Endogenous Vasopressin Research Articles

From species differences to individual differences

In his seminal work, The Origin of Species, Darwin begins with a long discourse on variation in domesticated species.1 He considers the differences in strains of pigeons, sheep, and dogs to address the fundamental questions of how and when new species form. Darwin suggests that new species are the result of extreme within-species variation. Individual changes become so extreme that a new species buds off from an existing one with either physical isolation or environmental pressure. Although Darwin could not know about modern genetics, in contemporary terms his hypothesis could be re-stated as within-species variation precedes between-species variation. Comparative genomics flips this hypothesis by proposing that regions that vary between species are likely to be hotspots that vary between individuals. Over the past decade, a series of comparative papers by Larry Young and his co-workers have demonstrated the extraordinary species variation in the sequence of the vasopressin V1a receptor gene (AVPR1a).2 This subtype of the vasopressin receptor is expressed in the brain, especially in the hypothalamus, lateral septum, amygdala, and, in some species, the ventral striatum. Activation of this receptor increases social interaction, but there are striking species differences in the behavioral response to activation and in the anatomic location of this receptor. As a general rule, the pattern of expression of this receptor correlates with social organization. Specifically, monogamous mammals, from rodents to primates, have abundant V1a receptors in the ventral striatum and non-monogamous species have few receptors in areas associated with reward.3 Most important, the pattern of receptor expression appears to be determined by variation in the length of a microsatellite in the promoter region of the AVPR1a.4 Readers of this journal are familiar with the variation in the serotonin transporter promoter and its role for altering the amount of protein. The AVPR1a promoter variation is similar, but its variation appears to influence not only the amount of protein, but where in the brain this protein is expressed. The model then is variation in promoter leads to variation in anatomical pattern resulting in species differences in social behavior following endogenous vasopressin release. Most recently, Hammock and Young have demonstrated the application of this model in a comparison of chimpanzees and bonobos, two closely related great apes with markedly different social behavior.4 Could this species difference in gene sequence, brain chemistry, and behavior be relevant to individual differences within the human species? In humans, AVPR1a is found on chromosome 12q14–15, with variation observed at three microsatellites (RS1 and RS3 in the promoter and an intronic allele identified as AVR). The paper by Yirmiya et al. in this issue of Molecular Psychiatry is the third report to test for an association between variations in one of these microsatellites and autism, which is fundamentally a deficit in social behavior.5, 6, 7 Kim et al.5 found 17 alleles of RS1, one of which showed increased transmission in a family-based study of 115 autism trios. Wassink et al.6 found significant disequilibrium with both RS1 and RS3 but only in cases without language deficits. In this new paper, Yirmiya et al.7 fail to find the association with either RS1 or RS3 but report significant transmission disequilibrium with the intronic microsatellite. They note moderate linkage disequilibrium between the intronic and the promoter microsatellites. The most significant association in this study is between the ADOS-G, a composite measure of autism deficits (especially social skills) and the microsatellite haplotypes. Taken together, these three papers suggest a link between variations in the AVPR1a and autism, possibly confirming the value of comparative genomics for identifying hot spots for variation in the human genome. Now the challenge will be to move from genetics to biology, as has been done already in studies of the vole AVPR1a.4 Are any of these variations in the human gene functional? Can a particular haplotype drive expression patterns in the human brain? Do patients with autism show altered patterns of V1a receptors in the social brain? Given the abundant evidence linking vasopressin and oxytocin to social behavior, we need comprehensive maps of the oxytocin and V1a receptors in the human brain and, with or without genotypes, we need measures of these receptors in brains from autistic patients. If, as suggested in this paper, the variations in AVPR1a genomic sequence are responsible for individual variations in social behavior, we will have a stunning confirmation of an idea that Darwin suggested 150 years ago: mechanisms of speciation can also be mechanisms of individual variation. Understanding the differences between species will lead inexorably to an understanding of differences within a species including those adverse individual differences we define as disease states.

Effects of water restriction on gene expression in mouse renal medulla: identification of 3βHSD4 as a collecting duct protein

To identify novel gene targets of vasopressin regulation in the renal medulla, we performed a cDNA microarray study on the inner medullary tissue of mice following a 48-h water restriction protocol. In this study, 4,625 genes of the possible approximately 12,000 genes on the array were included in the analysis, and of these 157 transcripts were increased and 63 transcripts were decreased by 1.5-fold or more. Quantitative, real-time PCR measurements confirmed the increases seen for 12 selected transcripts, and the decreases were confirmed for 7 transcripts. In addition, we measured transcript abundance for many renal collecting duct proteins that were not represented on the array; aquaporin-2 (AQP2), AQP3, Pax-8, and alpha- and beta-Na-K-ATPase subunits were all significantly increased in abundance; the beta- and gamma-subunits of ENaC and the vasopressin type 1A receptor were significantly decreased. To correlate changes in mRNA expression with changes in protein expression, we carried out quantitative immunoblotting. For most of the genes examined, changes in mRNA abundances were not associated with concomitant protein abundance changes; however, AQP2 transcript abundance and protein abundance did correlate. Surprisingly, aldolase B transcript abundance was increased but protein abundance was decreased following 48 h of water restriction. Several transcripts identified by microarray were novel with respect to their expression in mouse renal medullary tissues. The steroid hormone enzyme 3beta-hydroxysteroid dehydrogenase 4 (3betaHSD4) was identified as a novel target of vasopressin regulation, and via dual labeling immunofluorescence we colocalized the expression of this protein to AQP2-expressing collecting ducts of the kidney. These studies have identified several transcripts whose abundances are regulated in mouse inner medulla in response to an increase in endogenous vasopressin levels and could play roles in the regulation of salt and water excretion.

A new fast‐melting oral formulation of desmopressin: a pharmacodynamic study in children with primary nocturnal enuresis

To determine the pharmacodynamic properties of a new oral lyophilisate formulation of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 microg) in children with known primary nocturnal enuresis (PNE) and thus identify those dosages that could provide a duration of action corresponding to a typical length of night-time sleep in children with PNE; additional objectives were to determine the safety and tolerability of desmopressin in this population. Children with PNE (mean three or more wet nights/week), aged 6-12 years, were randomized into a double-blind, placebo-controlled study. An overhydration technique was used before dosing to suppress endogenous vasopressin production and thereby ensure that any antidiuresis could be attributed to treatment. Dosing with desmopressin or placebo occurred when urinary production was >0.13 mL/min/kg. Urinary volume, osmolality and duration of urinary-concentrating action (above three threshold levels: 125, 200 and 400 mOsm/kg) were determined as endpoints. All 72 participants receiving desmopressin had a pharmacodynamic response to the drug, while there was no change in urinary output in the 12 placebo-treated patients. There was a clear relationship between desmopressin dose and duration of action and osmolality during action, although the three highest-dose groups had similar results. The mean duration of action of desmopressin at the lowest osmolality threshold level was 3.6-10.6 h, according to dose; for the highest threshold, the values were 1.3-8.6 h. Desmopressin, as the oral lyophilisate, causes a marked decrease in urinary output in hydrated children with PNE. A small dose range (120-240 microg) is likely to control diuresis for a period corresponding to a night's sleep (7-11 h) in most children with PNE. However, some patients might require a higher dose to obtain antidiuresis for the complete night.

Does endogenous vasopressin induced by central salt loading increase vasopressin and oxytocin mRNA in the paraventricular and supraoptic nucleui of the hypothalamus in rats

Does endogenous vasopressin induced by central salt loading increase vasopressin and oxytocin mRNA in the paraventricular and supraoptic nucleui of the hypothalamus in rats

Shorter PFA-100-closure times in laparoscopic versus conventional hysterectomy are not caused by increased vasopressin levels

Background/Objectives Bleeding problems during laparoscopic surgery are infrequent. We hypothesised that increased abdominal pressure during the application of the pneumoperitoneum would lead to an increased release of endogenous vasopressin which could then contribute to the hemostasis by increasing platelet reactivity, FVIII and von Willebrand-factor. Patients and methods We compared the vasopressin levels, the platelet function as measured by the PFA-100-test, aPTT and FVIII in 39 consecutive patients who underwent elective hysterectomy (20 with the laparoscopic and 19 with the conventional, “open” method). Blood was sampled the day before surgery and 2, 4 and 72 h after the induction of anaesthesia. Results After two hours, the PFA-100 closure times with collagen/ADP decreased to lower levels in the laparoscopic group (from 93 ± 22 to 82 ± 20, mean ± SD) and even further down to 65 ± 13 s (compared to 82 ± 20 s) ( p = 0.024)) four hours after the beginning of surgery. Vasopressin levels and F VIII increased in both groups but there was no significant difference between the groups (21 vs. 17.8 pmol/l for vasopressin, differences of the mean). Bleeding was minimal, with a trend to lower Hb-levels in the laparotomy group. Conclusions The procedural difference of laparoscopic vs. open hysterectomy appears to enhance platelet reactivity by other mechanisms than increased vasopressin levels and may contribute to an enhanced hemostatic competence in laparoscopic surgery.

Vasopressin-independent regulation of collecting duct aquaporin-2 in food deprivation

Humans and animals are frequently subjected to food deprivation or starvation. However, the adaptation of the kidney to this condition is not well understood. The purpose of these studies was to examine the effects of food deprivation on water handling by the kidney, the expression levels of collecting duct (CD) water channel aquaporin-2 (AQP2), and to determine the role of vasopressin in the adaptation of AQP2 to food deprivation. Sprague-Dawley (SD) and Brattleboro rats were placed in metabolic cages and deprived of food but had free access to water for 72 hours. Water balance and urine osmolality were measured daily. Kidney tissues were isolated and examined for the expression of AQP2 using semiquantitative immunoblotting and Northern hybridization. The circulating level of vasopressin and the mRNA expression levels of its precursor were determined by radioimmunoassay and Northern hybridization, respectively. In SD rats, the first 24 hours of food deprivation is associated with a significant polyuria and decreased urine osmolality (Uosm). This correlated with a significant down-regulation of AQP2 in the cortex and outer medulla. After 72 hours of food deprivation, Uosm increased above baseline, and urine volume dropped to a lower value. This was associated with a rebound increase in AQP2 expression in the cortex and OM and its up-regulation in the inner medulla. Interestingly, vasopressin mRNA expression and plasma levels were unchanged during food deprivation. Further, in homozygous Brattleboro rats, in which endogenous vasopressin is absent, food deprivation caused changes in urine volume, urine osmolality, and AQP2 expression, which are qualitatively similar to those observed in normal rats. Food deprivation impairs water handling by the kidney by causing dual changes in urine volume and urine osmolality. This effect is associated with parallel alterations in the expression of AQP2 and is independent of vasopressin activity. It is concluded that the increase in water reabsorption in the CD is an adaptive response of the kidney to a long period of food deprivation and is mediated via a vasopressin-independent mechanism.

Regional differences in the expression of Fos-like immunoreactivity after central salt loading in conscious rats: modulation by endogenous vasopressin and role of the area postrema

In this study, we examined the quantitative relationship between centrally administered hypertonic saline (HS) concentrations and the expression of Fos-like immunoreactivity (FLI) in brain regions involved in the homeostasis of body fluids. The regions examined were the organum vasculosum laminae terminalis (OVLT), the median preoptic nucleus (MnPO), the subfornical organ (SFO), the paraventricular nucleus (PVN), the supraoptic nucleus of the hypothalamus, the nucleus of the solitary tract (NTS), and the area postrema (AP). The experiments were performed in conscious rats with attention to the actual changes in central [Na +]. Hypertonic saline (0.3, 0.67, or 1.0 M) was delivered at 1 μl/min for 20 min. The changes in cerebrospinal fluid [Na +] during i.c.v. administration of 0.3 M hypertonic saline were compatible with those expected for thermal dehydration. FLI increased in a dose-dependent manner in the dorsomedial cap of the PVN and NTS. Although the pressor responses during central salt loading were not significantly affected by pretreatment with the peripheral vasopressin V 1 receptor antagonist OPC-21268, FLI expression in the PVN was significantly augmented. In addition, in AP-lesioned rats, FLI expression in the lateral magnocellular part of the PVN and NTS was significantly enhanced after central salt loading. These results suggest that the peripheral vasopressin system participates in negative feedback to modulate neuronal activities in the PVN, probably through the AP or direct action at the PVN in response to central osmotic and/or Na + stimulation.

Vasopressin during cardiopulmonary resuscitation: A progress report

In patients undergoing cardiopulmonary resuscitation, circulating endogenous vasopressin concentrations were significantly higher in successfully resuscitated patients than in patients who died. These observations have prompted several investigations to assess the role of vasopressin to improve cardiopulmonary resuscitation management. Literature review. In the cardiopulmonary resuscitation laboratory, vasopressin improved vital organ blood flow, cerebral oxygen delivery, the probability of restoring spontaneous circulation, and neurologic recovery better than epinephrine. In pediatric preparations with asphyxia, epinephrine was superior to vasopressin, whereas in both pediatric pigs with ventricular fibrillation and adult porcine models with asphyxia, combinations of vasopressin and epinephrine proved to be highly effective. In addition, vasopressin enabled short- and long-term survival in a porcine model of uncontrolled hemorrhagic shock. In a recently published European, multiple-center trial, 1,219 adult patients with out-of-hospital cardiac arrest were randomized to receive two injections of either 40 IU of vasopressin or 1 mg of epinephrine followed by additional epinephrine if needed. The clinical study did not confirm laboratory data showing vasopressin to be more effective than epinephrine in ventricular fibrillation and pulseless electrical activity, but vasopressin was superior to epinephrine in patients with asystole. Vasopressin followed by epinephrine was more effective than epinephrine alone in the treatment of refractory cardiac arrest. According to new data from the European vasopressin study, we suggest, first, the administration of 1 mg of epinephrine, followed alternately by 40 IU of vasopressin and 1 mg of epinephrine every 3 mins in adult cardiac arrest victims, regardless of the initial electrocardiographic rhythm.

Synergistic interaction of endogenous platelet-activating factor and vasopressin in generating angina in rats

We examined the involvement of endogenous vasopressin and platelet-activating factor (PAF) in the pathogenesis of two types of experimental angina in urethane-anaesthetised male Wistar rats. In the first model, epinephrine (10 μg kg −1) was injected into the tail vein, followed at the development of the maximum blood pressure response, i.e., 30 s later, by phentolamine (15 mg kg −1). In the second model, the vasopressin V 1 receptor agonist ornithine-vasopressin (ornipressin; 0.5 IU kg −1, i.v.) was administered. The heart rate, mean arterial blood pressure and surface electrocardiogram (ECG, standard lead II) were registered simultaneously. As a measure of myocardial ischaemia, at 1 min after phentolamine or ornipressin administration, we found significant ST-segment depression, lasting for more than 10 or 5 min, respectively. Pretreatment (15 min, s.c.) with the vasopressin V 1 receptor antagonist Mca 1,Tyr(Me) 2AVP (the Manning peptide; 0.02–0.2 μg kg −1) or the platelet-activating factor receptor antagonist ginkgolide B (BN 52021; 0.25–2.5 mg kg −1) alone caused a dose-dependent reduction of the ST-segment depression. Concurrent administration of the two antagonists in their threshold doses (0.02 μg kg −1 and 0.25 mg kg −1) also attenuated the ST-segment depression in both models. Neither antagonist affected the blood pressure or heart rate changes throughout the studies. Our results suggest that endogenous vasopressin and platelet-activating factor interact synergistically in provoking myocardial ischaemia in vivo in experimental angina in the rat.

Site of action of acute alcohol administration in stimulating the rat hypothalamic-pituitary-adrenal axis: comparison between the effect of systemic and intracerebroventricular injection of this drug on pituitary and hypothalamic responses.

The peripheral injection of alcohol stimulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis, but the ready penetration of this drug in most bodily compartments has made it difficult to identify its specific sites of action. Here we determined whether alcohol can directly influence the corticotropes. We first determined whether alcohol acted within the brain to stimulate neurons in the paraventricular nucleus (PVN) of the hypothalamus, which synthesizes corticotropin-releasing factor (CRF) and vasopressin (VP). To test this hypothesis, we injected alcohol intracerebroventricularly (icv; 5 microl of 200-proof; 86 micromol) and compared these results with those obtained after its ip administration (3.0 g/kg). Although not causing neuronal damage and not leading to detectable levels of the drug in the general circulation, icv alcohol significantly up-regulated PVN CRF heteronuclear RNA levels and increased plasma ACTH levels, a change comparable to the one observed in the ip model. To determine whether alcohol stimulated the corticotropes independently of CRF and/or VP, we injected the drug ip or icv and measured changes in anterior pituitary proopiomelanocortin (POMC) transcripts and ACTH release in the presence or absence of endogenous CRF and/or VP. Intracerebroventricular and ip alcohol significantly increased POMC primary transcript levels, measured by ribonuclease protection assay, over a time-course that corresponded to ACTH release. Both the POMC and the ACTH responses were completely abolished by removal of CRF and VP. Collectively, these results indicate that alcohol-induced activation of the corticotropes does not represent a direct influence of the drug on the pituitary but requires CRF and VP.

Vasopressin vs. Epinephrine for Out-of-Hospital CPR

Since the discovery that survivors of cardiac arrest have high levels of endogenous vasopressin, the use of this agent for treating cardiac arrest has

Vasopressin-induced taurine efflux from rat pituicytes: a potential negative feedback for hormone secretion.

Previous work on the whole neurohypophysis has shown that hypotonic conditions increase release of taurine from neurohypophysial astrocytes (pituicytes). The present work confirms that taurine is present in cultured pituicytes, and that its specific release increases in response to a hypotonic shock. We next show that vasopressin (VP) and oxytocin (OT) also specifically release taurine from pituicytes. With an EC(50) of approximately 2 nm, VP is much more potent than OT, and the effects of both hormones are blocked by SR 49059, a V(1a) receptor antagonist. This pharmacological profile matches the one for VP- and OT-evoked calcium signals in pituicytes, consistent with the fact that VP-induced taurine efflux is blocked by BAPTA-AM. However, BAPTA-AM also blocks the taurine efflux induced by a 270 mosmol l(-1) challenge, which per se does not evoke any calcium signal, suggesting a permissive role for calcium in this case. Nevertheless, the fact that structurally unrelated calcium-mobilizing agents and ionomycin are able to induce taurine efflux suggests that calcium may also play a signalling role in this event. It is widely accepted that in hypotonic conditions taurine exits cells through anionic channels. Antagonism by the chloride channel inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) suggests the same pathway for VP-induced taurine efflux, which is also blocked in hypertonic conditions (330 mosmol l(-1)). Moreover, it is likely that the osmosensitivity of the taurine channel is up-regulated by calcium. These results, together with our in situ experiments showing stimulation of taurine release by endogenous VP, strengthen the concept of a glial control of neurohormone output.

Body sodium and volume homeostasis.

maintenance of a “milieu interieur,” which allows our cells to function away from the ancient sea, is one of the most important functions of the body. Maintenance of constant extracellular osmolarity and sodium concentration depends on a precise balance between intake and excretion of sodium and

Vasopressin in shock states

There is growing evidence that in end-stage shock or during cardiac arrest, inappropriately low endogenous vasopressin plasma levels may be responsible for pathologic vasodilatation, inadequate organ perfusion, and poor outcome. The purpose of this article is to review recent publications featuring arginine vasopressin as a potent vasoconstrictor in various shock states such as systemic vasodilatation, severe hypovolemia, or cardiac arrest. Several retrospective investigations give evidence that vasopressin at a dosage of 2-6 U/h is effective in reversing catecholamine-resistant vasodilatory shock due to sepsis or after cardiopulmonary bypass, but prospective randomized controlled trials are warranted. In experimental hypovolemic cardiac arrest or therapy-resistant (irreversible) hypovolemic shock, vasopressin may be an intriguing therapy, although human evidence is not available. Animal data gives strong evidence that vasopressin given during cardiopulmonary resuscitation improves both return of spontaneous circulation and neurological outcome. Clinical experience on the use of vasopressin for in-hospital cardiopulmonary resuscitation with short response time showed equipotency with epinephrine; in patients with out-of-hospital ventricular fibrillation, vasopressin showed improved 24 h survival in comparison with epinephrine. After the large European multicenter study completed in summer 2002, we will hopefully be able to better determine the role of vasopressin versus epinephrine in the management of adult cardiac arrest. Vasopressin administration is emerging as a rational and promising therapy in the management of various shock states and cardiac arrest.

In Vivo Gene Transfer Studies on the Regulation and Function of the Vasopressin and Oxytocin Genes

Novel genes can be introduced into the germline of rats and mice by microinjecting fertilized one-cell eggs with fragments of cloned DNA. A gene sequence can thus be studied within the physiological integrity of the resulting transgenic animals, without any prior knowledge of its regulation and function. These technologies have been used to elucidate the mechanisms by which the expression of the two genes in the locus that codes for the neuropeptides vasopressin and oxytocin is confined to, and regulated physiologically within, specific groups of neurones in the hypothalamus. A number of groups have described transgenes, derived from racine, murine and bovine sources, in both rat and mouse hosts, that mimic the appropriate expression of the endogenous vasopressin and genes in magnocellular neurones (MCNs) of the supraoptic and paraventricular nuclei. However, despite considerable effort, a full description of the cis-acting sequences mediating the regulation of the vasopressin-oxytocin locus remains elusive. Two general conclusions have nonetheless been reached. First, that the proximal promoters of both genes are unable to confer any cell-specific regulatory controls. Second, that sequences downstream of the promoter, within the structural gene and/or the intergenic region that separates the two genes, are crucial for appropriate expression. Despite these limitations, sufficient knowledge has been garnered to specifically direct the expression of reporter genes to vasopressin and oxytocin MCNs. Further, it has been shown that reporter proteins can be directed to the regulated secretory pathway, from where they are subject to appropriate physiological release. The use of MCN expression vectors will thus enable the study of the physiology of these neurones through the targeted expression of biologically active molecules. However, the germline transgenic approach has a number of limitations involving the interpretation of phenotypes, as well as the large cost, labour and time demands. High-throughput somatic gene transfer techniques, principally involving the stereotaxic injection of hypothalamic neuronal groups with replication-deficient adenoviral vectors, are now being developed that obviate these difficulties, and which enable the robust, long-lasting expression of biologically active proteins in vasopressin and oxytocin MCNs.

Putative Dynamics of Vasopressin in its V1a Receptor Binding Site

The molecular architecture of the GPCRs, including the dynamic set of interactions between the receptor and the ligand, is one of the key structural questions of biophysical approaches. In the present study, molecular dynamics (MD) simulations were performed on the well-validated molecular model of the vasopressin V1a receptor applying different parameters (i.e., force fields, time variation, use of constraints) in order to sample the conformational space of the endogenous ligand arginine vasopressin (AVP), to explore different putative binding modes, and to analyze the simulation results with respect to experimental data. Noteworthy, it is to mention that for the first time a model of the vasopressin receptor remained stable in a 500 ps MD simulation run under vacuo boundary conditions using the Kollman all-atom FF even though no constraints were imposed. Conclusively, we determined an optimized experimental procedure for studying the dynamics and structure-functionship of this highly important family of GPCRs: the use of MD simulations with the Kollman all-atom force-field parameters on a constrained receptor. Our simplified model may be used as a basis for structure based design of new GPCR ligands and for in silico screening of virtual combinatorial chemistry libraries.

Smoking and the pathogenesis of gastroduodenal ulcer--recent mechanistic update.

Peptic ulcer is a common disorder of gastrointestinal system and its pathogenesis is multifactorial, where smoking and nicotine have significant adverse effects. Smoking and chronic nicotine treatment stimulate basal acid output which is more pronounced in the smokers having duodenal ulcer. This increased gastric acid secretion is mediated through the stimulation of H2-receptor by histamine released after mast cell degranulation and due to the increase of the functional parietal cell volume or secretory capacity in smokers. Smoking and nicotine stimulate pepsinogen secretion also by increasing chief cell number or with an enhancement of their secretory capacity. Long-term nicotine treatment in rats also significantly decreases total mucus neck cell population and neck-cell mucus volume. Smoking also increases bile salt reflux rate and gastric bile salt concentration thereby increasing duodenogastric reflux that raises the risk of gastric ulcer in smokers. Smoking and nicotine not only induce ulceration, but they also potentiate ulceration caused by H. pylori, alcohol, nonsteroidal anti-inflammatory drugs or cold restrain stress. Polymorphonuclear neutrophils (PMN) play an important role in ulcerogenesis through oxidative damage of the mucosa by increasing the generation of reactive oxygen intermediates (ROI), which is potentiated by nicotine and smoking. Nicotine by a cAMP-protein kinase A signaling system elevates the endogenous vasopressin level, which plays an aggressive role in the development of gastroduodenal lesions. Smoking increases production of platelet activating factor (PAF) and endothelin, which are potent gastric ulcerogens. Cigarette smoking and nicotine reduce the level of circulating epidermal growth factor (EGF) and decrease the secretion of EGF from the salivary gland, which are necessary for gastric mucosal cell renewal. Nicotine also decreases prostaglandin generation in the gastric mucosa of smokers, thereby making the mucosa susceptible to ulceration. ROI generation and ROI-mediated gastric mucosal cell apoptosis are also considered to be important mechanism for aggravation of ulcer by cigarette smoke or nicotine. Both smoking and nicotine reduce angiogenesis in the gastric mucosa through inhibition of nitric oxide synthesis thereby arresting cell renewal process. Smoking or smoke extract impairs both spontaneous and drug-induced healing of ulcer. Smoke extract also inhibits gastric mucosal cell proliferation by reducing ornithine decarboxylase activity, which synthesises growth-promoting polyamines. It is concluded that gastric mucosal integrity is maintained by an interplay of some aggressive and defensive factors controlling apoptotic cell death and cell proliferation and smoking potentiates ulcer by disturbing this balance.

Autophagy in Hypothalamic Neurones of Rats Expressing a Familial Neurohypophysial Diabetes Insipidus Transgene

We have tested the hypothesis that familial neurohypophysial diabetes insipidus (FNDI) is initiated by a process of autophagy. FNDI is a dominant, progressive inherited disorder characterized by pronounced drinking and urination caused by loss of secretion of antidiuretic hormone (vasopressin). In rats expressing an FNDI mutant transgene (Cys67stop) in vasopressin magnocellular neurones, the mutant protein fails to enter the regulated secretory pathway, and accumulates in a swollen and distended endoplasmic reticulum (ER) that also contains wild-type, endogenous vasopressin. Transmission electron microscopy suggested that these are autophagic vesicles. We have now examined the expression of vesicular markers in our transgenic rats, and demonstrate that activation of autolysosomal processes is a consequence of the expression of Cys67stop. Swollen vesicles containing Cys67stop are immunoreactive for cathepsin D (a lysosomal protease), endolyn (a marker of late endosomes) and lysosomal associated membrane protein 1, suggesting that they may be degradative autolysosomes. In addition, there is an up-regulation of lysosomal markers specifically in cells expressing Cys67stop. The expression of Cys67stop affects neither the trans-Golgi network nor early endosomes. These data support the proposal that Cys67stop mutant protein aggregates within the ER, which is targeted for lysosomal degradation by autophagy.

Vasopressin in the Cardiac Surgery Intensive Care Unit

Although nearly 10% of patients experience profound vasodilatory shock after cardiopulmonary bypass, some patients remain refractory to traditional resuscitation. Among this subset are patients who have inappropriately low levels of endogenous vasopressin. Thus, vasopressin replacement is an intuitively attractive intervention. The purposes of this review are to outline the pathophysiology of vasodilatory shock after cardiopulmonary bypass, to discuss the physiological role of endogenous vasopressin, to explore the clinical basis for vasopressin replacement, and to review the pharmacology and dosing guidelines.

The Effects of Endogenous and Exogenous Vasopressin During Experimental Cardiopulmonary Resuscitation

The Effects of Endogenous and Exogenous Vasopressin During Experimental Cardiopulmonary Resuscitation