Antidiuretic Effect Research Articles

The effect of saponins from Ampelozizyphus amazonicus Ducke on the renal Na+ pumps’ activities and urinary excretion of natriuretic peptides

BackgroundIn a previous study, we showed that a saponin mixture isolated from the roots of Ampelozizyphus amazonicus Ducke (SAPAaD) reduces urine excretion in rats that were given an oral loading of 0.9 % NaCl (4 ml/100 g body weight). In the present study, we investigated whether atrial natriuretic peptides (ANP) and renal ATPases play a role in the SAPAaD- induced antidiuresis in rats.MethodsTo evaluate the effect of SAPAaD on furosemide-induced diuresis, Wistar rats (250-300 g) were given an oral loading of physiological solution (0.9 % NaCl, 4 ml/100 g body weight) to impose a uniform water and salt state. The solution containing furosemide (Furo, 13 mg/kg) was given 30 min after rats were orally treated with 50 mg/kg SAPAaD (SAPAaD + Furo) or 0.5 ml of 0.9 % NaCl (NaCl + Furo). In the SAPAaD + NaCl group, rats were pretreated with SAPAaD and 30 min later they received the oral loading of physiological solution. Animals were individually housed in metabolic cages, and urine volume was measured every 30 min throughout the experiment (3 h). To investigate the role of ANP and renal Na+ pumps on antidiuretic effects promoted by SAPAaD, rats were given the physiological solution (as above) containing SAPAaD (50 mg/kg). After 90 min, samples of urine and blood from the last 30 min were collected. Kidneys and atria were also removed after previous anesthesia. ANP was measured by radioimmunoassay (RIA) and renal cortical activities of Na+- and (Na+,K+)-ATPases were calculated from the difference between the [32P] Pi released in the absence and presence of 1 mM furosemide/2 mM ouabain and in the absence and presence of 1 mM ouabain, respectively.ResultsIt was observed that SAPAaD inhibited furosemide-induced diuresis (at 90 min: from 10.0 ± 1.0 mL, NaCl + Furo group, n = 5, to 5.9 ± 1.0 mL, SAPAaD + Furo group n = 5, p < 0.05), increased both Na+-ATPase (from 25.0 ± 5.9 nmol Pi.mg-1.min-1, control, to 52.7 ± 8.9 nmol Pi.mg-1.min-1, p < 0.05) and (Na+,K+)-ATPase (from 47.8 ± 13.3 nmol Pi.mg-1.min-1, control, to 79.8 ± 6.9 nmol Pi .mg-1.min-1, p < 0.05) activities in the renal cortex. SAPAaD also lowered urine ANP (from 792 ± 132 pg/mL, control, to 299 ± 88 pg/mL, p < 0.01) and had no effect on plasma or atrial ANP.ConclusionWe concluded that the SAPAaD antidiuretic effect may be due to an increase in the renal activities of Na+- and (Na+,K+)-ATPases and/or a decrease in the renal ANP.

Chelidonium majus leaves methanol extract and its chelidonine alkaloid ingredient reduce cadmium-induced nephrotoxicity in rats

The kidney is one of the critical target organs for chronic cadmium toxicity. Cadmium is a cumulative nephrotoxicant, and preferentially accumulates and persists in the kidneys. The natriuretic and antidiuretic effects of methyl alcohol extracts of Chelidonium majus L. (C. majus) leaves were evaluated in kidney of cadmium-intoxicated rats. Ninety-six male Sprague-Dawley Albino rats were divided into two major groups (toxicity and biochemical, 60 and 36 rats, respectively). There was a decrease in kidney weight and serum electrolytes, but an increase in urinary volume, excretion of electrolytes, serum urea and creatinine, after 9weeks of cadmium chloride intoxication. Treatment of C. majus methyl alcohol extract for 10weeks starting 1week before cadmium administration shifted the above parameters towards the normal values. These results were supported by molecular and histological investigations. Treatment with C. majus methyl alcohol extract has natriuretic and antidiuretic effects against cadmium-induced nephrotoxicity in rats.

The role of neurohypophysis in the long‐term blood pressure regulation in rats

Evidence suggest that arginine vasopressin (AVP) may contribute to the development and/or maintenance of hypertension in humans and experimental animals. This is partially explained by the antidiuretic (increased vascular volume) and vasopressor effects (increased blood vessels resistance) of AVP. Here we propose that rats with long‐term low blood levels of AVP will cause increases in both; urine output and water intake and diminution of the mean blood pressure (MBP). Young male Wistar rats were divided in sham operated (SHAM) and neurointermediate pituitary lobectomized (NIL) (n=15 in each group). Water intake and urine output where measured once a week by placing the animals in a metabolic box. Five weeks after surgeries MBP was measured by an intra carotid catheter connected to a blood pressure transducer and a data acquisition system (BIOPAC Systems Inc.). AVP, Na+ and K+ serum levels were also measured. Results shown that as compared with SHAM group, NIL animals developed significant low AVP levels, no changes in Na+ and K+ levels and an initial increase in urine output and water intake (diabetes insipidus), to return to normality during second week. In NIL animals a significant diminution of MBP occurred: SHAM, 105±9.2 versus 65±6 mmHg of the NIL animals, p&lt;0.001. These results suggest that neurohypophyseal AVP may be an important factor in the long‐term blood pressure regulation.

Arginine vasopressin (AVP) expressional changes in the hypothalamic paraventricular and supraoptic nuclei of stroke-prone spontaneously hypertensive rats

Arginine vasopressin (AVP) is a neuropeptide with vasoconstrictive, antidiuretic, cardiovascular regulative and hepatic glycogenolysis effects, that also affects other behaviors including modulating learning. A number of studies on AVP regulation have been conducted in various metabolic diseases (disorders). In this study, the immunoreactivities of AVP in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) and mRNA expressions in the hypothalamus were investigated by immunohistochemistry and quantitative real-time PCR (RT-qPCR) in stroke-prone spontaneously hypertensive rats at different ages (i.e., at postnatal months [PM] 1, 8, and 12). Blood glucose levels in the PM 8 group were higher than in the other groups. However, cresyl violet positive neurons were detected in the PVN and SON of all animals, and numbers of cresyl violet positive neurons were similar in all aged groups. In addition, AVP immunoreactivity was detected in the PVN and SON of all age groups, and AVP immunoreactivity and mRNA expression levels were found to be increased in proportion to age by immunohistochemistry and RT-qPCR. These results suggest that the diabetic condition is temporally generated after hypertension has developed. Furthermore, our findings suggest that increased AVP expressions in the hypothalamic PVN and SON are associated with hypertension by age.

Brain levels of arginine–vasotocin and isotocin in dominant and subordinate males of a cichlid fish

The nonapeptides arginine–vasotocin (AVT) and isotocin (IT), which are the teleost homologues of arginine–vasopressin and oxytocin in mammals, have well established peripheral effects on osmoregulation and stress response, and central effects on social behavior. However, all studies that have looked so far into the relationship between these nonapeptides and social behavior have used indirect measures of AVT/IT activity (i.e. immunohistochemistry of AVT/IT immunoreactive neurons, or AVT/IT or their receptors mRNA expression with in situ hybridization or qPCR) and therefore direct measures of peptide levels in relation to social behavior are still lacking. Here we use a recently developed high-performance liquid chromatography analysis with fluorescence detection (HPLC-FL) method to quantify the levels of both AVT and IT in macro-dissected brain areas [i.e. olfactory bulbs, telencephalon, diencephalon, optic tectum, cerebellum, and hindbrain (= rhombencephalon minus cerebellum)] and pituitary of dominant and subordinate male cichlid fish (Oreochromis mossambicus). The pituitary shows higher levels of both peptides than any of the brain macroareas, and the olfactory bulbs have the highest AVT among all brain areas. Except for IT in the telencephalon there is a lack of correlations between central levels and pituitary peptide levels, suggesting an independent control of hypophysial and CNS nonapeptide secretion. There were also no correlations between AVT and IT levels either for each brain region or for the pituitary gland, suggesting a decoupled activity of the AVT and IT systems at the CNS level. Subordinate AVT pituitary levels are significantly higher than those of dominants, and dominant hindbrain IT levels are significantly higher than those of subordinates, suggesting a potential involvement of AVT in social stress in subordinate fish and of IT in the regulation of dominant behavior at the level of the hindbrain. Since in this species dominant males use urine to communicate social status and since AVT is known to have an antidiuretic effect, we have also investigated the effect of social status on urine storage. As predicted, dominant males stored significantly more urine than subordinates. Given these results we suggest that AVT/IT play a key role in orchestrating social phenotypes, acting both as central neuromodulators that promote behavioral plasticity and as peripheral hormones that promote integrated physiological changes.

Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat

Oxytocin (OT) and arginine vasopressin (AVP), in their capacities as neuromodulators, are believed to play an important role in mood control, including regulation of the anxiety response. In the present study, the contributions of oxytocin and vasopressin receptor modulation to anxiety-like behaviors were examined in male Sprague-Dawley rats. The behavioral effects of the OT receptor agonist, carbetocin (intracerebroventricular, intravenous and intraperitoneal routes), the AVP receptor agonist desmopressin (intravenous route), and the OT/AVP(1A) receptor antagonist atosiban (intravenous route) were evaluated in the elevated plus maze. The benzodiazepine diazepam was included as a positive control. Central but not systemic administration of carbetocin produced pronounced anxiolytic-like behavioral changes comparable to those measured following systemic diazepam treatment. The anxiolytic efficacy of carbetocin was maintained following 10 days of once-daily treatment, contrasting with the effects of diazepam which were no longer distinguishable from saline treatment. Systemic administration of desmopressin produced anxiogenic-like effects whereas systemic atosiban produced anxiolytic-like effects. Co-administration of desmopressin with atosiban resulted in saline-like behavioral responses, implicating an AVP(1A) receptor mechanism in the anxiolytic and anxiogenic effects of these neuropeptides following systemic administration. A peripherally-mediated antidiuretic effect of desmopressin on water consumption was also demonstrated. These results highlight the potential therapeutic utility of AVP(1A) receptor blockade in the modulation of anxiety-related behaviors; AVP(1A) receptor blockade appears to be a more promising pharmacological target than does OT receptor activation following systemic drug administration.

Familial forms of diabetes insipidus: clinical and molecular characteristics

Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy.

Nasal administration of desmopressin by spray and drops.

A solution of desmopressin was administered intranasally as a spray using a metered dose pump, or as drops using a single dose pipette or rhinyle catheter. Volunteers, and patients with diabetes insipidus, were given an intranasal dose of 20 micrograms desmopressin by each method. The antidiuretic activity was measured by determination of urine osmolality and diuresis. Each delivery system was equally effective in producing a rapid onset of activity, a highly reproducible magnitude of effect and duration of the antidiuretic effect which lasted for more than 8 h. The pipette and spray pump offer a choice of single dose administration without preservative, or for chronic use, well-controlled, reproducible dosing, respectively.

Blockade of 5-hydroxytryptamine antidiuresis in rats by 2-bromlysergic acid diethylamide tartrate and 1-methyl-lysergic acid butanolamide.

Abstract The effects of two lysergic acid derivatives, 2-bromlysergic acid diethylamide ‘BOL 148’ and 1-methyl-lysergic acid butanolamide ‘UML 491’ on the antidiuresis induced by 5-hydroxytryptamine ‘5-HT’ has been studied in rats given a dose of 1 mg./kg. 5-HT subcutaneously. BOL 148, 5 mg./kg., and UML 491, 2·5 mg./kg., counteracted the induced antidiuresis. By contrast, the antidiuretic effect of posterior pituitary extract was not blocked or diminished by BOL 148 or by UML 491. BOL 148 and UML 491 alone did not have a diuretic or antidiuretic action.

Antidiuretic effect of bremazocine and U-50,488 in rats after α2-adrenoceptor blockade

The role of alpha 2-adrenoceptors and kappa-opioid receptors in urination was studied in rats. In water-loaded rats (40 mL kg-1 p.o.) the kappa-opioid agonist bremazocine (0.05 0.2 mg kg-1 i.p.) induced a dose-related diuretic response in the second hour after administration, but had no effect in the first hour. When rats were pretreated with the alpha 2-adrenoceptor antagonist idazoxan (1 mg kg-1 s.c.), bremazocine induced a dose-related antidiuretic response in the first hour; thereafter the rats showed an increase of urination similar to that with bremazocine alone. The antidiuretic effect of bremazocine was dependent on the dose of idazoxan with maximal response after 1-3 mg kg-1. Similar results were obtained with bremazocine in the presence of yohimbine (1 mg kg-1 s.c.). The antidiuretic profile of bremazocine after idazoxan was shared by U-50,488 (2.5-10 mg kg-1 i.p.), although this compound alone at the high dose reduces urine output in the first hour. The antidiuresis induced by bremazocine in the presence of idazoxan in water-loaded rats was completely antagonized by 10 but not 2 mg kg-1 i.p. of the opioid antagonist naloxone. Thus, kappa-opioid agonists, in addition to their diuretic effect, also produce an antidiuretic response which may be mediated by alpha 2-adrenoceptors.

Pharmacological Characterization of FE 202158, a Novel, Potent, Selective, and Short-Acting Peptidic Vasopressin V1aReceptor Full Agonist for the Treatment of Vasodilatory Hypotension

FE 202158, ([Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]vasopressin, where Hgn is homoglutamine and iPr is isopropyl), a peptidic analog of the vasoconstrictor hormone [Arg(8)]vasopressin (AVP), was designed to be a potent, selective, and short-acting vasopressin type 1a receptor (V(1a)R) agonist. In functional reporter gene assays, FE 202158 was a potent and selective human V(1a)R agonist [EC(50) = 2.4 nM; selectivity ratio of 1:142:1107:440 versus human vasopressin type 1b receptor, vasopressin type 2 receptor (V(2)R), and oxytocin receptor, respectively] contrasting with AVP's lack of selectivity, especially versus the V(2)R (selectivity ratio of 1:18:0.2:92; human V(1a)R EC(50) = 0.24 nM). This activity and selectivity profile was confirmed in radioligand binding assays. FE 202158 was a potent vasoconstrictor in the isolated rat common iliac artery ex vivo (EC(50) = 3.6 nM versus 0.8 nM for AVP) and reduced rat ear skin blood flow after intravenous infusion in vivo (ED(50) = 4.0 versus 3.4 pmol/kg/min for AVP). The duration of its vasopressor effect by intravenous bolus in rats was as short as AVP at submaximally effective doses. FE 202158 had no V(2)R-mediated antidiuretic activity in rats by intravenous infusion at its ED(50) for reduction of ear skin blood flow, in contrast with the pronounced antidiuretic effect of AVP. Thus, FE 202158 seems suitable for treatment of conditions where V(1a)R activity is desirable but V(2)R activity is potentially deleterious, such as vasodilatory hypotension in septic shock. In addition to the desirable selectivity profile, its short-acting nature should allow dose titration with rapid onset and offset of action to optimize vasoconstriction efficacy and safety.

Vaptans for the treatment of hyponatremia

The vaptans constitute a new class of pharmaceuticals developed for the treatment of the hypervolemic and euvolemic forms of hyponatremia. These agents are nonpeptide vasopressin antagonists that interfere with the antidiuretic effect of the hormone by competitively binding to V(2) receptors in the kidney. This blockade results in water diuresis (aquaresis) that, if not offset by increased fluid intake, reduces body water content and raises plasma sodium levels. Probably as a result of this rise in plasma sodium, thirst and plasma vasopressin concentration increase, potentionally limiting the effects of the vasopressin antagonists. Nonetheless, vaptans are particularly useful to treat hypervolemic hyponatremia associated with severe congestive heart failure or chronic liver failure, as the only other treatments currently available, such as fluid restriction and diuretics, are slow-acting and minimally effective. Vaptans are also useful for treating euvolemic hyponatremia associated with the syndrome of inappropriate antidiuretic hormone (SIADH), at least when it is chronic and/or minimally symptomatic. However, because their effects vary unpredictably from patient to patient, vaptans are less useful than hypertonic saline infusion in cases of acute, severe and symptomatic hyponatremia. Vaptan therapy is absolutely contraindicated in hypovolemic hyponatremia (in which total body water is reduced) and is ineffective in the vasopressin-independent form of inappropriate antidiuresis caused by constitutive activating mutations of V(2) receptors.

Cooperative mechanisms of acute antidiuretic response to bendroflumethiazide in rats with lithium-induced nephrogenic diabetes insipidus

The exact mechanism underlying thiazides-induced paradoxical antidiuresis in diabetes insipidus is still elusive, but it has been hypothesized that it is exerted either via Na+-depletion activating volume-homeostatic reflexes to decrease distal delivery, or direct stimulation of distal water reabsorption. This study examined how these two proposed mechanisms actually cooperate to induce an acute bendroflumethiazide (BFTZ)-antidiuretic effect in nephrogenic diabetes insipidus (NDI). Anaesthetized rats with lithium (Li)-induced NDI were prepared in order to measure their renal functional parameters, and in some of them, bilateral renal denervation (DNX) was induced. After a 30 min control clearance period, we infused either BFTZ into 2 groups, NDI+BFTZ and NDI/DNX+BFTZ, or its vehicle into a NDI+V group, and six 30 min experimental clearance periods were taken. During BFTZ infusion in the NDI+BFTZ group, transiently elevated Na+ excretion was associated with rapidly increased urinary osmolality and decreased free water clearance, but Li clearance and urine flow declined in the later periods. However, in the NDI/DNX+BFTZ group, there was persistently elevated Na+ excretion with unchanged Li clearance and urine flow during the experimental period, while alterations in free water clearance and urinary osmolality resembled those in the NDI+BFTZ group. In conclusion, BFTZ initially exerted two direct effects of natriuresis-diuresis and stimulating free water reabsorption at the distal nephron in NDI, which together elevated Na+ excretion and urinary osmolality but kept the urine volume unchanged in the first hour. Thereafter, the resultant sodium depletion led to the activation of neural reflexes that reduced distal fluid delivery to compensate for BFTZ-induced natriuresis-diuresis which, in cooperation with the direct distal BFTZ-antidiuretic effect, resulted in excretion of urine with a low volume, high osmolality, and normal sodium.

The control of Malpighian tubule secretion in a predacious hemipteran insect, the spined soldier bug Podisus maculiventris (Heteroptera, Pentatomidae)

Spined soldier bugs, Podisus maculiventris, are heteropteran insects that feed voraciously on other insects, particular the soft bodied larval forms of Lepidoptera and Coleoptera. The response of P. maculiventris Malpighian tubules (MTs) to serotonin and known diuretic and antidiuretic peptides has been investigated, and is compared with that of MT from the hematophagous and phytophagous heteropteran bugs Rhodnius prolixus and Acrosternum hilare, respectively. A CRF-related peptide diuretic hormone (DH) from the termite Zootermopsis nevadensis (Zoone-DH) stimulated MT secretion, which was reversed by a member of the CAP 2b family of peptides from A. hilare (Acrhi-CAP 2b-2), an antidiuretic effect. Serotonin had no effect on secretion, neither did a representative calcitonin-like DH, kinin, tachykinin-related peptide, and an antidiuretic factor from the mealworm Tenebrio molitor (Tenmo-ADFb) in both P. maculiventris or A. hilare. Serotonin is a DH in R. prolixus, and its lack of effect on MT from P. maculiventris and A. hilare suggests this is an adaptation to hematophagy. On the other hand, the antidiuretic activity of members of the CAP 2b family in all three bugs is consistent with this being a heteropteran feature rather than a specialism for hematophagy.

High plasma mid-regional pro-adrenomedullin levels in children with severe dengue virus infections

Background Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is characterized by hemorrhage, plasma leakage and shock. Adrenomedullin and vasopressin are vaso-active hormones that mediate endothelial permeability, vascular tone and water balance and may therefore play a role during DHF/DSS. Adrenomedullin reduces endothelial permeability and has vasodilatory properties, while vasopressin is a potent vasoconstrictor with anti-diuretic effects. Objectives To determine mid-regional pro-adrenomedullin (MR-proADM) and copeptin, which are reliable and stable markers for adrenomedullin and vasopressin response, respectively, and relate their plasma concentrations to outcome and markers of plasma leakage in Indonesian children with DHF and DSS. Study design In this observational cohort study Indonesian children with DHF/DSS were enrolled. On study days 0 and 2, plasma MR-proADM and copeptin concentrations as well as parameters of plasma leakage were determined. Plasma MR-proADM and copeptin concentrations were compared to values of healthy controls. Results MR-proADM was increased in both DHF ( n = 43) and DSS ( n = 28) vs. controls ( n = 17), with median (IQR) values of 0.47 (0.40–0.68), 0.56 (0.44–1.00) vs. 0.22 (0.19–0.29) nmol/L, respectively. Additionally, MR-proADM correlated with signs of increased vascular leakage such as low albumin and increased pleural effusion. Copeptin concentrations showed no significant changes as compared to controls. Conclusions MR-proADM concentrations are elevated in children with DHF and DSS and correlate with the severity of plasma leakage, in contrast to copeptin concentrations. We speculate that adrenomedullin has a functional role in limiting endothelial hyperpermeability during DHF/DSS. Finally, MR-proADM may be a candidate biomarker to predict development of DHF/DSS.

Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis: A study in healthy volunteers

The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus –pituitary –adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10 mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.

Carbamazepine can induce kidney water absorption by increasing aquaporin 2 expression

Carbamazepine (Carba) is an anticonvulsant and psychotropic drug used widely for the treatment of intellectual disability and severe pains, but the incidence of hyponatremia is a common related occurrence. This hyponatremia is frequently attributed to a SIADH induced by this drug. It is also known that Carba is used to decrease the urinary volume in Diabetes Insipidus (DI) because it has an antidiuretic effect. Lithium (Li) is one of the most important drugs used to treat bipolar mood disorders. However Li has the undesirable capacity to induce DI. Nowadays, the association of these drugs is used in the treatment of patients with psychiatric and neurological problems. In vivo and in vitro (microperfusion) experiments were developed to investigate the effect of Carba in the rat Inner Medullary Collecting Duct (IMCD). The results revealed that Carba was able to stimulate the V2 vasopressin receptor-Protein G complex increasing the (Pf) and water absorption. In vivo studies showed that in rats with lithium-induced DI, Carba decreased the urinary volume and increased the urinary osmolality. AQP2 expression was increased both in normal IMCD incubated with Carba and in IMCD from lithium-induced DI after Carba addition to the diet, when compared with the control. These results showed that the hyponatremia observed in patients using this anticonvulsant drug, at least in part, is due to the Carba capacity to increase IMCD's Pf and that the Lithium-Carbamazepine association is beneficial to the patient.

Antagonistas del receptor de vasopresina: los vaptanes

The non-peptide vasopressin antagonists (VPA), called vaptans, were developed in the 1990s to antagonize both the pressor and antidiuretic effects of vasopressin. There are three subtypes of VPA receptors: V1a, V1b and V2. V1a receptors are widely distributed in the body, mainly the blood vessels and myocardium. The V1b receptors are located mainly in the anterior pituitary gland and play a role in ACTH release. V2 receptors are located in the collecting tubular renal cells. Both V1a and V1b receptors act through the intracellular phosphoinositol signalling pathway, Ca ++ being the second messenger. V2 receptors work through AMPc generation, which promotes aquaporin 2 (AQP2) trafficking and allows water to enter the cell. The vaptans act competitively at the AVP receptor. The most important are mozavaptan, lixivaptan, satavaptan and tolvaptan, all of which are selective V2 antagonists and are administered through the oral route. In contrast, conivaptan is a dual V1 and V2 antagonist administered through the endovenous route. The main characteristics of vaptans are their effect on free water elimination without affecting electrolyte excretion. There are several studies on the effects of these drugs in hypervolemic hyponatremia (heart failure, hepatic cirrhosis) as well as in normovolemic hyponatremia (inappropriate secretion of ADH [SIADH]). Current studies show that the vaptans are effective and well tolerated, although knowledge of these drugs remains limited. There are no studies of the use of vaptans in severe hyponatremia. Osmotic demyelination syndrome due to excessively rapid correction of hyponatremia has not been described.

Jack bean urease alters serotonin-induced effects on Rhodnius prolixus anterior midgut

Urease isoforms from jack bean seeds are toxic to insects, and this entomotoxic effect is mostly due to the release of a peptide by insect digestive enzymes. We previously demonstrated that jack bean urease (JBU) has antidiuretic effects on Rhodnius prolixus Malpighian tubules, decreasing the serotonin-stimulated secretion of fluid. Now, we evaluate the toxicity of the intact JBU and its effect on R. prolixus anterior midgut, to further elucidate the mechanism of action of JBU in insects. JBU decreases the serotonin-induced fluid transport by the anterior midgut in vitro when injected into the lumen. A decrease in the levels of cAMP is observed in tissues treated with JBU (in the presence of serotonin). JBU also causes a dose-dependent increase in the frequency of serotonin-induced contractions in the anterior midgut, but does not alter the frequency of spontaneous contractions. The cyclooxygenase inhibitor indomethacin and the prostaglandin antagonist AH6809 block JBU's potentiation of serotonin-induced contractions, indicating that prostaglandins might act as second messengers for JBU action. Prostaglandin E 2 (PGE 2) increases the frequency of serotonin-induced contractions, again supporting the role of prostaglandins as second messengers for JBU action. JBU and PGE 2 increase cGMP levels in the anterior midgut, indicating that this molecule might also be part of the JBU pathway.

A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model

Desmopressin is a synthetic vasopressin analogue mainly used in treatment of diabetes insipidus and nocturia. Studies in rats have revealed a sex difference in the response to a vasopressin infusion, which was diminished after treatment with an NSAID. This study was performed in man to investigate the influence of sex and concomitant treatment of piroxicam on the pharmacokinetics and dynamics of desmopressin, and to validate a previously described indirect response model. Eight healthy males and eight healthy females participated in the trial, which was conducted in a pharmacokinetic (PK) part followed by a pharmacodynamic (PD) part. Desmopressin was administered intravenously as a single dose (PK = dose 2 microg, PD = dose 0.2 microg). Piroxicam was administered to achieve steady state. The pharmacokinetic parameters of desmopressin were estimated and calculated by means of two-compartmental analysis. In the dynamic part a study design based on an oral hydration model was used. Parameters for urine flow and urine osmolality were estimated. Individual estimates of the pharmacokinetic parameters served as input to the indirect response model that subsequently was fitted to urine osmolality data. The pharmacokinetics of desmopressin after a fixed bolus injection was neither influenced by piroxicam nor sex of the subject. The pharmacodynamics of desmopressin showed a sex difference where females exhibited a more pronounced antidiuretic effect than males, which was statistically significant when the effects were submaximal (>4.5 h after dose). The sex differences were diminished after pre-treatment with piroxicam, indicating a prostaglandin PGE(2)-mediated mechanism. The indirect response model was confirmed, although the modelling could not distinguish a sex difference, indicating a limitation of this model compared with traditional descriptive statistics.