postulate, therefore, that diprenorphine potently and preferentially inhibits the vasopressin response to an acute hypovolemic stimulus by antagonizing the effect of some endogenous opioidergic system critical in the volume control system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

The effect of selective opioid antagonists on vasopressin secretion in the rat.

We have shown previously that the nonselective opioid antagonist diprenorphine inhibits the vasopressin response to an acute hypovolemic stimulus in rats. To elucidate the type of endogenous opioid receptor at which this inhibition occurs, we investigated whether more selective antagonists, administered alone or in combination with diprenorphine, also inhibited the vasopressin response to hypovolemia induced by ip injection of polyethylene glycol. We found that the rise in plasma vasopressin was inhibited by the kappa-antagonist Mr 2266 BS at doses 30- to 300-fold higher than those of diprenorphine. Over the same dose range (0.003-100 mumol/kg), the kappa 1-selective antagonist norbinaltorphimine and the mu-selective antagonist naloxone had no effect or enhanced the vasopressin response, whereas the delta-antagonist ICI 154,129 had no effect. By augmenting the vasopressin response to hypovolemia, higher doses of naloxone or nor-binaltorphimine offset the inhibitory effect of concurrently administered diprenorphine. Mr 2266 BS did not facilitate, inhibit, or offset the action of diprenorphine. The results support the hypothesis that the inhibition of vasopressin by diprenorphine is due to antagonism of an opioid receptor and suggest that it is one of the recently discovered kappa-subtypes. They also suggest that the vasopressin response to acute hypovolemia is normally restrained by simultaneous activation of a distinct inhibitory pathway that is blocked by kappa 1- or mu-antagonists.

Animals↗