Long-Residence Time Peptide Antagonist for the Vasopressin V2 Receptor to Treat Autosomal Dominant Polycystic Kidney Disease.

The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2 receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33 exhibited a high binding affinity for the V2R (Ki = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33 exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.

Therapeutic potential of vasopressin in the treatment of neurological disorders.

Vasopressin (VP) is a nonapeptide made of nine amino acids synthesized by the hypothalamus and released by the pituitary gland. VP acts as a neurohormone, neuropeptide and neuromodulator and plays an important role in the regulation of water balance, osmolarity, blood pressure, body temperature, stress response, emotional challenges, etc. Traditionally VP is known to regulate the osmolarity and tonicity. VP and its receptors are widely expressed in the various region of the brain including cortex, hippocampus, basal forebrain, amygdala, etc. VP has been shown to modulate the behavior, stress response, circadian rhythm, cerebral blood flow, learning and memory, etc. The potential role of VP in the regulation of these neurological functions have suggested the therapeutic importance of VP and its analogues in the management of neurological disorders. Further, different VP analogues have been developed across the world with different pharmacotherapeutic potential. In the present work authors highlighted the therapeutic potential of VP and its analogues in the treatment and management of various neurological disorders.

Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes.

BACKGROUND: Obesity-associated dysfunctional intestinal permeability contributes to systemic chronic inflammation leading to the development of metabolic diseases. The inflammasomes constitute essential components in the regulation of intestinal homeostasis. We aimed to determine the impact of the inflammasomes in the regulation of gut barrier dysfunction and metabolic inflammation in the context of obesity and type 2 diabetes (T2D). METHODS: Blood samples obtained from 80 volunteers (n = 20 normal weight, n = 21 OB without T2D, n = 39 OB with T2D) and a subgroup of jejunum samples were used in a case-control study. Circulating levels of intestinal damage markers and expression levels of inflammasomes as well as their main effectors (IL-1ß and IL-18) and key inflammation-related genes were analyzed. The impact of inflammation-related factors, different metabolites and Akkermansia muciniphila in the regulation of inflammasomes and intestinal integrity genes was evaluated. The effect of blocking NLRP6 by using siRNA in inflammation was also studied. RESULTS: Increased circulating levels (P < 0.01) of the intestinal damage markers endotoxin, LBP, and zonulin in patients with obesity decreased (P < 0.05) after weight loss. Patients with obesity and T2D exhibited decreased (P < 0.05) jejunum gene expression levels of NLRP6 and its main effector IL18 together with increased (P < 0.05) mRNA levels of inflammatory markers. We further showed that while NLRP6 was primarily localized in goblet cells, NLRP3 was localized in the intestinal epithelial cells. Additionally, decreased (P < 0.05) mRNA levels of Nlrp1, Nlrp3 and Nlrp6 in the small intestinal tract obtained from rats with diet-induced obesity were found. NLRP6 expression was regulated by taurine, parthenolide and A. muciniphila in the human enterocyte cell line CCL-241. Finally, a significant decrease (P < 0.01) in the expression and release of MUC2 after the knockdown of NLRP6 was observed. CONCLUSIONS: The increased levels of intestinal damage markers together with the downregulation of NLRP6 and IL18 in the jejunum in obesity-associated T2D suggest a defective inflammasome sensing, driving to an impaired epithelial intestinal barrier that may regulate the progression of multiple obesity-associated comorbidities.

Oxytocin and vasopressin signaling in health and disease.

Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT/VP signaling system in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development.

Discovery and Characterization of RGH-122, a Potent, Selective, and Orally Bioavailable V1a Receptor Antagonist.

The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved in vitro and in vivo profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound 43 (RGH-122). The CNS activity of the compound was determined in a 3-chamber social preference test of autism in which RGH-122 successfully enhanced social preference with the lowest effective dose of 1.5 mg/kg.

Arginine vasopressin induces ferroptosis to promote heart failure via activation of the V1aR/CaN/NFATC3 pathway.

Arginine vasopressin (AVP) is a key contributor to heart failure (HF), but the underlying mechanisms remain unclear. In the present study, a mouse model of HF and human cardiomyocyte (HCM) cells treated with dDAVP are generated in vivo and in vitro, respectively. Hematoxylin and eosin (HE) staining is used to evaluate the morphological changes in the myocardial tissues. A colorimetric method is used to measure the iron concentration, Fe 2+ concentration and malondialdehyde (MDA) level. Western blot analysis is used to examine the protein levels of the V1a receptor (V1aR), calcineurin (CaN), nuclear factor of activated T cells isoform C3 (NFATC3), glutathione peroxidase 4 (GPX4) and acyl-CoA synthase long chain family member 4 (ACSL4). Immunoprecipitation (IP) and luciferase reporter assays are performed to determine the interaction between NFATC3 and ACSL4. Both in vivo and in vitro experiments reveal that the V1aR-CaN-NFATC3 signaling pathway and ferroptosis are upregulated in HFs, which are verified by the elevated protein levels of V1aR, CaN, NFATC3 and ACSL4; reduced GPX4 protein level; and enhanced Fe 2+ and MDA levels. We further find that inhibiting NFATC3 by suppressing the V1aR/CaN/NFATC3 pathway via V1aR/CaN inhibitors or sh-NFATC3 not only alleviates HF but also inhibits AVP-induced ferroptosis. Mechanistically, sh-NFATC3 significantly reverses the increase in AVP-induced ACSL4 protein level, Fe 2+ concentration, and MDA level by directly interacting with ACSL4. Our results demonstrate that AVP enhances ACSL4 expression by activating the V1aR/CaN/NFATC3 pathway to induce ferroptosis, thus contributing to HF. This study may lead to the proposal of a novel therapeutic strategy for HF.

Subcutaneous therapy for portal hypertension: PHIN-214, a partial vasopressin receptor 1A agonist.

Cirrhosis is a liver disease that leads to increased intrahepatic resistance, portal hypertension (PH), and splanchnic hyperemia resulting in ascites, variceal bleeding, and hepatorenal syndrome. Terlipressin, a prodrug that converts to a short half-life vasopressin receptor 1 A (V1a) full agonist [8-Lys]-Vasopressin (LVP), is an intravenous treatment for PH complications, but hyponatremia and ischemic side effects require close monitoring. We developed PHIN-214 which converts into PHIN-156, a more biologically stable V1a partial agonist. PHIN-214 enables once-daily subcutaneous administration without causing ischemia or tissue necrosis and has a 10-fold higher therapeutic index than terlipressin in healthy rats. As V1a partial agonists, PHIN-214 and PHIN-156 exhibited maximum activities of 28 % and 42 % of Arginine vasopressin (AVP), respectively. The potency of PHIN-156 and LVP relative to AVP is comparable for V1a (5.20 and 1.65 nM, respectively) and V1b (102 and 115 nM, respectively) receptors. However, the EC50 of PHIN-156 to the V2 receptor was 26-fold higher than that of LVP, indicating reduced potential for dilutional hyponatremia via V2 agonism compared to terlipressin/LVP. No significant off-target binding to 87 toxicologically relevant receptors were observed when evaluated in vitro at 10 µM concentration. In bile duct ligated rats with PH, subcutaneous PHIN-214 reduced portal pressure by 13.4 % ± 3.4 in 4 h. These collective findings suggest that PHIN-214 could be a novel pharmacological treatment for patients with PH, potentially administered outside of hospital settings, providing a safe and convenient alternative for managing PH and its complications.

Interplay of Angiotensin Peptides, Vasopressin, and Insulin in the Heart: Experimental and Clinical Evidence of Altered Interactions in Obesity and Diabetes Mellitus.

The present review draws attention to the specific role of angiotensin peptides [angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)], vasopressin (AVP), and insulin in the regulation of the coronary blood flow and cardiac contractions. The interactions of angiotensin peptides, AVP, and insulin in the heart and in the brain are also discussed. The intracardiac production and the supply of angiotensin peptides and AVP from the systemic circulation enable their easy access to the coronary vessels and the cardiomyocytes. Coronary vessels and cardiomyocytes are furnished with AT1 receptors, AT2 receptors, Ang (1-7) receptors, vasopressin V1 receptors, and insulin receptor substrates. The presence of some of these molecules in the same cells creates good conditions for their interaction at the signaling level. The broad spectrum of actions allows for the engagement of angiotensin peptides, AVP, and insulin in the regulation of the most vital cardiac processes, including (1) cardiac tissue oxygenation, energy production, and metabolism; (2) the generation of the other cardiovascular compounds, such as nitric oxide, bradykinin (Bk), and endothelin; and (3) the regulation of cardiac work by the autonomic nervous system and the cardiovascular neurons of the brain. Multiple experimental studies and clinical observations show that the interactions of Ang II, Ang(1-7), AVP, and insulin in the heart and in the brain are markedly altered during heart failure, hypertension, obesity, and diabetes mellitus, especially when these diseases coexist. A survey of the literature presented in the review provides evidence for the belief that very individualized treatment, including interactions of angiotensins and vasopressin with insulin, should be applied in patients suffering from both the cardiovascular and metabolic diseases.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation.

INTRODUCTION: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. METHODS: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). RESULTS: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. DISCUSSION: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

First report on female monozygotic twins discordant for congenital nephrogenic diabetes insipidus.

Ninety percent of congenital nephrogenic diabetes insipidus (NDI) are X-linked inherited and are caused by mutations in the vasopressin type 2 receptor gene (AVPR2). Most affected individuals are males. Only sporadic female cases have been reported. Here, we first reported a female monozygotic twin with discordant phenotypes for NDI carrying a missense variant c.845T>C (p.Leu282Pro) in exon 4 of AVPR2. Intracellular cAMP concentrations in COS7 cells transfected with AVPR2-L282P were significantly decreased by about 60% compared with those in wild-type AVPR2 plasmid transfected cells, suggesting this variation was pathogenic. The X-inactivation pattern was investigated in peripheral leukocytes and urine sediments in both the unaffected and affected pair. Results showed that the affected pair had a skewed X chromosome inactivation (XCI) pattern in urine sediments and a random XCI pattern in leukocytes, while the unaffected pair showed a random XCI pattern both in leukocytes and urine sediments. This was the first report of monozygotic twins who developed different phenotypes of NDI. Our study suggested that the development of NDI symptoms is more closely associated with the XCI pattern in urine sediments compared with the XCI pattern in peripheral leukocytes. Analysis of XCI in peripheral leukocytes may not be enough to explore possible mechanisms.

Vasopressin V2 receptor, tolvaptan, and ERK1/2 phosphorylation in the renal collecting duct.

Tolvaptan, a vasopressin antagonist selective for the V2-subtype vasopressin receptor (V2R), is widely used in the treatment of hyponatremia and autosomal-dominant polycystic kidney disease (ADPKD). Its effects on signaling in collecting duct cells have not been fully characterized. Here, we perform RNA-seq in a collecting duct cell line (mpkCCD). The data show that tolvaptan inhibits the expression of mRNAs that were previously shown to be increased in response to vasopressin including aquaporin-2, but also reveals mRNA changes that were not readily predictable and suggest off-target actions of tolvaptan. One such action is activation of the MAPK kinase (ERK1/ERK2) pathway. Prior studies have shown that ERK1/ERK2 activation is essential in the regulation of a variety of cellular and physiological processes and can be associated with cell proliferation. In immunoblotting experiments, we demonstrated that ERK1/ERK2 phosphorylation in mpkCCD cells was significantly reduced by vasopressin, in contrast to the increases seen in non-collecting-duct cells overexpressing V2R in prior studies. We also found that tolvaptan has a strong effect to increase ERK1/ERK2 phosphorylation in the presence of vasopressin and that tolvaptan's effect to increase ERK1/ERK2 phosphorylation is absent in mpkCCD cells in which both protein kinase A (PKA)-catalytic subunits have been deleted. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and is not due to an off-target effect of tolvaptan. We conclude that in cells expressing V2R at endogenous levels: 1) vasopressin decreases ERK1/ERK2 activation; 2) in the presence of vasopressin, tolvaptan increases ERK1/ERK2 activation; and 3) these effects are PKA-dependent.NEW & NOTEWORTHY Vasopressin is a key hormone that regulates the function of the collecting duct of the kidney. ERK1 and ERK2 are enzymes that play key roles in physiological regulation in all cells. The authors used collecting duct cell cultures to investigate the effects of vasopressin and the vasopressin receptor antagonist tolvaptan on ERK1 and ERK2 phosphorylation and activation.

Desmopressin enhances random-pattern skin flap survival in rats: Possible role of vasopressin Type-1a and 2 receptors.

BACKGROUND: Many drugs have been explored for their role in improving skin flap survival. 1-deamino-8-D-arginine vasopressin (DDAVP or desmopressin) is a synthesized form of anti-diuretic hormone (ADH) and a selective agonist for vasopressin type-2 receptors (V2 receptors). Desmopressin has been shown to improve endothelial function, induce vasodilation, and reduce inflammation. We aimed to evaluate its efficacy in enhancing flap survival and assess the role of vasopressin receptors in this process. MATERIALS AND METHODS: We randomly assigned six male Wistar rats to each study group. Different doses of desmopressin were injected intraperitoneally to find the most effective amount (8 µg/rat). SR-49059, a selective V1a receptor antagonist, was given at 2µg/rat before providing the most effective dose of desmopressin (8µg/rat). Histopathological assessments, quantitative measurements of interleukin-1ß (IL-1ß), Tumor necrosis factor-alpha (TNF-α), and Nuclear Factor-κB (NF-κB), optical imaging, and measurement of the expression levels of V2 receptor in the rat skin tissue were performed. RESULTS: Desmopressin (8µg/rat) significantly reduced the mean percentage of necrotic area compared to the control group (19.35% vs 73.57%). Histopathological evaluations revealed a notable reduction in tissue inflammation, edema, and degeneration following administration of desmopressin (8). The expression of the V2 receptor was increased following desmopressin administration. It also led to a reduction in IL-1ß, TNF-α, and NF-κB levels. The protective effect of desmopressin on flap survival was reversed upon giving SR-49059. The optical imaging revealed enhanced blood flow in the desmopressin group compared to the control group. CONCLUSIONS: Desmopressin could be repurposed to improve flap survival. V1a and V2 receptors probably mediate this effect.

Genomic Signatures of Positive Selection in Human Populations of the OXT, OXTR, AVP, AVPR1A and AVR1B Gene Variants Related to the Regulation of Psychoemotional Response.

The neurobiological systems of maintenance and control of behavioral responses result from natural selection. We have analyzed the selection signatures for single nucleotide variants (SNV) of the genes of oxytocin (OXT, OXTR) and vasopressin (AVP, AVPR1A, AVPR1B) systems, which are associated with the regulation of social and emotional behavior in distinct populations. The analysis was performed using original WGS (whole genome sequencing) data on Eastern Slavs (SlEast), as well as publicly available data from the 1000 Genomes Project on GBR, FIN, IBR, PUR, BEB, CHB, and ACB populations (the latter were taken as reference). To identify selection signatures, we rated the integrated haplotype scores (iHS), the numbers of segregating sites by length (nSl), and the integrated haplotype homozygosity pooled (iHH12) measures; the fixation index Fst was implemented to assess genetic differentiation between populations. We revealed that the strongest genetic differentiation of populations was found with respect to the AVPR1B gene, with the greatest differentiation observed in GRB (Fst = 0.316) and CHB (Fst = 0.325) in comparison to ACB. Also, high Fst values were found for SNVs of the AVPR1B gene rs28499431, rs33940624, rs28477649, rs3883899, and rs28452187 in most of the populations. Selection signatures have also been identified in the AVP, AVPR1A, OXT, and OXTR genes. Our analysis shows that the OXT, OXTR, AVP, AVPR1A, and AVPR1B genes were subject to positive selection in a population-specific process, which was likely contributing to the diversity of adaptive emotional response types and social function realizations.

ß-Arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor.

The vasopressin type 2 receptor (V2R) is an essential G protein-coupled receptor (GPCR) in renal regulation of water homeostasis. Upon stimulation, the V2R activates Gαs and Gαq/11, which is followed by robust recruitment of ß-arrestins and receptor internalization into endosomes. Unlike canonical GPCR signaling, the ß-arrestin association with the V2R does not terminate Gαs activation, and thus, Gαs-mediated signaling is sustained while the receptor is internalized. Here, we demonstrate that this V2R ability to co-interact with G protein/ß-arrestin and promote endosomal G protein signaling is not restricted to Gαs, but also involves Gαq/11. Furthermore, our data imply that ß-arrestins potentiate Gαs/Gαq/11 activation at endosomes rather than terminating their signaling. Surprisingly, we found that the V2R internalizes and promote endosomal G protein activation independent of ß-arrestins to a minor degree. These new observations challenge the current model of endosomal GPCR signaling and suggest that this event can occur in both ß-arrestin-dependent and -independent manners.

Metabolic effects of vasopressin in pathophysiology of diabetic kidney disease.

The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.

Oxytocin increases itch sensitivity of mice in late pregnancy and its peripheral receptor mechanism of itch-promoting effect.

Oxytocin (OXT) is secreted in a large amount during the middle and late pregnancy. Except for the regulation of functions related to childbirth, OXT is involved in the regulation of cognition, social behavior, addiction, pain and so on. Our aim is to confirm the increase of OXT content in mice in late pregnancy is the main cause of itch during pregnancy and observe whether exogenously administered OXT can induce or increase itch sensitivity. The research shows that itch sensitivity of mice increased significantly in late pregnancy and basically returned to normal one day after delivery. The number of OXT-positive neurons in paraventricular nucleus (PVN) and the content of OXT in serum of the late pregnant mice increased significantly, and decreased sharply after delivery. Intradermal injection of low concentration of OXT (0.2 nmol/L) could not induce scratching behavior in mice, but high concentration of OXT (5 nmol/L, 10 nmol/L) could do this in a dose-dependent manner. Low concentration of OXT significantly increased the itch sensitivity to histamine. Intradermal injection of oxytocin receptor (OXTR) or arginine vasopressin-1a receptor (AVPR1A) antagonist did not affect histamine-induced scratching behavior, but both reversed the increase of itch sensitivity in late pregnant mice or the facilitated itch sensitivity by OXT. Study suggests that both endogenous and exogenous increases in OXT can increase the body's sensitivity to itch, and even induce itch directly. Pruritus during pregnancy is closely related to the increase of OXT content in vivo. In the periphery, the itch-promoting effect of OXT is mediated by OXTR and AVPR1A.

OCE-205, A Novel, Selective Vasopressin Receptor Mixed Agonist-Antagonist: Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics from a Phase 1 Study in Healthy Volunteers.

BACKGROUND: OCE-205, a novel, selective vasopressin V1a receptor mixed agonist/antagonist with no V2 receptor activity, may treat the portal hypertension-related complications of end-stage liver disease with an improved therapeutic profile over currently utilized nonselective full-agonist vasopressin analogs. OBJECTIVES: This Phase 1, double-blind, placebo-controlled, within-dose-group randomized trial investigated the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of OCE-205 in healthy adults. METHODS: Subjects received a single intravenous dose of OCE-205 0.1, 0.3, 0.45, 0.6, or 0.9 mg, or placebo infused over 6 h. Safety and tolerability were assessed, and blood samples were obtained for pharmacokinetic analyses. Sixty-four subjects were randomized and treated. RESULTS: Area under the concentration-time curve (AUC) and maximum plasma concentrations (Cmax) were approximately dose-proportional across doses from 0.1 to 0.9 mg. OCE-205 terminal half-life was ~ 1.5 h. Diastolic, and to a lesser extent systolic, blood pressure increased in all OCE-205 dose groups; pulse rate decreased. Overall changes in mean arterial pressure were similar to changes in diastolic blood pressure. Absolute changes in cardiac output, by echocardiogram, were somewhat dose-dependent, with mean reductions of 3-12% after the 0.9 mg dose, and individual reductions ≤ 20 to 25% across all doses. The most frequent adverse events were abdominal pain, abnormal gastrointestinal sounds, and diarrhea, with no reported cases of mesenteric ischemia. Adverse events were generally mild or moderate in severity. CONCLUSION: OCE-205 was safe and well tolerated, with a pharmacodynamic profile achieving submaximal partial agonism consistent with mixed agonism-antagonism of the V1a receptor. OCE-205 shows promise as a treatment for some complications of end-stage liver disease.

Characterization of rat gastric myogenic contractions and modulation by oxytocin and arginine-vasopressin.

BACKGROUND: Interstitial cells of Cajal generate slow wave gastric electrical activity, initiating spontaneous muscle contractions. This becomes dysrhythmic during nausea when [Arg8]-vasopressin (AVP) is also released. In human stomach AVP increased spontaneous contraction activity and muscle tone, not neuronally-mediated contractions. Rodents cannot vomit, releasing the related hormone, oxytocin (OT) instead. We hypothesised that rat stomach would behave differently. EXPERIMENTAL APPROACH: Spontaneous and electrically-evoked (EFS) contractions were measured in rat forestomach and antrum circular muscle. Custom software defined spontaneous contractions by analysing eight motility parameters. RESULTS: The forestomach was quiescent. Irregular antrum contractions became regular adjacent to the pylorus (1.7 ± 0.4 mN; 1.2 ± 0.1 contractions/min, n = 12). These were unaffected by tetrodotoxin (10-6 M), atropine (10-6 M) and L-NAME (3 × 10-4 M). In both regions, AVP (pEC50∼9.0) and OT (∼0.5 log10-unit less potent) caused contraction (greater in antrum), competitively antagonized by, respectively, SR49059 (pKB∼9.5) and L371257 (pKB∼9.0), reduced by tetrodotoxin but unaffected by atropine. In the antrum, AVP and OT (∼2 log10-units less potent/efficacious) regularized and increased spontaneous contraction amplitude, frequency, rates of contraction/decay. In both regions, EFS-evoked contractions, abolished by atropine/tetrodotoxin, were reduced by AVP and OT, with AVP more potent and efficacious, particularly in forestomach. CONCLUSION: Irregular spontaneous contractions of gastric antrum suggest variable ICC-muscle coupling. AVP and less potently, OT, enhanced frequency and force of contractions via V1A and OT receptors. Compared with human, differences in contraction regularity, potency and ability of AVP/OT to affect neuronal function suggests caution when using rat stomach to model ICC functions and nauseagenic stimuli.