Biological half-life and organ distribution of [3H]8-arginine vasopressin following administration of vasopressin receptor antagonist OPC-31260

The effects of the antidiuretic (V(2)) non-peptide receptor antagonist OPC-31260 on the plasma vasopressin level and the biological half-life and organ distribution of radiochemically pure, biologically active [(3)H]8-arginine vasopressin [spec. act.: 15.9 mCi/mmol (588 GBq/mmol)] were studied in Wistar rats. The plasma vasopressin level increased significantly throughout the whole experimental period (24 h). There was no change in the fast phase of the curves of total radioactivity disappearance from the plasma after the administration of [(3)H]arginine vasopressin (control: 1.51+/-0.17 min, OPC-31260-treated: 1.42+/-0.12 min, n=10). The fast phase of the disappearance curves of intact [(3)H]arginine vasopressin did not change either following the administration of OPC-31260 in a dose of 30 mg/kg p.o. (control: 1.06+/-0.19 min, OPC-31260-treated: 1.00+/-0.15 min, n=6). The slow phase of the biological half-life, which is characteristic for the examined compound, proved to be significantly longer (total radioactivity control: 9.29+/-0.61 min, OPC-31260-treated: 12.33+/-0.42 min, P<0.05, n=10; [(3)H]arginine vasopressin radioactivity: control: 5.96+/-0.58 min, OPC-31260-treated: 8.90+/-0.37 min, P<0.05, n=6). In the control rats, the radioactivity was accumulated to the greatest extent in the neurohypophysis, adenohypophysis and kidney. Following OPC-31260 administration, significantly more radioactive compounds accumulated in the kidney (control: 0.30+/-0.052 total radioactivity %/100 mg organ weight, OPC-31260-treated: 0.50+/-0.133 total radioactivity %/100 mg organ weight, P<0.05, n=10) and neurohypophysis (control: 0.37+/-0.053 total radioactivity %/100 mg organ weight, OPC-31260-treated: 0.52+/-0.076 total radioactivity %/100 mg organ weight, P<0.05, n=10). Our results permit the conclusion that the antidiuretic antagonist OPC-31260 not only blocks the V(2) receptors, but also increases the biological half-life of vasopressin. The longer biological half-life of vasopressin following OPC-31260 administration may play a role in the elevation of the plasma vasopressin level.     

Probes for vasopressin receptors. Attachment of affinity and fluorescent groups in vasopressin

Fluorescent, photoreactive, and biotinylated analogs of vasopressin have been prepared in which one of these three groups has been attached to a reactive amino group in either position 4 or position 7. Using solid phase methodology, we have synthesized two active parent compounds, [1-desamino,4-lysine,7-hydroxyproline]arginine vasopressin and [1-desamino,7-aminoproline]arginine vasopressin, and acylated them to obtain biotinyl, azidobenzoyl, and fluoresceinyl derivatives. We have also prepared analogs in which a "spacer arm" was inserted between lysine in position 4 and the marker group. Some of these derivatives have good antidiuretic activity and could be valuable probes in studying hormone-receptor interaction and in receptor visualization and purification.     

Antidiuretic reaction of the human and rat kidney to peroral administration of arginine-vasopressin and desmopressin

Water in amount of 5 ml/100 g body weight was administered through a gastric probe into the stomach in alert rats; subjects-volunteers drank 20 ml of water per 1 kg of body weight. This resulted in diuresis at the peak of which the excreted water fraction reached 23% in rats and 12.4% in human subjects, whereas excretion of the osmotically free water amounted to 0.103 +/- 0.018 ml/min/100 g body weight and 10.0 +/- 1.8 ml/min/1.73 m2 of the body surface, respectively. These data indicate a practically complete inhibition of the arginine vasopressin secretion. On intragastric administration of 10 micrograms of arginine vasopressin or 0.2 microgram of desmopressin, with water in rats, a prolonged and quite obvious antidiuretic response occurred, with a marked increase of reabsorption of the osmotically free water in kidneys. A direct correlation has been found between the dose of the intragastrically administered vasopressin in the dose range from 0.1 to 10 micrograms/100 g body weight and a decrease of clearance of the osmotically free water. In subjects volunteers, an antidiuretic reaction to administration of 0.2 mg of desmopressin with water, was found. The data obtained provide a direct proof of intestinal absorption of nanopeptides without loss of their physiological activity. Significance of the data obtained for physiology of digestion and for clinical medicine, is discussed.     

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.     

Corticotropin releasing factor activity of CRF 41 in normal man is potentiated by angiotensin II and vasopressin but not by desmopressin

Multiple hypothalamic factors seem to influence ACTH release. In vitro and/or in vivo animal models have shown that angiotensin II, vasopressin and some of its analogs are ACTH secretagogues capable of potentiating the corticotropin releasing activity of CRF41. Since these effects are controversial in man, we investigated in 3 groups of volunteers the corticotropin releasing activity of a 2h-infusion of angiotensin II (7 ng/kg/min), vasopressin (1 ng/kg/min) and desmopressin (1 ng/kg/min) given alone or in combination with a bolus injection of 100 micrograms CRF41 by measuring plasma concentrations of ACTH, cortisol, dehydroepiandrosterone and delta 4-androstenedione. Given alone angiotensin II and desmopressin had no significant effect in contrast to vasopressin which increased significantly the ACTH and steroid levels. Angiotensin II and vasopressin were both able to potentiate the corticotropin releasing activity of CRF41, whereas desmopressin was unable to produce such a potentiation. These results suggest that in man vasopressin and angiotensin II may well regulate the responsiveness of the pituitary-adrenal axis in various physiological or pathophysiological situations.     

Vasopressin receptor subtypes in dorsal hindbrain and renal medulla

We have investigated the ability of a series of synthetic vasopressin analogues and related peptides to compete with (3H)-arginine8 vasopressin for binding sites in rat renal medulla and dorsal hindbrain. In renal medulla, arginine8 vasopressin and deamino arginine8 vasopressin, a selective antidiuretic, were equipotent while two antagonists of the pressor action of arginine vasopressin were less potent. In the dorsal hindbrain, arginine8 vasopressin and the pressor antagonists were more potent than the synthetic antidiuretic. Potency profiles of these and other analogues suggest that the renal medulla and dorsal hindbrain vasopressin receptors represent different subtypes.     

Desmopressin, but not vasopressin, decreases activity of the hypothalamo-neurohypophysial system in Brattleboro rats

The pituitary neural lobe of homozygous Brattleboro rats has high rates of glucose utilization not affected by chronic treatment with exogenous vasopressin, despite attenuation of polydipsia and polyuria. We evaluated whether this effect may result from the inability of vasopressin to affect the hypothalamo-neurohypophysial metabolism or from the development of resistance to chronic vasopressin treatment. We used the [14C]deoxyglucose method to compare 28-h effects of vasopressin treatment (5 U/kg, i.m., twice a day) with that of desmopressin (100 micrograms/kg, i.p., once a day), a long-lasting antidiuretic hormone, on glucose utilization of the hypothalamo-neurohypophysial system and related structures in conscious homozygous Brattleboro rats. Vasopressin and desmopressin reduced water intake, plasma osmolality and plasma Na+ concentration similarly. Vasopressin decreased glucose utilization in the supraoptic nucleus, subfornical organ and median preoptic nucleus, but did not alter activity in the paraventricular nucleus and neural lobe. Desmopressin decreased glucose utilization in all these structures. The results indicate that desmopressin has a more potent inhibitory action on the hypothalamo-neurohypophysial system than vasopressin over this short duration of treatment. The lack of response in the neural lobe from chronic treatment with vasopressin seems to be due to its inability to affect the paraventricular nucleus metabolism. The maintenance of metabolic activity in the paraventricular nucleus of vasopressin-treated Brattleboro rats suggests that this structure contributes importantly to the metabolism of neural lobe.     

Evaluation of synthetic antidiuretic hormone as a corrective substance following a head-down tilt

The effects of the administration of desmopressin, a synthesized analog of antidiuretic hormone, together with a water-salt supplement on the renal function and orthostatic stability were investigated. Six healthy men spent 12 h in the head-down tilt (HDT) position. It was demonstrated that administration of desmopressin led to normalization of salt and water homeostasis; moreover, the tolerance of the standard 20 min passive standing test was improved significantly. These observations indicate that intake of the synthetic vasopressin analog combined with water-salt supplement counteracts hypohydration of the body during HDT and improved orthostatic tolerance.     

Antidiuretic Response of Kidneys to Different Modes of Vasopressin Administration

The effect of vasopressin given simultaneously with a water load was studied in healthy human volunteers. During maximal water diuresis induced by oral water load of 20 ml water per kilogram body weight, the excreted water fraction was 12.4%, whereas the excretion of osmotically free water was 10.0 ± 1.8 ml/min per 1.73 m² of body surface area. These data suggest that the secretion of arginine vasopressin by the neurohypophysis was almost completely blocked. A water load simultaneously with 8 g sublingual or 0.2 mg oral desmopressin caused a strong and long-lasting antidiuretic response accompanied by a drastic increase in the reabsorption of osmotically free water in the kidneys. It was shown that the magnitude and the time course of the antidiuretic response to therapeutic doses of desmopressin depended on the mode of its administration.     

The role of protein kinase C in the establishment of the mechanism of vasopressin antidiuretic action in the rat kidney during mammalian postnatal development

The kidney of immaturely born mammals in early postnatal development is insensitive to the effect of the antidiuretic hormone, vasopressin. It has been demonstrated that water permeability of the epithelial cells in the collecting ducts of a rat kidney increases during development; in this process, the response to desmopressin, an agonist of vasopressin V2 receptors, appears at the age of 20 days. The observed increase in water permeability is connected with an increased content of the water channel proteins aquaporins AQP2 and AQP3 in the plasma membrane. The calcium-dependent protein kinase C isoforms are the likely components of the vasopressin signal transduction and are possibly involved in the mechanisms underlying the maturation of sensitivity to this hormone. The contents of three protein kinase C isoforms (α,δ, and ζ) in rats at different periods of their postnatal development were estimated using Western blot hybridization. It has been shown that the contents of protein kinase C isoforms α and δ increase with development, whereas the content of isoform ζ remains constant. The most likely participant of the mechanism providing for maturation of the cell’s hormonal competence for vasopressin is the calcium-dependent protein kinase Cα, because it’s content in the plasma membrane is maximal on days 20–24, which coincides with the time when the vasopressin action appears.     

Effect of enkephalins on vasopressin and aldosterone levels in acute experimental myocardial ischemia

It has been demonstrated in experiments on rats that acute myocardial ischemia gives rise to a decrease in diuresis, elevation of antidiuretic activity of blood plasma and the blood concentration of immunoreactive aldosterone. Intraperitoneal injection of a synthetic enkephalin analog D-ala2-leu5-arg6-enkephalin in a dose of 1.25 nmol/kg bw resulted in partial normalization of diuresis, reduction in antidiuretic activity of blood plasma and blood aldosterone level to the control values. Naloxone eliminated the effects described. It is concluded that enkephalins have an inhibitory action on aldosterone and vasopressin secretion, with this action being mediated via opiate receptors.     

Desensitization of renal vasopressin-stimulated adenylate cyclase by a vasopressor and antidiuretic antagonist, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-ethyl)-D-tyrosine, 4-valine]arginine vasopressin

Desensitization of the renal antidiuretic (V2) receptor has been regarded as agonist-specific. We found that a vasopressor and antidiuretic (V1V2) antagonist d(CH2)5DTyr(Et)VAVP induced desensitization of the receptor and that a vasopressor (V1) antagonist d(CH2)5Tyr(Me)AVP, which is a weak antidiuretic (V2) agonist, counteracted the potent desensitizing action of 1-deamino-8-D-arginine-vasopressin and endogenous arginine vasopressin.     

Resistance of 1-deamino-[8-D-arginine]-vasopressin to in vitro degradation as compared with arginine vasopressin

In order to elucidate the mechanism(s) responsible for the prolonged antidiuretic activity of 1-deamino-[8-D-arginine]-vasopressin (dDAVP), antidiuretic activities of dDAVP and arginine vasopressin (AVP) were determined in the rat following either oral administration or incubation with AVP-degrading enzymes and reagents. Oral administration of dDAVP to conscious water-loaded rats resulted in significant antidiuresis while AVP resulted in slight and transient antidiuresis. In the ethanol anesthetized water-loaded rats, antidiuretic activities of 136pg of AVP and 50pg of dDAVP, which were found to be equipotent, were compared after incubation with digestive enzymes (pepsin, trypsin, alpha-chymotrypsin), late pregnancy plasma, or sodium thioglycollate. The antidiuretic activity of AVP was completely destroyed by 30-min incubation with trypsin, alpha-chymotrypsin, or late pregnancy plasma and almost all AVP was inactivated by 0.2 M sodium thioglycollate. On the other hand, the antidiuretic activity of dDAVP was not destroyed by trypsin or pregnancy plasma but was partly destroyed by alpha-chymotrypsin and sodium thioglycollate. Neither the antidiuretic activity of AVP nor that of dDAVP was affected by pepsin. Thus, the antidiuresis observed after oral administration of dDAVP might be brought about by the resistance to digestive enzymes. Furthermore, the resistance of dDAVP to digestive enzymes, late pregnancy plasma and sodium thioglycollate might be responsible for the prolonged antidiuretic action of dDAVP in vivo.     

Modulation of plasma arginine vasopressin during rehydration in the Bedouin goat

When severely dehydrated Bedouin goats were allowed to drink to satiation their plasma arginine vasopressin concentration immediately dropped from a value of 19.9±9.4 pmol·l^-1 to 9.4±3.9 pmol·l^-1 (P<0.05). It continued to drop further until a concentration of 1.8±2.9 pmol·l^-1 was recorded, similar to that reported for goats allowed to drink freely. When the goats were shown the water but drinking was denied, plasma arginine vasopressin immediately dropped to 11.7±4.0 pmol·l^-1 (P<0.05) and further decreased to 10.0±4.8 pmol·l^-1 5 min following their sighting the water. This level, however, was not sustained and 2 h after the initial drop the high pre-trial concentration of plasma arginine vasopression was regained. Presumably, sighting of water by dehydrated goats induces an abrupt drop in their plasma arginine vasopressin level even before drinking commences. When rehydrated, by introducing water directly to the rumen, circumventing both the sensing of the water and the drinking proper, no immediate drop in the plasma arginine vasopression concentration of the newly rehydrated goats was observed. A delayed drop in the plasma arginine vasopressin levels took place slowly, concurrently with the drop in osmolality and concentration of Na⁺ in the plasma. It is suggested that sighting of water by dehydrated goats is involved in the modulation of plasma arginine vasopressin.     

Modulation of cardiovascular reflexes by arginine vasopressin

Arginine vasopressin (AVP), a potent vasoconstrictor, does not raise arterial pressure in normal humans or neurally intact animals, even during infusions that achieve pathophysiological plasma concentrations. It has been proposed that this is because AVP facilitates the baroreflex control of the circulation. We performed a series of investigations to test this hypothesis, and to determine sites at which AVP might act to augment the baroreflex. In anesthetized rabbits, vasopressin (36 pmol.kg-1.min-1) increased discharge from both medullated and nonmedullated single fibres from aortic baroreceptor nerves during elevations in aortic arch pressure. Similarly, vasopressin (36 pmol.kg-1.min-1) increased the response of left ventricular mechanoreceptor single fibre discharge to elevations of left ventricular end-diastolic pressure. These observations suggest that sensitization of high and low pressure baroreceptors is one mechanism by which vasopressin may facilitate baroreflexes. In a further series of experiments in sinoaortic denervated anesthetized rabbits, vasopressin (18 pmol.kg-1.min-1) facilitated vagally mediated reflex inhibition of renal sympathetic nerve activity during volume expansion. In humans, AVP (0.37 pmol.kg-1.min-1) raised plasma AVP to an antidiuretic level (22 +/- 4 fmol/mL), but did not change blood pressure or the baroreflex control of heart rate or forearm vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunoreactive vasopressin in bull seminal fluid

Immunoreactive arginine vasopressin (irAVP) was measured in seminal fluid with and without extraction using a specific radioimmunoassay (RIA). A large fraction of irAVP was removed after extraction on octadecasilylsilica cartridges. The measured amount of irAVP corresponded to the levels found in blood plasma. Dilutions of seminal plasma extracts were parallel with the RIA standard curve. On reversed phase HPLC the extracted material coeluted with synthetic AVP. These findings suggest an identity of this immunoreactive material with intact AVP. During incubations of synthetic AVP and its analogue 8-D-arginine vasopressing (8-DAVP) in seminal plasma, immunoreactivity decreased considerably with the former peptide, while the concentration of 8-DAVP was not significantly altered.     

Effects of desmopressin on prolonging survival in stable hypothermia in rats

The aim of the present study was to examine whether minimizing plasma volume loss due to cold-induced diuresis can increase the survival time of rats maintained in long-term stable hypothermia (~24 h at a body temperature of 19 degrees C). Infusion of desmopressin (0.5-2.0 microg), a potent antidiuretic agent, during the cooling period enhanced survival over saline controls in a dose-related manner. The enhanced survival was accompanied by a significant delay in the expected increase of hematocrit and decrease of plasma volume as compared with those seen in saline controls. In contrast, treating the rats with the same dose range of another vasopressin analog, [beta-mercapto-beta,beta-cyclopentamethyl enepropionyl]-vasopressin, which has no antidiuretic action, failed to enhance survival over saline control. Further, treating the rats with the optimal dose of desmopressin (1 microg) at the later stage of hypothermia failed to elicit any beneficial effect. Our results indicate that by using desmopressin early during the cooling phase of the hypothermia, plasma volume and rheological parameters important for sustaining microcirculation can be better maintained than those seen in saline controls. These improvements may have contributed to the observed longer survival time in hypothermia.     

Pyridobenzodiazepines: a novel class of orally active, vasopressin V2 receptor selective agonists

Our efforts in seeking low molecular weight agonists of the antidiuretic peptide hormone arginine vasopressin (AVP) have led to the identification of the clinical candidate WAY-151932 (VNA-932). Further exploration of the structural requirements for agonist activity has provided another class of potent, orally active, non-peptidic vasopressin V2 receptor selective agonists exemplified by the 5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepine as a candidate for further development.     

Effect of two-week infusion of deamino D-arginine vasopressin in rats

Our purpose was to investigate a method of prolonged desmopressin (DDAVP) infusion in a free roaming rat to better understand the SIADH (syndrome of inappropriate antidiuretic hormone secretion) syndrome in man. DDAVP was infused for 2 weeks from implanted self-powered osmotic minipumps. At the end of that time, plasma DDAVP and urine osmolality were both significantly elevated in experimental as compared with control animals. However, hyponatremia and hypoosmolality, which are characteristic in the SIADH, did not develop. Our observations suggest that inappropriate high antidiuretic hormone levels do not necessarily lead to the SIADH either by urine sodium loss or by water retention if animals decrease water intake.     

Analogs of arginine vasopressin modified in position 3 with (R)-alpha-hydroxymethylphenylalanine.

This study describes the synthesis and some pharmacological properties of three new analogs of arginine vasopressin (AVP) substituted in position 3 with (R)-alpha-hydroxymethylphenylalanine ([R]-HmPhe). All new peptides were tested for vasopressor and antidiuretic as well as uterotonic activity. None of the 3 analogs showed any pressor activity and their uterotonic activity was negligible. Only analog [Mpa1,(R)-HmPhe3]AVP exhibited significant antidiuretic activity.