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Frontiers in Endocrinology 2022Owing to the increasing prevalence of type 2 diabetes, the development of novel hypoglycemic drugs has become a research hotspot, with the ultimate goal of developing... (Review)
Review
Owing to the increasing prevalence of type 2 diabetes, the development of novel hypoglycemic drugs has become a research hotspot, with the ultimate goal of developing therapeutic drugs that stimulate glucose-induced insulin secretion without inducing hypoglycemia. Vasoactive intestinal peptide (VIP), a 28-amino-acid peptide, can stimulate glucose-dependent insulin secretion, particularly by binding to VPAC2 receptors. VIP also promotes islet β-cell proliferation through the forkhead box M1 pathway, but the specific molecular mechanism remains to be studied. The clinical application of VIP is limited because of its short half-life and wide distribution in the human body. Based on the binding properties of VIP and VPAC2 receptors, VPAC2-selective agonists have been developed to serve as novel hypoglycemic drugs. This review summarizes the physiological significance of VIP in glucose homeostasis and the potential therapeutic value of VPAC2-selective agonists in type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Insulin Secretion; Receptors, Vasoactive Intestinal Peptide, Type II; Vasoactive Intestinal Peptide
PubMed: 36204104
DOI: 10.3389/fendo.2022.984198 -
International Journal of Molecular... Jul 2022Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Vasoactive Intestinal Peptide (VIP) are neuropeptides involved in a diverse array of physiological and... (Review)
Review
Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Vasoactive Intestinal Peptide (VIP) are neuropeptides involved in a diverse array of physiological and pathological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors (GPCRs): VIP receptor 1 (VPAC1R), VIP receptor 2 (VPAC2R), and PACAP type I receptor (PAC1R). VIP and PACAP share nearly 70% amino acid sequence identity, while their receptors PAC1R, VPAC1R, and VPAC2R share 60% homology in the transmembrane regions of the receptor. PACAP binds with high affinity to all three receptors, while VIP binds with high affinity to VPAC1R and VPAC2R, and has a thousand-fold lower affinity for PAC1R compared to PACAP. Due to the wide distribution of VIP and PACAP receptors in the body, potential therapeutic applications of drugs targeting these receptors, as well as expected undesired side effects, are numerous. Designing selective therapeutics targeting these receptors remains challenging due to their structural similarities. This review discusses recent discoveries on the molecular mechanisms involved in the selectivity and signaling of the PACAP subfamily of receptors, and future considerations for therapeutic targeting.
Topics: Amino Acid Sequence; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Signal Transduction; Vasoactive Intestinal Peptide
PubMed: 35897648
DOI: 10.3390/ijms23158069 -
Global Pediatric Health 2021Many children needing pediatric intensive care units care require inotropes, which are started peripherally prior to securing a central venous access. However, many...
Many children needing pediatric intensive care units care require inotropes, which are started peripherally prior to securing a central venous access. However, many hospitals in low- and middle-income countries (LMIC) may not have access to central lines and the vasoactive medications are frequently given through a peripheral venous access. : The aim of our study was to describe the role of peripheral vasoactive inotropes in children. : Children requiring peripheral vasoactive medications were included in this study. We retrospectively collected data at 2 time points on use and complications of peripheral vasoactive medications. : Eighty-four children (51 pre-COVID era and 33 COVID pandemic) received peripheral vasoactive medications. Only 3% of children (3/84) developed extravasation injury, all of whom recovered completely. : Results from our study suggest that extravasation injury due to peripheral inotrope infusion is very low (3%) and it may be safely administered in children at a diluted concentration.
PubMed: 34104702
DOI: 10.1177/2333794X211022250 -
F1000Research 2019Vasoactive intestinal peptide (VIP), a gut peptide hormone originally reported as a vasodilator in 1970, has multiple physiological and pathological effects on... (Review)
Review
Vasoactive intestinal peptide (VIP), a gut peptide hormone originally reported as a vasodilator in 1970, has multiple physiological and pathological effects on development, growth, and the control of neuronal, epithelial, and endocrine cell functions that in turn regulate ion secretion, nutrient absorption, gut motility, glycemic control, carcinogenesis, immune responses, and circadian rhythms. Genetic ablation of this peptide and its receptors in mice also provides new insights into the contribution of VIP towards physiological signaling and the pathogenesis of related diseases. Here, we discuss the impact of VIP on gastrointestinal function and diseases based on recent findings, also providing insight into its possible therapeutic application to diabetes, autoimmune diseases and cancer.
Topics: Animals; Gastrointestinal Diseases; Gastrointestinal Tract; Mice; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Signal Transduction; Vasoactive Intestinal Peptide
PubMed: 31559013
DOI: 10.12688/f1000research.18039.1 -
Journal of Clinical Medicine Jan 2021Vasoactive and inotropic medications are essential for sepsis management; however, the association between the maximum Vasoactive-Inotropic score (VISmax) and clinical...
Vasoactive and inotropic medications are essential for sepsis management; however, the association between the maximum Vasoactive-Inotropic score (VISmax) and clinical outcomes is unknown in adult patients with sepsis. We investigated the VISmax as a predictor for mortality among such patients in the emergency department (ED) and compared its prognostic value with that of the sequential organ failure assessment (SOFA) score. This single-center retrospective study included 910 patients diagnosed with sepsis between January 2016 and March 2020. We calculated the VISmax using the highest doses of vasopressors and inotropes administered during the first 6 h on ED admission and categorized it as 0-5, 6-15, 16-30, 31-45, and >45 points. The primary outcome was 30-day mortality. VISmax for 30-day mortality was significantly higher in non-survivors than in survivors. The mortality rates in the five VISmax groups were 17.2%, 20.8%, 33.3%, 54.6%, and 70.0%, respectively. The optimal cut-off value of VISmax to predict 30-day mortality was 31. VISmax had better prognostic value than the cardiovascular component of the SOFA score and initial lactate levels. VISmax was comparable to the APACHE II score in predicting 30-day mortality. Multivariable analysis showed that VISmax 16-30, 31-45, and >45 were independent risk factors for 30-day mortality. VISmax in ED could help clinicians to identify sepsis patients with poor prognosis.
PubMed: 33572578
DOI: 10.3390/jcm10030495 -
Children (Basel, Switzerland) May 2024Twins resulting from a complicated monochorionic (MC) twin pregnancy are at risk for postnatal evolution of pulmonary hypertension (PH) and cardiac dysfunction (CD)....
OBJECTIVES
Twins resulting from a complicated monochorionic (MC) twin pregnancy are at risk for postnatal evolution of pulmonary hypertension (PH) and cardiac dysfunction (CD). Both pathologies are important contributors to short- and long-term morbidity in these infants. The aim of the present retrospective single-center cohort study was to evaluate the need for vasoactive treatment for PH and CD in these neonates.
METHODOLOGY
In-born neonates following a complicated MC twin pregnancy admitted to the department of neonatology of the University Children's Hospital Bonn (UKB) between October 2019 and December 2023 were screened for study inclusion. Finally, 70 neonates were included in the final analysis, with 37 neonates subclassified as recipient twins (group A) and 33 neonates as donor twins (group B).
RESULTS
The overall PH incidence at day of life (DOL) 1 was 17% and decreased to 6% at DOL 7 ( = 0.013), with no PH findings at DOL 28. The overall incidence of CD was 56% at DOL 1 and decreased strongly until DOL 7 (10%, = 0.015), with no diagnosis of CD at DOL 28. The use of dobutamine, norepinephrine, and vasopressin at DOL 1 until DOL 7 did not differ between the subgroups, whereas the dosing of milrinone was significantly higher in Group B at DOL 1 ( = 0.043). Inhaled nitric oxide (iNO) was used in 16% of the cohort, and a levosimendan therapy was administered in 34% of the neonates. One-third of the cohort was treated with oral beta blockers, and in 10%, an intravenous beta blockade (landiolol) was administered. The maximum levosimendan vasoactive-inotropic score (LVIS) increased from DOL 1 (12.4 [3/27]) to DOL 2 (14.6 [1/68], = 0.777), with a significant decrease thereafter as measured at DOL 7 (9.5 [2/30], = 0.011).
CONCLUSION
Early PH and CD are frequent diagnoses in neonates following a complicated MC twin pregnancy, and an individualized vasoactive treatment strategy is required in the management of these infants.
PubMed: 38790543
DOI: 10.3390/children11050548 -
The Annals of Pharmacotherapy Jul 2023Critically ill patients are often prescribed both inhaled beta-agonists and intravenous vasoactive; however, the interaction of the additive beta-agonist effects of...
BACKGROUND
Critically ill patients are often prescribed both inhaled beta-agonists and intravenous vasoactive; however, the interaction of the additive beta-agonist effects of these 2 agents remains largely uncharacterized.
OBJECTIVE
The purpose of this study was to evaluate how concomitant use of albuterol and vasoactive or inotropes affected ventilator-free days (VFDs) by re-analyzing the data from the Albuterol to Treat Acute Lung Injury (ALTA) trial.
METHODS
In this study, subjects were grouped to albuterol-vasoactive (n = 84) (vs) placebo-vasoactive (n = 62). Ventilator-free days, intensive care unit (ICU)-free days, organ failure-free days, cardiovascular adverse events, and 90-day mortality were compared. The primary outcome was VFDs.
RESULTS
Patients in the albuterol-vasoactive group had significantly fewer VFDs than patients in the placebo-vasoactive group (11 vs 19, = 0.05). Patients in the albuterol-vasoactive group also had significantly fewer ICU-free days (9.5 vs 18.5, = .006). The 90-day mortality was similar between groups (36.9% vs 27.4%, = .20). Similarly, no significant difference in cardiac adverse events between the groups (14.3% vs 11.3%, = 0.59).
CONCLUSION AND RELEVANCE
This study has shown fewer VFDs for patients who received both vasoactive and albuterol. There were also fewer ICU-free days when compared to those on vasoactive only. Given the common use of both agents, a prospective evaluation of the additive adverse effects of beta-agonism is warranted.
Topics: Humans; Acute Lung Injury; Administration, Intravenous; Albuterol; Drug-Related Side Effects and Adverse Reactions; Intensive Care Units
PubMed: 36189647
DOI: 10.1177/10600280221128014 -
PloS One 2022Vasoactive intestinal peptide (VIP) as a neurocrine factor released by enteric neurons has been postulated to participate in the regulation of transcellular active...
Vasoactive intestinal peptide and cystic fibrosis transmembrane conductance regulator contribute to the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer.
Vasoactive intestinal peptide (VIP) as a neurocrine factor released by enteric neurons has been postulated to participate in the regulation of transcellular active calcium transport across intestinal epithelium, but the preceding evidence is scant and inconclusive. Herein, transepithelial calcium flux and epithelial electrical parameters were determined by Ussing chamber technique with radioactive tracer in the intestinal epithelium-like Caco-2 monolayer grown on Snapwell. After 3-day culture, Caco-2 cells expressed mRNA of calcium transporters, i.e., TRPV6, calbindin-D9k, PMCA1b and NCX1, and exhibited transepithelial resistance of ~200 Ω cm2, a characteristic of leaky epithelium similar to the small intestine. VIP receptor agonist was able to enhance transcellular calcium flux, whereas VIP receptor antagonist totally abolished calcium fluxes induced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Since the intestinal cystic fibrosis transmembrane conductance regulator (CFTR) could be activated by VIP and calciotropic hormones, particularly parathyroid hormone, we sought to determine whether CFTR also contributed to the 1,25(OH)2D3-induced calcium transport. A selective CFTR inhibitor (20-200 μM CFTRinh-172) appeared to diminish calcium fluxes as well as transepithelial potential difference and short-circuit current, both of which indicated a decrease in electrogenic ion transport. On the other hand, 50 μM genistein-a molecule that could rapidly activate CFTR-was found to increase calcium transport. Our in silico molecular docking analysis confirmed direct binding of CFTRinh-172 and genistein to CFTR channels. In conclusion, VIP and CFTR apparently contributed to the intestinal calcium transport, especially in the presence of 1,25(OH)2D3, thereby supporting the existence of the neurocrine control of intestinal calcium absorption.
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Calcium; Vasoactive Intestinal Peptide; Caco-2 Cells; Receptors, Vasoactive Intestinal Peptide; Genistein; Molecular Docking Simulation; Ion Transport; Intestinal Mucosa; Calcium, Dietary
PubMed: 36399482
DOI: 10.1371/journal.pone.0277096 -
Birth Defects Research May 2022Many previous studies have identified risk factors for stillbirth, but few examine stillbirth among pregnancies affected with birth defects. Because many hypothesized...
BACKGROUND
Many previous studies have identified risk factors for stillbirth, but few examine stillbirth among pregnancies affected with birth defects. Because many hypothesized etiologies of stillbirth work through vascular pathologies of the placenta, we examined maternal use of vasoactive medications in relation to stillbirth among pregnancies affected with birth defects.
METHODS
Data were analyzed from the National Birth Defects Prevention Study (1997-2011). We examined use of nonsteroidal anti-inflammatory drugs (NSAIDs), decongestants, short- or long-acting beta-agonists (SABA/LABA), and antihypertensive medications in relation to pregnancies affected by birth defects ending in stillbirth compared to live birth. Associations were measured with odds ratios (ORs) for early pregnancy use and hazard ratios (HRs) for time-varying late pregnancy use.
RESULTS
Among all birth defects (n = 12,394), the risk of stillbirth was associated with use of antihypertensive medications in early (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.0, 3.1) and late pregnancy (HR: 2.0; 95% CI: 1.1, 3.6). Other vasoactive medications were not associated with increased risk of stillbirth. Of 27 specific defect groups, increased risks were observed for only one medication/defect pair: early decongestant use was more common among mothers of stillbirth versus live birth cases with spina bifida (OR: 2.4; 95% CI: 0.9, 6.5).
CONCLUSION
This exploratory analysis of vasoactive medication use suggests that use of NSAIDs, decongestants, and SABA/LABA is not associated with increased risk of stillbirth among pregnancies affected with birth defects. Our finding of increased risks associated with antihypertensive medication use raises questions of confounding by indication, which we were not able to fully address.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Female; Humans; Nasal Decongestants; Odds Ratio; Pregnancy; Stillbirth
PubMed: 35238183
DOI: 10.1002/bdr2.1996 -
Frontiers in Pediatrics 2021We aimed to determine the association of vasoactive-inotropic score (VIS) and vasoactive-ventilation-renal (VVR) score with in-hospital mortality and functional outcomes...
We aimed to determine the association of vasoactive-inotropic score (VIS) and vasoactive-ventilation-renal (VVR) score with in-hospital mortality and functional outcomes at discharge of children who receive ECMO. A sub-analysis of the multicenter, prospectively collected data by the Collaborative Pediatric Critical Care Research Network (CPCCRN) for Bleeding and Thrombosis on ECMO (BATE database) was conducted. Of the 514 patients who received ECMO across eight centers from December 2012 to February 2016, 421 were included in the analysis. Patients > 18 years of age, patients placed on ECMO directly from cardiopulmonary bypass or as an exit procedure, or patients with an invalid or missing VIS score were excluded. Higher VIS (OR = 1.008, 95% CI: 1.002-1.014, = 0.011) and VVR (OR: 1.006, 95% CI: 1.001-1.012, = 0.023) were associated with increased mortality. VIS was associated with worse Pediatric Cerebral Performance Category (PCPC) (OR = 1.027, 95% CI: 1.010-1.044, = 0.002) and Pediatric Overall Performance Category (POPC) score (OR = 1.023, 95% CI: 1.009-1.038, = 0.002) at discharge. No association was found between VIS or VVR and Functional Status Score (FSS) at discharge. Using multivariable analyses, controlling for ECMO mode, ECMO location, ECMO indication, primary diagnosis, and chronic diagnosis, extremely high VIS and VVR were still associated with increased mortality.
PubMed: 34917562
DOI: 10.3389/fped.2021.769932