Analog Of Arginine Vasopressin Research Articles

Structures of the arginine-vasopressin and oxytocin receptor signaling complexes.

Arginine-vasopressin (AVP) and oxytocin (OT) are neurohypophysial hormones which share a high sequence and structure homology. These are two cyclic C-terminally amidated nonapeptides with different residues at position 3 and 8. In mammals, AVP and OT exert their multiple biological functions through a specific G protein-coupled receptor family: four receptors are identified, the V1a, V1b, V2 receptors (V1aR, V1bR and V2R) and the OT receptor (OTR). The chemical structure of AVP and OT was elucidated in the early 1950s. Thanks to X-ray crystallography and cryo-electron microscopy, it took however 70 additional years to determine the three-dimensional structures of the OTR and the V2R in complex with their natural agonist ligands and with different signaling partners, G proteins and β-arrestins. Today, the comparison of the different AVP/OT receptor structures gives structural insights into their orthosteric ligand binding pocket, their molecular mechanisms of activation, and their interfaces with canonical Gs, Gq and β-arrestin proteins. It also paves the way to future rational drug design and therapeutic compound development. Indeed, agonist, antagonist, biased agonist, or pharmacological chaperone analogues of AVP and OT are promising candidates to regulate different physiological functions and treat several pathologies.

Synthesis and Investigation of the Antidepressant Properties of Novel Analogs of Arginine-Vasopressin

Synthesis and Investigation of the Antidepressant Properties of Novel Analogs of Arginine-Vasopressin

Impact of activity-based recovery training and desmopressin on spinal cord injury-induced polyuria in Wistar rats

Background: Activity-based recovery training (ABRT) reverses spinal cord injury (SCI) induced polyuria and alterations of biomarkers involved with fluid balance, including expression levels of kidney vasopressin 2 receptors. However, void volumes do not return to pre-injury baseline levels, indicating a combinatorial approach may be necessary. Objective/Design: In the current study, acute effects of a pharmacological intervention versus placebo were examined in male rats that had received 70 daily ABRT sessions. The treatment, desmopressin (DDAVP – synthetic analogue of arginine vasopressin), an antidiuretic therapy used for the management of bedwetting in children and central diabetes insipidus, has previously shown some promise in a few limited cohorts of SCI individuals having nocturnal polyuria. Results: A total of 70 sessions of ABRT over a 10-week timeframe again reduced the overproduction of urine, but not completely to pre-SCI baseline levels. DDAVP treatment maintained but did not further reduce the level of urine output in the ABRT group without continuous exercise, demonstrating either intervention/treatment alone is effective, despite no additive effect. Although intake did not change from pre-injury levels despite polyuria, DDAVP treatment also reduced drink volume. Conclusions: Further studies are needed as the mechanisms underlying changes in fluid and solute balance are likely multi-factorial involving a complex interaction between the neural (both central and peripheral) control of systems mediating thirst, urinary output, and cardiovascular regulation.

IDF21-0084 Role of serum copeptin levels in Type II Diabetes Mellitus patients with progressive stages of diabetic nephropathy

Background: Type II Diabetes mellitus (DM) is one of the leading metabolic diseases. It has multiple serious complications. Diabetic nephropathy is one of them. Progressive deterioration in renal functions due to DM makes the patient’s life completely handicapped. Thus, patients start depending on dialysis and ultimately develop its complications. Arginine Vasopressin (AVP) maintains glucose hemostasis and therefore, plays an important role in the pathophysiology of DM and its related complications such as diabetic nephropathy. Copeptin is an inactive analogue of AVP and considered as a reliable surrogate biomarker of AVP. Therefore, it is hypothesized that changes in the levels of copeptin can be correlated with diabetic and renal markers and thus may have potential role in predicting progressive stages of DM and diabetic nephropathy. Aim: The aim of the study is to find out the relation of copeptin with different diabetic and renal function biomarkers and to find out a potential role of copeptin as a predictive biomarker in DM and its associated progressive diabetic nephropathy. Method: It was a comparative cross-sectional study. A total number of 120 individuals were recruited into four groups i.e. controls, pre- diabetes, DM without nephropathy and DM with nephropathy as per the criteria of American Diabetes Association (ADA) 2018 and National Kidney Foundation/ Kidney Disease Outcome Quality Initiative (NKF/ KDOQI) 2018 guidelines. All cases were controlled hypertensive. Serum copeptin levels were measured by sandwich ELISA. While, Blood Urea Nitrogen (BUN), creatinine, Glycosylated Hemoglobin (HbA1c), urine micro albumin (UAE) and urinary creatinine were got done using spectrophotometry on Abbott Architect c8000 and electrolytes (Na+, K+ and Cl−) by iso electric method from Dow Diagnostic Research and Reference Laboratory (DDRRL), Dow University of Health Sciences. Statistical analysis was done using Analysis of Variance (ANOVA) and Pearson’s correlation tests on SPSS. Confounders were controlled using univariate linear regression. Results: The average copeptin levels of the study population were 215.096 pg/ml. Copeptin levels were significantly elevated in subjects with positive family history of DM (p = 0.025), levels were also raised in pre diabetes patients (252.85pg/ml) as compared to other groups. Copeptin levels were positively correlated with HbA1c r=0.171 (p=0.101), urea r=0.244 (p=0.007), creatinine r=0.215 (p=0.018), UAE r=0.310 (p=0.001), UACR r=0.375 (p=< 0.001). No significant correlation of copeptin was found with major electrolytes of the body. However, copeptin is found to be significantly associated with progressive stages of albuminuria and declining Glomerular Filtration Rate (GFR). Discussion: The raised levels of copeptin in subjects with positive family history of DM recommends its role in the early prediction of DM. Moreover, significant association of copeptin with progressive stages of albuminuria and declining GFR suggest the contribution of copeptin in the worsening of renal functions in DM and its associated nephropathy.

Diabetes insipidus

Diabetes insipidus (DI) is a disorder characterized by a high hypotonic urinary output of more than 50ml per kg body weight per 24 hours, with associated polydipsia of more than 3 liters a day [1,2]. Central DI results from inadequate secretion and usually deficient synthesis of Arginine vasopressin (AVP) in the hypothalamus or pituitary gland. Besides central DI further underlying etiologies of DI can be due to other primary forms (renal origin) or secondary forms of polyuria (resulting from primary polydipsia). All these forms belong to the Polyuria Polydipsia Syndrom (PPS). In most cases central and nephrogenic DI are acquired, but there are also congenital forms caused by genetic mutations of the AVP gene (central DI) [3] or by mutations in the gene for the AVP V2R or the AQP2 water channel (nephrogenic DI) [4]. Primary polydipsia (PP) as secondary form of polyuria includes an excessive intake of large amounts of fluid leading to polyuria in the presence of intact AVP secretion and appropriate antidiuretic renal response.Differentiation between the three mentioned entities is difficult [5], especially in patients with Primary polydipsia or partial, mild forms of DI [1,6], but different tests for differential diagnosis, most recently based on measurement of copeptin, and a thorough medical history mostly lead to the correct diagnosis. This is important since treatment strategies vary and application of the wrong treatment can be dangerous [7]. Treatment of central DI consists of fluid management and drug therapy with the synthetic AVP analogue Desmopressin (DDAVP), that is used as nasal or oral preparation in most cases. Main side effect can be dilutional hyponatremia [8].In this review we will focus on central diabetes insipidus and describe the prevalence, the clinical manifestations, the etiology as well as the differential diagnosis and management of central diabetes insipidus in the out- and inpatient setting.

Timeline of Changes in Biomarkers Associated with Spinal Cord Injury-Induced Polyuria.

Deficits in upper and lower urinary tract function, which include detrusor overactivity, urinary incontinence, detrusor-sphincter dyssynergia, and polyuria, are among the leading issues that arise after spinal cord injury (SCI) affecting quality of life. Given that overproduction of urine (polyuria) has been shown to be associated with an imbalance in key regulators of body fluid homeostasis, the current study examined the timing of changes in levels of various relevant hormones, peptides, receptors, and channels post-contusion injury in adult male Wistar rats. The results show significant up- or downregulation at various time points, beginning at 7 days post-injury, in levels of urinary atrial natriuretic peptide, serum arginine vasopressin (AVP), kidney natriuretic peptide receptor-A, kidney vasopressin-2 receptor, kidney aquaporin-2 channels, and kidney epithelial sodium channels (β- and γ-, but not α-, subunits). The number of AVP-labeled neurons in the hypothalamus (supraoptic and -chiasmatic, but not paraventricular, nuclei) was also significantly altered at one or more time points. These data show significant fluctuations in key biomarkers involved in body fluid homeostasis during the post-SCI secondary injury phase, suggesting that therapeutic interventions (e.g., desmopressin, a synthetic analogue of AVP) should be considered early post-SCI.

Weight-reducing, lipid-lowering and antidiabetic activities of a novel arginine vasopressin analogue acting at the V1a and V1b receptors in high-fat-fed mice.

To assess the beneficial metabolic effects of the nonapeptide hormone, arginine vasopressin (AVP), on metabolism. We exchanged amino acids at position 3 and 8 of AVP, namely phenylalanine and arginine, with those of oxytocin, to generate novel analogues with altered receptor selectivity. Secondary modification by N-terminal acetylation was used to impart stability to circulating endopeptidases. Analogues were screened for degradation, bioactivity in rodent/human clonal beta cells and primary murine islets, together with evaluation of receptor activation profile. Analogue Ac3IV, which lacked effects at the V2 receptors responsible for modulation of fluid balance, was selected as the lead compound for assessment of antidiabetic efficacy in high-fat-fed mice. Twice-daily administration of Ac3IV, or the gold standard control exendin-4, for 22 days, reduced energy intake as well as body weight and fat content. Both interventions decreased circulating glucose levels, enhanced insulin sensitivity, and substantially improved glucose tolerance and related insulin secretion in response to an intraperitoneal or oral glucose challenge. The peptides decreased total- and increased HDL-cholesterol, but only Ac3IV decreased LDL-cholesterol, triglyceride and non-fasting glucagon concentrations. Elevations of islet and beta-cell areas were partially reversed, accompanied by suppressed islet cell proliferation, decreased beta-cell apoptosis and, in the case of exendin-4, also decreased alpha-cell apoptosis. AVP-based therapies that exclusively target V1a and V1b receptors may have significant therapeutic potential for the treatment of obesity and related diabetes, and merit further clinical exploration.

Chapter 21 - Nocturnal enuresis in children: The role of arginine–vasopressin

Nocturnal enuresis is the involuntary pass of urine during sleep beyond the age of 5 years. It is a common condition in childhood and has an impact on the child's well-being. Research into the pathophysiology of the condition in the last decades has led to a paradigm shift, and enuresis is no longer considered a psychiatric disorder but rather a maturation defect with a somatic background. An excess urine production during sleep is a common finding in children with enuresis and disturbances in the circadian rhythm of arginine-vasopressin (AVP) is found in the majority of children with nocturnal polyuria. Children with enuresis and nocturnal polyuria lack the physiologic increase in AVP levels during sleep and treatment with the AVP analogue desmopressin can restore this rhythm and lead to dry nights. The reasons for this aberrant circadian AVP rhythm are not established. Furthermore, not all children with enuresis and nocturnal polyuria can be successfully treated with desmopressin suggesting that factors beyond renal water handling can be implicated such as natriuresis, hypercalciuria, and sleep-disordered breathing. The advances in the research of the genetic background of the condition may shed further light on the enuresis pathophysiology.

Regulation of urinary calcium excretion by vasopressin.

BackgroundThe antidiuretic hormone (ADH) or arginine vasopressin (AVP) regulates the body's water balance. Recently, modifications in AVP levels have been related to osteoporosis during ageing and microgravity/bed rest. Therefore the present study was devised to assess whether the absence of AVP, as in patients with central diabetes insipidus (CDI), modulates renal calcium excretion.MethodsWe retrospectively analysed data from 12 patients with CDI with measured 24-h urinary excretion levels of calcium. Data were available at the moment of the diagnosis when patients were drug-free and after therapy with dDAVP, an analog of AVP. Hypercalciuria was defined as 24-h urinary Ca2+ >275 mg/day in males and >250 mg/day in females and a urinary calcium (Ca):creatinine (Cr) ratio >0.20 mg/mg.ResultsUntreated CDI patients had a daily urinary Ca2+ excretion of 383 ± 47 mg/day and a urinary Ca:Cr ratio of 0.26 ± 0.38 mg/mg. The urine osmolarity significantly increased after the administration of dDAVP by 210% and the urinary flow decreased by 72%. Furthermore, the estimated glomerular filtration rate (eGFR) increased by 7%, which did not reach statistical significance. dDAVP treatment did not significantly modify the urinary Ca2+ concentration; however, the daily calcium excretion and the urinary Ca:Cr ratio were significantly decreased (160 ± 27 mg/day and 0.11 ± 0.02 mg/mg, respectively).ConclusionsPatients with CDI show hypercalciuria even though urine is more diluted than normal controls, and dDAVP reverses this effect. These data support the intriguing relationship between AVP and osteoporosis in ageing and microgravity/bed rest.

Pediatric Pharmacology of Desmopressin in Children with Enuresis: A Comprehensive Review.

Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication-nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration-time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200µg tablet and 120µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed.

Comparison of the pharmacologic profiles of arginine vasopressin and oxytocin analogs at marmoset, titi monkey, macaque, and human oxytocin receptors

The oxytocin-arginine vasopressin (OT-AVP) ligand-receptor family influences a variety of physiological, behavioral, and social behavioral processes in the brain and periphery. The OT-AVP family is highly conserved in mammals, but recent discoveries have revealed remarkable diversity in OT ligands and receptors in New World Monkeys (NWMs) providing a unique opportunity to assess the effects of genetic variation on pharmacological signatures of peptide ligands. The consensus mammalian OT sequence has leucine in the 8th position (Leu8-OT), whereas a number of NWMs, including the marmoset, have proline in the 8th position (Pro8-OT) resulting in a more rigid tail structure. OT and AVP bind to OT’s cognate G-protein coupled receptor (OTR), which couples to various G-proteins (Gi/o, Gq, Gs) to stimulate diverse signaling pathways. CHO cells expressing marmoset (mOTR), titi monkey (tOTR), macaque (qOTR), or human (hOTR) OT receptors were used to compare AVP and OT analog-induced signaling. Assessment of Gq-mediated increase in intracellular calcium (Ca2+) demonstrated that AVP was less potent than OT analogs at OTRs from species whose endogenous ligand is Leu8-OT (tOTR, qOTR, hOTR), relative to Pro8-OT. Likewise, AVP-induced membrane hyperpolarization was less potent at these same OTRs. Evaluation of (Ca2+)-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Understanding more fully the contributions of structure activity relationships for these peptide ligands at vasopressin and OT receptors will help guide the development of OT-mediated therapeutics.

Development and therapeutic potential of vasopressin synthetic analog [V4Q5]dDAVP as a novel anticancer agent.

Since its discovery, arginine vasopressin (AVP) was subjected to several modifications with the aim of obtaining novel derivatives with increased potency and selectivity for biomedical use. Desmopressin (dDAVP) is a first generation synthetic analog of AVP with hemostatic and antimetastatic activity. dDAVP acts as a selective agonist of the arginine vasopressin type 2 receptor (AVPR2) present in microvascular endothelium and cancer cells. Considering its selective effects on AVPR2-expressing malignant and vascular tissue, and interesting antitumor profile, dDAVP was used as a lead compound for the development of novel peptide analogs with enhanced anticancer efficacy. After conducting different structure-activity relationship studies to determine key aminoacidic positions for its antitumor activity against AVPR2-expressing malignant cells, dDAVP was rationally modified and a wide panel of synthetic analogs with different sequence and structural modifications was assessed. As a result of this structure-based drug derivatization novel AVP analog [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine-8-d-arginine vasopressin) was selected as the most active candidate and further developed. [V4Q5]dDAVP was evaluated in highly aggressive and metastatic cancer preclinical models deploying enhanced cytostatic, antimetastatic and angiostatic effects in comparison to parental peptide dDAVP. In addition, novel compound demonstrated good tolerability as evaluated in several toxicological studies, and cooperative therapeutic effects after combination with standard-of-care chemotherapy. In summary, due to its ability to inhibit growth and tumor-associated angiogenesis, as well as impairing progression of metastatic disease, AVP analogs such as novel [V4Q5]dDAVP are promising compounds for further development as coadjuvant agents for the management of advance or recurrent cancers.

Management of Nocturia and Nocturnal Polyuria

Nocturnal polyuria (NP), characterized by overproduction of urine at night (greater than 20%-33% of total 24-hour urine volume depending on age), is a major contributing factor in most nocturia cases. Nocturia can be caused by intake, urological, nephrological, hormonal, sleep, and cardiovascular factors. It is therefore important to accurately diagnose both the type of nocturia and the potentially associated medical conditions to determine appropriate treatment. Diagnostic tools, in addition to a thorough history and physical examination, include voiding/bladder diary analyses and questionnaires to diagnose nocturia type (NP, diminished nocturnal/global bladder capacity, global polyuria) and causative factors. Lifestyle modifications are the first intervention implemented for the management of nocturia and NP but, as symptoms progress, such measures may be insufficient, and pharmacotherapy may be initiated. While drugs for benign prostatic hyperplasia and overactive bladder have demonstrated statistically significant reductions in nocturnal voids, patients often fail to achieve a clinically meaningful response. Antidiuretic treatment is warranted for patients with nocturia due to NP because, in many patients, it treats the underlying cause (ie, insufficient secretion of antidiuretic hormone arginine vasopressin) that leads to overproduction of urine at night and has been shown to provide statistically significant reductions in nocturnal voids. Desmopressin, a synthetic analog of arginine vasopressin, is the only antidiuretic treatment indicated specifically for nocturia due to NP. Overall, the pathophysiology of NP is complex and differs from that of other types of nocturia. A multidisciplinary approach is necessary to effectively diagnose and manage this bothersome condition.

Future Considerations in Nocturia and Nocturnal Polyuria

Nocturnal polyuria (NP), the most common etiology of nocturia, can be caused by various medical conditions, including cardiovascular disease, obstructive sleep apnea, renal tubular dysfunction, as well as medications (eg, diuretics) and/or behavioral patterns. NP in the absence of underlying medical conditions has been described as NP syndrome and is thought be the result of impaired circadian release of endogenous arginine vasopressin. Desmopressin, a synthetic arginine vasopressin analog, has been shown to be an effective replacement therapy in adults with nocturia due to NP. Further studies on the subset of patients with NP syndrome are warranted to maximize benefit from antidiuretic treatment. In addition, a connection between the pathophysiological mechanisms underlying NP and essential hypertension has been suggested, and hypertension has been shown to be a significant risk factor for nocturia, while an association between NP and brain natriuretic peptide levels has also been reported in patients with nocturia. Hypertension is now viewed as a disorder of blood vessels and treatment is directed at the vasculature rather than the blood pressure, with the latter currently serving as a biomarker for arterial injury. Nocturia is thought to be associated with the beginning of this cardiovascular continuum as studies have reported a link between coronary heart disease and nocturia. Therefore, there is an increasing need to elucidate the complex mechanisms implicated in the association between nocturia and hypertension to promote the development of more individualized therapies for the treatment of nocturia.

Effects of Arginine Vasopressin (AVP) Deficiency, Conivaptan and Desmopressin on Clinical Symptoms and Blood Cytokine Levels in Rats with Experimental Autoimmune Encephalomyelitis

IntroductionThe experimental autoimmune encephalomyelitis (EAE), the rat paradigm for the human multiple sclerosis (MS), are autoimmune diseases mediated by Th1 and Th17 cells and responsible of the nervous system demyelination and progressive paralysis. It is know that lymphocytes possess AVP receptors and that EAE increases AVP serum levels along the disease. Neurointermediate pituitary lobectomy (NIL) in rats causes AVP and oxytocin permanent low serum levels and decreased humoral and cell‐mediated immune responses. Nevertheless the role of AVP as a direct immune regulatory factor has not been well clarified.ObjectiveTo investigate the effects of AVP deficiency (by NIL), and the treatment with desmopressin (DP, a synthetic analog of AVP) and conivaptan (CNV, an AVP V1a‐V2 receptor antagonist) on the clinical symptoms of EAE, and to determine the serum levels of Interleukine‐2 (IL‐2), IL‐4, IL‐6, IL‐10, IL‐17A, INF‐γ and TNF‐α in the experimental groups.MethodsGroups of female Lewis rats were divided in: (1) Intact control (Control) (2) Control+EAE, (3) Sham‐operated (SHAM), (4) Control+CNV, (5) NIL and (6) NIL+DP. Except the Control the remaining groups were immunized for EAE three weeks post‐NIL. DP and CNV administrations started 3 days before EAE immunizations. Serum cytokines were analyzed by flow cytometry and EAE clinical symptoms were evaluated by a conventional numerical scale.ResultsEAE clinical symptoms, INF‐γ, TNF‐α, and the IL‐2, IL‐6 and IL‐17A were significantly decreased in both NIL and CNV groups, whereas the IL‐4 and IL‐10 increased in the CNV group. In NIL+DP group we found a significant increase in TNF‐α, whereas the IL‐4 was significantly decreased.Conclusions1) The present clinical and molecular findings demonstrate that AVP deficiency and the block of the AVP receptors decreased immune response, and that DP restores the susceptibility of the NIL animals to develop EAE. 2) The results strongly support that acting directly on the AVP receptors, AVP plays an important immuneregulatory role in the generation and maintenance of the immune‐competence, 3) AVP receptors may be therapeutic targets in the treatment of the human MS.Support or Funding InformationSupported by UAA‐PIFF14‐1 and CONACYT‐221262 (AQS). México.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Drugs for the treatment of central diabetes insipidus: historical background and modern opportunities

Central diabetes insipidus is a severe disease with disturbance of arginine vasopressin secretion, which leads to excretion of large amounts of hypotonic urine. The polyuria-polydipsia syndrome is essential as a clinical presentation and high impact condition. Desmopressin, a synthetic analog of arginine vasopressin, is used to compensate a water-electrolyte balance is available in forms of tablets and intranasal spray. Free drug choice is obligated for proper treatment.

Activation of the metabolic sensor AMP-activated protein kinase inhibits aquaporin-2 function in kidney principal cells.

Aquaporin-2 (AQP2) is essential to maintain body water homeostasis. AQP2 traffics from intracellular vesicles to the apical membrane of kidney collecting duct principal cells in response to vasopressin [arginine vasopressin (AVP)], a hormone released with low intravascular volume, which causes decreased kidney perfusion. Decreased kidney perfusion activates AMP-activated kinase (AMPK), a metabolic sensor that inhibits the activity of several transport proteins. We hypothesized that AMPK activation also inhibits AQP2 function. These putative AMPK effects could protect interstitial ionic gradients required for urinary concentration during metabolic stress when low intravascular volume induces AVP release. Here we found that short-term AMPK activation by treatment with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR; 75 min) in kidney tissue prevented baseline AQP2 apical accumulation in principal cells, but did not prevent AQP2 apical accumulation in response to the AVP analog desmopressin (dDAVP). Prolonged AMPK activation prevented AQP2 cell membrane accumulation in response to forskolin in mouse collecting duct mpkCCDc14 cells. Moreover, AMPK inhibition accelerated hypotonic lysis of Xenopus oocytes expressing AQP2. We performed phosphorylation assays to elucidate the mechanism by which AMPK regulates AQP2. Although AMPK weakly phosphorylated immunoprecipitated AQP2 in vitro, no direct AMPK phosphorylation of the AQP2 COOH-terminus was detected by mass spectrometry. AMPK promoted Ser-261 phosphorylation and antagonized dDAVP-dependent phosphorylation of other AQP2 COOH-terminal sites in cells. Our findings suggest an increasing, time-dependent antagonism of AMPK on AQP2 regulation with AICAR-dependent inhibition of cAMP-dependent apical accumulation and AVP-dependent phosphorylation of AQP2. This inhibition likely occurs via a mechanism that does not involve direct AQP2 phosphorylation by AMPK.

Desmopressin in adult urological disease: clinical evidences.

Desmopressin is a synthetic analogue of arginine vasopressin, commercially available since 1974. Desmopressin is proven effective for the treatment primary nocturnal enuresis and polyuria. It has been considered by several investigators for the treatment of nocturia with positive results and is now an established treatment for this indication. In this review, we assessed the available clinical data on desmopressin in adult urological disease.

Effects of terlipressin on patients with sepsis via improving tissue blood flow

Terlipressin (TP), an analog of arginine vasopressin, was reported beneficial in sepsis patients when combined use with norepinephrine (NE), but the undetermined action, mechanism, and safety limited it to become the first-line vasopressor for sepsis patients. With 32 septic shock patients, we investigated the effects of a small dose of TP (1.3 μg/kg/h) on hemodynamic, tissue blood flow, vital organ function, acid–base balance, and coagulation function to systemically know the beneficial effect and side effects of TP on septic shock. The results showed that as compared with the single use of NE group (17 patients), a small dose of TP (1.3 μg/kg/h) in combination with NE continuous infusion, except for decreasing the mortality and NE requirement, could better improve and stabilize the hemodynamics, improve the tissue blood flow, increase the blood oxygen saturation and urine volume, and decrease the lactate level and complication rate (47% versus 82.3% in NE group). Meanwhile, TP + NE did not induce blood bilirubin increase and platelet count decrease and hyponatremia that vasopressin has. The results show that low dose of TP continuous infusion can help NE achieve the good resuscitation effect by improving tissue blood flow, stabilizing hemodynamics, and protecting organ function in septic shock patients while did not induce the side effects that high dose or bonus of TP or vasopressin induced. Low dose of TP may be recommended as the first-line vasopressor for refractory hypotension after severe sepsis or septic shock.

The analog of arginine-vasopressin (6-9) fragment, Ac-D-SPRG, exhibits antidepressant action in rats in case of intranasal injection

The antidepressant properties of newly synthesized analog of arginine-vasopressin fragment analog, Ac-D-SPRG, were tested using Porsolt’s swimming test on white rats. It was demonstrated that this substance when injected intranasally decreases the depression in comparison with the control group.