Efficacy of Nx4 to Reduce Plasma Cortisol and Gastrin Levels in Norwegian Sled Dogs During an Exercise Induced Stress Response: A Prospective, Randomized, Double Blinded, Placebo-Controlled Cohort Study

Introduction: An exercise induced stress response is commonly seen in high performance sled dogs, resulting in increased plasma cortisol. A stress induced rise of cortisol might result in increased prevalence of gastritis and gastric ulcers mediated by an increase of gastrin. Neurexan® (Nx4) is a medicinal product used for stress relief by reduction of cortisol. The aim of the study was to show that Nx4 reduces plasma cortisol and plasma gastrin in high performance sled dogs and to show tolerability of Nx4 in dogs.Material and Methods: First, a pilot study was done to validate the increase of cortisol by performance. The data from the pilot study was used for sample size estimation via an adapted power analysis as well as the identification of important variables. These were then used in the randomization procedure of the main study. Second, a prospective randomized, double blinded, placebo-controlled cohort study was conducted. The main study included 45 sled dogs, assigning 23 dogs to the Nx4 group, and 22 dogs to the placebo group, to analyze plasma cortisol and plasma gastrin at four time points: before, directly after and 30 and 120 min after performance.Results: For the main target variable, area under the curve (AUC) of plasma cortisol, a significantly lower adjusted mean value in the Nx4 group compared to the placebo group (p = 0.031) was found. Plasma gastrin was also significantly reduced in the Nx4 group 30 min after performance (p = 0.023), resulting in a significantly reduced plasma gastrin AUC in the Nx4 group compared to the placebo group (p = 0.049).Discussion: Within the limitation of the study, the results carry implications for the usefulness of Nx4 to reduce exercise induced plasma cortisol and gastrin levels. The reduction of the exercise induced stress response could help to improve the welfare of high-performance sled dogs. Since activation of the hypothalamic-pituitary-adrenal axis resulting in increased cortisol is similar for exercise induced stress and psychologic stress, the same might be true independent of the stressor, making Nx4 potentially useful in any stressful situation for dogs.

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

Background It is known that increased gastrin concentration is negatively correlated with cardiovascular mortality, and plasma gastrin levels are increased in patients after myocardial infarction (MI). However, whether gastrin can play a protective role in MI remains unknown. Methods Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery (LAD) and subcutaneous infusion of gastrin (120 μg/Kg body weight/day, 100 μL in the pump) for 28 days after MI. Plasma gastrin concentrations were measured through an ELISA detection kit. Mice were analyzed by echocardiography after surgery. CD31 and VEGF expression were quantified using immunofluorescence staining or/and western blot to assess the angiogenesis in peri-infarct myocardium. Capillary-like tube formation and cell migration assays were performed to detect gastrin-induced angiogenesis. Results We found that gastrin administration significantly ameliorated MI-induced cardiac dysfunction and reduced fibrosis at 28 days in post-MI hearts. Additionally, gastrin treatment significantly decreased cardiomyocyte apoptosis and increased angiogenesis in the infarct border zone without influencing cardiomyocyte proliferation. In vitro results revealed that gastrin up-regulated the PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway and promoted migration and tube formation of human coronary artery endothelial cells (HCAECs). Cholecystokinin 2 receptor (CCK2R) mediated the protective effect of gastrin since the CCK2R blocker CI988 attenuated the gastrin-mediated angiogenesis and cardiac function protection. Conclusion Our data revealed that gastrin promoted angiogenesis and improved cardiac function in post-MI mice, highlighting its potential as a therapeutic target candidate.

Diagnostic Performance of Plasma Gastrin Concentration for the Diagnosis of Type 1 Abomasal Ulcer in Water Buffalo: A Preliminary Case Control Study

The type 1 abomasal ulcer (AU1) does not have specific clinical signs, and there is a need to identify some early biochemical markers for diagnosis of AU1 in cattle and buffaloes. Plasma gastrin is reported to reflect the gastric mucosa damage but its utility for diagnosis of AU1 in buffaloes has not been evaluated. The objective of this study was to study the test performance of plasma gastrin to distinguish healthy buffaloes and buffaloes with AU1. Twenty-three buffaloes with AU1 and six buffaloes without abomasal ulcer were used. Blood samples were collected from the buffaloes, slaughtered in a buffalo specific slaughter house, for estimation of plasma gastrin. After slaughter abomasa were examined for presence of AU1 and were confirmed by histology. The mean plasma gastrin concentration of ulcer positive buffaloes was significantly (p<0.05) higher than the ulcer negative buffaloes. The ROC curve analysis suggested optimal value of plasma gastrin for diagnosis of AU1 was 106.2 pg/ml. Since the abomasal ulcer negative animals were established to be ulcer negative on histopathological examination we consider the values of gastrin valid for detection of abomasal ulceration in buffaloes. The sensitivity, specificity, positive predictive value and negative predictive value of plasma gastrin to diagnose AU1 in buffalo were 78.3, 100, 100 and 69.9, respectively.

Gastric acid secretion in experimental acute uremia

This study was conducted to evaluate gastric acid secretion in acute renal failure, highlighting the roles of renal mass and gastrin hormone. Acute uremic rats were divided into bilateral nephrectomized and bilateral ureteric obstruction groups. Gastric juice was collected for 2 h and analyzed for volume, free acidity, total acidity, and total acid output. Plasma levels of creatinine, urea, and gastrin were also determined. Bilateral nephrectomized and bilateral ureteric obstruction groups showed a significant increase in levels of free acidity, total acidity, and plasma gastrin. Compared with the ureteric obstruction group, nephrectomized rats showed a significant increase in gastric juice volume, total acid output, and plasma gastrin levels. Following pentagastrin stimulation, gastric juice volume, total acid output, free acidity, and total acidity were increased in the bilateral nephrectomy and ureteric obstruction groups compared with the respective control groups. The free and total acidity and total acid output also increased compared with the respective non-stimulated groups. Plasma creatinine and urea levels were significantly positively correlated with plasma gastrin, free acidity, and total acidity. Creatinine was positively correlated with total acid output, and gastrin was positively correlated with total acidity. In conclusion, acute renal failure promotes gastric acid hypersecretion that could potentially be attributed to high levels of gastrin hormone and uremic state per se.

Gastrin stimulates expression of plasminogen activator inhibitor-1 in gastric epithelial cells

Plasminogen activator inhibitor (PAI)-1 is associated with cancer progression, fibrosis and thrombosis. It is expressed in the stomach but the mechanisms controlling its expression there, and its biological role, are uncertain. We sought to define the role of gastrin in regulating PAI-1 expression and to determine the relevance for gastrin-stimulated cell migration and invasion. In gastric biopsies from subjects with elevated plasma gastrin, the abundances of PAI-1, urokinase plasminogen activator (uPA), and uPA receptor (uPAR) mRNAs measured by quantitative PCR were increased compared with subjects with plasma concentrations in the reference range. In patients with hypergastrinemia due to autoimmune chronic atrophic gastritis, there was increased abundance of PAI-1, uPA, and uPAR mRNAs that was reduced by octreotide or antrectomy. Immunohistochemistry revealed localization of PAI-1 to parietal cells and enterochromaffin-like cells in micronodular neuroendocrine tumors in hypergastrinemic subjects. Transcriptional mechanisms were studied by using a PAI-1-luciferase promoter-reporter construct transfected into AGS-GR cells. There was time- and concentration-dependent increase of PAI-1-luciferase expression in response to gastrin that was reversed by inhibitors of the PKC and MAPK pathways. In Boyden chamber assays, recombinant PAI-1 inhibited gastrin-stimulated AGS-GR cell migration and invasion, and small interfering RNA treatment increased responses to gastrin. We conclude that elevated plasma gastrin concentrations are associated with increased expression of gastric PAI-1, which may act to restrain gastrin-stimulated cell migration and invasion.

Morphofunctional characteristic of gastric adipocytes in patients with type 2 diabetes mellitus

Aim. To measure gastrointestinal hormones in plasma, evaluate morphofunctional state of G- and beta-cells in patients with gastric pathology and concomitanttype 2 diabetes mellitus (DM2). Materials and methods. A total of 84 patients with gastric ulcer (GU) and chronic gastritis (CG) were available for observation including 46 with DM2.Semi-quantitative evaluation of stomach infection by H.pylori. was performed by a histological method. Stained G- and beta-cells were counted under 400xmagnification in 10 fields of vision for each medicinal preparation used in the study. Chromogranin A, somatostatin, and gastrin were detected by immunohistochemicalmethods, gastrin-17 and somatostatin-14 by the respective immunoassays. Control group comprised 10 practically healthy volunteers. Results. Patients with combined GU (or CG) and DM2 pathology had smaller density of G- and beta-cells, lower plasma gastrin and somatostatin levelsthan those without DM2 (p