Treatment of central diabetes insipidus in adults and children with desmopressin.

Modification of the natural vasopressin molecule to form desmopressin acetate (DDAVP) resulted in a compound with prolonged antidiuretic activity and virtual elimination of vasopressor activity. Twenty-one patients with central diabetes insipidus who ranged in age from 3 to 68 years were treated with DDAVP, which was administered intranasally in a dosage ranging from 10 microgram every 12 hours to 20 microgram every eight hours. Effective control of symptoms was obtained in all cases. There were no consequential toxic effects. As previously reported, DDAVP appears to be the preferred drug for the management of central diabetes insipidus. Biochemical alteration of hormones may enhance desired therapeutic activity and eliminate toxic effects. The development of DDAVP is an example of the potential for development of useful therapeutic peptides.

[Diabetes insipidus after surgery of intracranial arterial aneurysms--with special reference to the human ADH and aldosterone secretion (author's transl)].

The cases of diabetes insipidus (DI) after surgery of intracranial aneurysms were reported and discussed. 1. Of 112 patients operated on for intracranial arterial aneurysm (microsurgical approach), four patients (3.6%) showed DI in the postoperative period. In 3 cases of these 4, the aneurysms located on the anterior communicating artery and the remaining one was the posterior inferior cerebellar artery. 2. The exact mechanism of occurrence of DI is obscure. We suppose that not only vascular spasm of branches of the anterior cerebral and anterior communicating arteries supplying to the paraventricular and preoptic nucleus, but also surgical trauma with direct tissue injury might explain the symptoms. 3. All patients showed a monophasic type of DI which started 1 to 4 days after surgery and lasted from 6 up to 9 days. 4. Two patients with DI showed decreased plasma ADH values below 0.6 microunits/ml in the few days prior to the appearance of abnormally large amount of urinary output. Therefore, once the diagnosis of postoperative DI is made, the patients should be managed promptly with the replacement therapy of Aqueous pitressin. 5. A slow continuous infusion of Aqueous pitressin in the range of 1 to 1.5 IU/hr effectively reduce the polyuria which were not controlled by intermittent intramuscular injections.

Myometrial response to a long-acting vasopressin analogue in early pregnancy.

Intrauterine pressure was recorded for 4 to 6 hours in 21 healthy women having a therapeutic abortion at 6 to 9 weeks gestation. Fourteen of the women received an intravenous injection of 300 microgram of N-alpha-triglycyl-(8-lysine)-vasopressin (TGLVP) and seven were used as controls. Uterine tone and the amplitude and duration of uterine contractions increased in all women receiving the drug, uterine tone usually rising first, with a change in contractions as a secondary effect which lasted for the rest of the observation period. Uterine activity did not change in the controls. These results suggest that TGLVP might be used for the induction of abortion during the first trimester of pregnancy.

Influence of lower body negative pressure upon arginine vasopressin release.

Lower body negative pressure (9-12 kPa) was applied to ten normal subjects. Large increases in plasma arginine vasopression concentration occurred only in subjects that experienced syncopal symptoms and developed hypotension. Blood samples obtained from the superior vena cava at 1/2 min intervals during application of negative pressure showed that maximal plasma vasopressin concentrations occurred with hypotension. Chromatography of the presyncopal plasma on Sephadex G-25 gave a large peak which eluted in the position of synthetic arginine vasopressin.

Ionic and metabolic requirements for the hydroosmotic response to antidiuretic hormone in toad urinary bladder.

A study has been conducted to determine the ionic and metabolic requirements for full expression of the hydroosmotic response to antidiuretic hormone in the toad urinary bladder. By appropriate manipulation of incubation conditions it can be shown that there is a pool of serosal sodium necessary for a full hormone response. This serosal sodium pool is not related to the transepithelial sodium transport pool A full hydroosmotic response also requires serosal potassium; however, no specific anion requirement was demonstrated. Additionally, anaerobic or aerobic metabolism support a full hydroosmotic response equally well.

The relationship of radioimmunoassay to bioassay: in vitro studies with synthetic lysine vasopressin in aqueous solution inactivated by heat.

The relationship of radioimmunoassay to pressor assay and antidiuretic assay was investigated in a simple in vitro system of synthetic lysine vasopressin in aqueous solution inactivated by heating at 100 degrees C for 9, 18, 27, 36, 54 and 72 h. An apparent dissociation between radioimmunoassay and bioassay was demonstrated, with biological activity being lost more rapidly than immunological activity. The half-times were 32 h for radioimmunoassay, 23 h for antidiuretic assay and 22 h for pressor assay. However, ion-exchange chromatography showed immunological heterogeneity but biological homogeneity of the lysine vasopressin used, and indicated that the presence of impurities in the vasopressin might to some extent explain the discrepancy between assay results. Synthetic arginine vasopressin and arginine vasopressin of pituitary origin showed a similar immunological heterogeneity by ion-exchange chromatography.

Plasma arginine vasopressin concentrations and antidiuretic action of carbamazepine.

Twelve subjects given therapeutic doses of carbamazepine showed no change in their plasma electrolyte concentrations. Ten of the 12 had abnormal water metabolism, however, their ability to excrete water loads being decreased. Plasma arginine vasopressin (AVP) concentrations fell while the subjects were taking the drug, indicating that the mechanism is unlikely to be increased secretion of antidiuretic hormone. We suggest that the water-retaining property of carbamazepine is a physiological effect of the drug, mediated by increased renal sensitivity to normal plasma concentrations of AVP and resetting of osmoreceptors.

Increased vasopressin excretion in patients with hypothyroidism.

Twenty-four h urinary vasopressin excretion was measured by bioassay in 15 patients with untreated hypothyroidism and compared with plasma sodium concentration. Four patients had raised excretion of an antidiuretic substance and in 3 of these patients excretion was reduced after thyroid replacement therapy. The criteria applied supported the view that the antidiuretic substance was arginine vasopressin. Plasma sodium concentration was normal in all these 4 patients. A further 4 patients had hyponatraemia without raised arginine vasopressin excretion. The results suggest that: (1) excess arginine vasopressin secretion is not the cause of the hyponatraemia of hypothyroidism and (2) an increased secretion of arginine vasopressin does occur in some cases of normonatraemic hypothyroidism, the cause requiring further elucidation.

1-deamino-8-D-arginine vasopressin in the treatment of central diabetes insipidus in childhood.

The effectiveness of therapy with carbamazepine and clofibrate (oral therapy), intramuscular pitressin-in-oil, and intranasal 1-deamino-8-D-arginine vasopressin has been compared in 15 children with partial or complete central diabetes insipidus. Mean daily urine volume without therapy was 5.4 l and dropped to 1.1 and 1.6 l/day while receiving pitressin and DDAVP, respectively. Oral agents decreased the daily urine volume to 2.2 l in patients with partial DI, with good symptomatic control except for some nocturia. These agents had no effect in patients with complete DI and did not alter pitressin requirements. Duration of pitressin action was 24 to 36 hours with a significant incidence of hyponatremia. The duration of DDAVP effect was 8 to 20 hours, varying in individual patients. Children with partial DI required smaller doses of DDAVP and the duration of action was longer than in those with complete DI. Control of serum electrolytes was excellent using two doses per day and nocturia was eliminated. All patients who had received pitressin had growth hormone antibodies, but continued to grow normally unless there was pre-existing growth hormone deficiency. These antibodies gradually disappeared after approximately one year of therapy with oral agents or DDAVP. DDAVP did not alter growth hormone, cortisol, or prolactin levels during sleep. DDAVP is the antidiuretic therapy of choice in children with either complete or partial DI; to date, no side effects have been demonstrated.

[Effect of saralasin on plasma renin activity and arginine-vasopressin in patients with angiotensin-dependent hypertension (author's transl)]. / Einfluss von Saralasin auf Plasma Renin Aktivität und Arginin-Vasopressin bei Patienten mit angiotensinabhängiger Hypertonie.

A central stimulatory effect of angiotensin II (AII) on the secretion of arginine-vasopressin (AVP) has been described. The competitive blocker of AII, saralasin (SAR) has been used for diagnostic purposes in angiotensin-dependent hypertension. In addition SAR has a partially agnoistic effect. The aim of the present study was to demonstrate whether AVP-levels can be influenced during SAR-induced renin stimulation. In 9 patients with essential hypertension blood pressure dropped significantly under SAR (10 microgram/kg/min over a 30 min period). Before and after SAR plasma renin activity (PRA) and AVP were measured by RIA, SAR evoked significantly increments of PRA in all patients and of AVP in 6 patients. The increased serum concentrations of AVP following SAR may be explained either by the depressor effect of SAR, its diminished concentration at the central receptor, or a partial AII-agonistic effect.

Reduction of free water clearance with cephalic venous hypertension.

A laboratory model was developed in the dog to quantitate the effects of cerebral venous hypertension on inappropriate antidiuretic hormone (ADH) secretion. When cerebral venous pressure was abruptly increased during continuous water loading, there was a sharp rise in urine osmolality within 30 minutes. Urine osmolality continued to increase during, and ten minutes after, the period of hypertension. On lowering cerebral venous pressure, the osmolality returned to baseline within 60 minutes. The effects could be extended for at least three hours and presumably longer. A 50% response threshold for this ADH effect occurred at a cerebral venous pressure between 18 and 19 cm of water. The effect correlated with plasma ADH levels. The study paralled documented clinical observations. The results are discussed in light of the recognition and management of surgical states where increased cerebral venous pressure might produce a severe antidiuretic effect.

Rapid stimulation by vasopressin, oxytocin and angiotensin II of glycogen degradation in hepatocyte suspensions.

1. The hormonal control of glycogen breakdown was studied in hepatocytes isolated from livers of fed rats. 2. Glucose release was stimulated by [8-arginine]vasopressin (10pm-10nm), oxytocin (1nm-1mum), and angiotensin II (1nm-0.1mum). These responses are all at least as sensitive to hormone as is glucose output in the perfused rat liver. 3. The effect of these three hormones on glucose release was critically dependent on extracellular Ca(2+), unlike that of glucagon. Half-maximal restoration of the vasopressin response occurred if 0.3mm-Ca(2+) was added back to the incubation medium. 4. Glycogen breakdown was more than sufficient to account for the glucose released into the medium, in the absence or presence of hormones. Lactate release by hepatocytes was not affected by vasopressin, but was inhibited by glucagon. 5. If Ca(2+) was omitted from the extracellular medium, vasopressin stimulated glycogenolysis, but not glucose release. 6. The phosphorylase a content of hepatocytes was increased by vasopressin, oxytocin and angiotensin II; minimum effective concentrations were 0.1pm, 0.1nm and 10pm respectively. This response was also dependent on Ca(2+). 7. These results demonstrate that hepatocytes can respond to low concentrations of vasopressin and angiotensin II, i.e. these effects are likely to be relevant in the intact animal. The role of extracellular Ca(2+) in the effects of these hormones on hepatic glycogenolysis and glucose release is discussed.

Ultrastructure and morphometry of ACTH-producing cell in the rat anterior pituitary gland stimulated by lysin-vasopressin and prostaglandin E1.

The aim of this study was to investigate the qualitative and quantitative changes of ACTH-cells in the rat after application of a specific and a non-specific stimulus. A CRF-analog (lysin-vasopressin) and a prostaglandin (prostaglandin E1) were used. 40 rats were injected lysin-vasopressin or prostaglandin E1, respectively, for 4 weeks. The pituitary glands were investigated by means of light microscopy, electron microscopy and morphometry. Activation of the ACTH-cells could be observed after use of both substances, the effect of lysin-vasopressin being more intense than that of prostaglandin E1. Enlargement of the nucleus, the cytoplasm and the organelles involved in hormone-production and -transport were found and verified by morphometry. Additionally an increase in number of the cells could be demonstrated. Prostaglandin influenced not only ACTH-cells, but also other cells of the anterior pituitary.

Dissociation between antidiuretic response and renal medullary cyclic AMP levels in the rat.

In vivo experiments were performed in male Wistar rats to elucidate the probable relation between renal concentrating ability and medullary cyclic AMP content as influenced by changes of hydration and by administration of antidiuretic hormone (ADH). Cyclic AMP levels were 37% lower in water diuretic than in control animals (P less than 0.01), but were not significantly changed during prolonged antidiuresis induced by dehydration or ADH administration. Nor could any change of cyclic AMP levels be demonstrated between 2 and 20 min after ADH injection. Significant increases of medullary cyclic AMP content occurred following stress, anesthesia, and administration of isoproterenol and 3-isobutyl-1-methylxanthin. The results suggest that the level of cyclic AMP in the renal medulla may not be an important determinant of the antidiuretic response produced by ADH in rats.