Pancreatic Blood Flow Research Articles

Arterial Spin Labeling (ASL) MRI in Evaluating Pancreatic Blood Perfusion in Subjects With Different Glucose Tolerances.

The pancreas plays a central role in type 2 diabetes mellitus (T2DM), and its blood flow is usually associated with insulin release demand. To noninvasively assess pancreatic blood flow (PBF) changes and modulation in people with different glucose tolerance following a glucose challenge using ASL MRI. Prospective. Fourteen prediabetes, 22 T2DM, and 40 normal. Pseudo-continuous ASL with a turbo gradient spin echo sequence at 3.0 T. All normal and subjects (diagnosed by oral glucose tolerance test) underwent ASL after fasting for at least 6 hours. The normal and prediabetes groups additionally had ASL scans at 5, 10, 15, 20, and 25 minutes following oral glucose (50 mL, 5%). PBF maps were generated from the ASL data and measured at body and tail. The ability of baseline PBF (BL-PBF) of body, tail (BL-PBFtail), and their average to determine abnormal glucose tolerance and stage was assessed. ANOVA, Mann-Whitney U test, Kruskal-Wallis H test, paired sample t-test, intra-class correlation coefficient, repeated measures ANOVA, correlation analysis, receiver operating characteristic analysis, and logistic regression analysis. A P value <0.05 was considered significant. There were significant differences in BL-PBF among the three groups. The prediabetes group exhibited significantly lower PBF than the normal group at all time points; Both groups showed similar changing trends in PBF (peaking at the 15th minute and subsequently declining). The BL-PBFtail had the highest diagnostic performance when evaluating abnormal glucose tolerance or stage (area under the curves = 0.800, 0.584, respectively) and was an independent risk factor for glucose tolerance status. ASL can noninvasively assess changes in PBF among individuals with varying glucose tolerance and in response to glucose challenge, which could be linked to insulin release demand and might help characterize changes in pancreatic endocrine function. 2 TECHNICAL EFFICACY: Stage 1.

Local Dialogues Between the Endocrine and Exocrine Cells in the Pancreas.

For many years, it has been taught in medical textbooks that the endocrine and exocrine parts of the pancreas have separate blood supplies that do not mix. Therefore, they have been studied by different scientific communities, and patients with pancreatic disorders are treated by physicians in different medical disciplines, endocrinologists and gastroenterologists, respectively. The conventional model that every islet in each pancreatic lobule receives a dedicated arterial blood supply was first proposed in 1932 and it has been inherited to date. Recently, in vivo intravital recording of red blood cell flow in mouse islets as well as in situ structural analysis of 3D pancreatic vasculature from hundreds of islets provided evidence for preferentially integrated pancreatic blood flow in 6 mammalian species. The majority of islets have no association with the arteriole and there is bidirectional blood exchange between the two segments. Such vascularization may allow an entire downstream region of islets and acinar cells to be simultaneously exposed to a topologically and temporally specific plasma content, which could underlie an adaptive sensory function as well as common pathogeneses of both portions of the organ in pancreatic diseases including diabetes.

Pancreatic regional blood flow links the endocrine and exocrine diseases.

An increasing number of studies have demonstrated that disease states of the endocrine or exocrine pancreas aggravate one another, which implies bidirectional blood flow between islets and exocrine cells. However, this is inconsistent with the current model of unidirectional blood flow, which is strictly from islets to exocrine tissues. This conventional model was first proposed in 1932, and it has never to our knowledge been revisited to date. Here, large-scale image capture was used to examine the spatial relationship between islets and blood vessels in the following species: human, monkey, pig, rabbit, ferret, and mouse. While some arterioles passed by or traveled through islets, the majority of islets had no association with them. Islets with direct contact with the arteriole were significantly larger in size and fewer in number than those without contact. Unique to the pancreas, capillaries directly branched out from the arterioles and have been labeled as "small arterioles" in past studies. Overall, the arterioles emerged to feed the pancreas regionally, not specifically targeting individual islets. Vascularizing the pancreas in this way may allow an entire downstream region of islets and acinar cells to be simultaneously exposed to changes in the blood levels of glucose, hormones, and other circulating factors.

Healing effect of warfarin in the course of cerulein-induced acute pancreatitis in rats.

Acute pancreatitis (AP) is the most common gastrointestinal disease leading to hospitalizations and unexpected deaths. The development of AP leads to damage of the pancreatic microcirculation with a cascade of subsequent events resulting, among others, in coagulopathy. Previous research showed that anticoagulants can be important therapeutic agents. Heparin and acenocoumarol can alleviate the course of AP, as well as accelerate healing and post-inflammatory regeneration of the pancreas. The aim of this study was to determine whether warfarin, a drug with more stable effects than acenocoumarol, affects the healing and regeneration of the pancreas in the cerulein-induced AP. AP was evoked in Wistar male rats by intraperitoneal administration of cerulein. The first dose of warfarin (45, 90 or 180 μg/kg) was administered 24 hours after the first dose of cerulein and the doses of warfarin were repeated once a day in subsequent 10 days. The severity of AP was assessed immediately after the last dose of cerulein, as well as at days 1, 2, 3, 5, and 10 after AP induction. Treatment with warfarin dose-dependently increased international normalized ratio (INR) and attenuated the severity of pancreatitis in histological examination and accelerated pancreatic recovery. These effects were accompanied with a faster reduction in the AP-evoked increase in serum activity of amylase and lipase, the serum concentration of pro-inflammatory interleukin-1β, and the plasma level of D-Dimer. In addition, treatment with warfarin decreased pancreatic weight (an index of pancreatic edema) and improved pancreatic blood flow in rats with AP. The therapeutic effect was particularly pronounced after the administration of warfarin at a dose of 90 μg/kg. We conclude that treatment with warfarin accelerated regeneration of the pancreas and recovery in the course of cerulein-induced mild-edematous acute pancreatitis.

The effects of targeted vagus nerve stimulation on glucose homeostasis in STZ-induced diabetic rodents.

During type 1 diabetes, an autoimmune attack destroys pancreatic β-cells leading to the inability to maintain glucose homeostasis. These β-cells are neuroresponsive endocrine cells which normally secrete insulin partially in response to input from the vagus nerve. This neural pathway can be utilized as a point of therapeutic intervention by delivering exogenous stimulation to drive increased insulin secretion. In this study, a cuff electrode was implanted on the pancreatic branch of the vagus nerve just prior to pancreatic insertion in rats, and a continuous glucose meter was implanted into the descending aorta. Streptozotocin (STZ) was used to induce a diabetic state, and changes in blood glucose were assessed using various stimulation parameters. Stimulation driven changes in hormone secretion, pancreatic blood flow, and islet cell populations were assessed. We found increased changes in the rate of blood glucose change during stimulation which subsided after stimulation ended paired with increased concentration of circulating insulin. We did not observe increased pancreatic perfusion, which suggests that the modulation of blood glucose was due to the activation of b-cells rather than changes in the extra-organ transport of insulin. Pancreatic neuromodulation showed potentially protective effects by reducing deficits in islet diameter, and ameliorating insulin loss after STZ treatment.

Administration of Warfarin Inhibits the Development of Cerulein-Induced Edematous Acute Pancreatitis in Rats.

Acute pancreatitis (AP) is a severe disease with high morbidity and mortality in which inflammation and coagulation play crucial roles. The development of inflammation leads to vascular injury, endothelium and leukocytes stimulation, and an increased level of tissue factor, which results in the activation of the coagulation process. For this reason, anticoagulants may be considered as a therapeutic option in AP. Previous studies have shown that pretreatment with heparin, low-molecular-weight heparin (LMWH), or acenocoumarol inhibits the development of AP. The aim of the present study was to check if pretreatment with warfarin affects the development of edematous pancreatitis evoked by cerulein. Warfarin (90, 180, or 270 µg/kg/dose) or saline were administered intragastrically once a day for 7 days consecutively before the induction of AP. AP was evoked by the intraperitoneal administration of cerulein. The pre-administration of warfarin at doses of 90 or 180 µg/kg/dose reduced the histological signs of pancreatic damage in animals with the induction of AP. Additionally, other parameters of AP, such as an increase in the serum activity of lipase and amylase, the plasma concentration of D-dimer, and interleukin-1β, were decreased. In addition, pretreatment with warfarin administered at doses of 90 or 180 µg/kg/dose reversed the limitation of pancreatic blood flow evoked by AP development. Warfarin administered at a dose of 270 µg/kg/dose did not exhibit a preventive effect in cerulein-induced AP. Conclusion: Pretreatment with low doses of warfarin inhibits the development of AP evoked by the intraperitoneal administration of cerulein.

Elucidation of Drug Transport Mechanism by Serum Protein and Development for Pancreatic Cancer Treatment

Human serum albumin (HSA) and α1-acid glycoprotein (AGP) are the major drug-binding proteins in the blood and regulate the tissue transfer of bound drugs. We succeeded in clarifying the three-dimensional structure of AGP for the first time in the world from X-ray crystal structure analysis. Using a site-directed mutagenesis method by constructing yeast expression systems as well as the three-dimensional structure, we elucidated the properties of drug binding sites of AGP. We also found that structural change due to the interaction between AGP and cell membranes causes the release of bound drugs and reported an "AGP-mediated drug transport process." Pancreatic cancer has an extremely low response rate to anticancer drugs compared to other cancers and is resistant to starvation of nutrients including fatty acids. We clarified that glutamine metabolism is involved in this tolerance. Furthermore, aiming at efficient drug delivery and effective treatment for pancreatic cancer, we focused on nitric oxide (NO) which increases pancreatic blood flow and has a cell-killing effect on tumors and surrounding stromal tissues. We successfully synthesized nitrated phenylbutyrate (NPB), which binds to HSA and has an antitumor effect in vitro and vivo. The binding of NPB to HSA is considered to be useful for delivery to tumors through the enhanced permeability and retention (EPR) effect and HSA receptors.

Protective Effect on Pancreatic Acinar Cell by Maintaining Cardiac Output in Canine Heart Failure Model With Decreased Pancreatic Blood Flow.

Heart failure cause hypoperfusion-induced damage to abdominal organs due to decreased cardiac output (CO). Using a model dog with heart failure caused by rapid ventricular pacing (RVP), we have previously demonstrated that a decrease in CO reduces pancreatic blood flow (PBF). Furthermore, we have revealed that pancreatic acinar cell atrophy, which is a change in the pre-stage of pancreatitis was caused. However, the mechanism by which pancreatic acinar cell atrophy was caused in RVP dogs remains unknown. This study aimed to clarify the association between cardiac function, PBF, and histopathological changes in pancreatic acinar cells by administrating pimobendan, which increase CO, to RVP dogs. RVP dogs were divided into the control group (no medication, n = 5) and the pimobendan group (pimobendan at 0.25 mg/kg BID, n = 5). Non-invasive blood pressure measurement, echocardiography, and contrast-enhanced ultrasonography for PBF measurement were performed before initiating RVP and at 4 weeks after initiating RVP (4 weeks). At 4 weeks, the decreases in CO, mean blood pressure and PBF due to RVP were suppressed in pimobendan group. Furthermore, histopathological examination showed no changes in pancreatic acinar cells in the pimobendan group. Overall, it was clarified that the decrease in PBF due to cardiac dysfunction was a direct cause of pancreatic acinar cell atrophy. This suggests that maintaining PBF is clinically important for treating dogs with heart failure. In addition, these findings offer a reliable basis for developing new therapeutic strategies for heart failure in dogs, that is, pancreatic protection.

359-OR: Imaging Pancreatic Blood Flow during Stimulation of Insulin Secretion in Humans

Non-invasive imaging of endocrine pancreatic function could provide valuable insights into the magnitude and temporal pattern of β-cell dysfunction in diabetes. Islets comprise 1-2% of pancreatic mass, but receive about 10-20% of pancreatic blood flow, which increases further during stimulation of insulin secretion. We examined the relationship between pancreatic blood flow (PBF) and insulin secretory dynamics in 12 healthy volunteers (6M / 6F, age = 29 ± 5 yrs, BMI = 24.0 ± 2.7 kg/m², HbA1c = 5.1 ± 0.3 %, FPG = 88 ± mg/dl, fasting insulin = 3.7 ± 2.3 μU/ml) . PBF was measured by pseudo-continuous arterial spin labeling (ASL) MRI, with the labeling plane positioned 5-6 cm superior to the imaging slice to label blood in the descending aorta. Fasting subjects were placed in a 3T scanner, and PBF was measured during 1) a 15 min basal period, 2) a +100 mg/dl hyperglycemic clamp for 40 min, followed by 3) a 5 gm bolus of arginine to assess maximal acute insulin response (AIRmax) . First phase (0-min) insulin response to hyperglycemia was 181 ± 96 μU/ml · min, and AIRmax after arginine + hyperglycemia (40-50 min) was 1097 ± 629 μU/ml · min. Basal PBF (188 ± 53 ml/100 gm/min) increased during first phase insulin release, peaking at 212 ± 66 at 12 min, subsequently returned to basal levels (176 ± 59) from 10-40 min during sustained hyperglycemia,and peaked again at 2± 62 at 2 min after arginine. Although there were no significant correlations between glucose, insulin or c-peptide levels and PBF, time-series Granger causality analysis demonstrated that the time-derivative of c-peptide and insulin concentrations, reflectingacute changes in insulin secretion, preceded the increase in PBF (p=0.03 for d[c-peptide]/dt, and p = 0.for d[insulin]/dt) . Conclusions: 1) Changes in PBF during stimulation of insulin secretion in humans can be imaged non-invasively by ASL, 2) Insulin secretion precedes changes in PBF, and 3) The rate of change in insulin and c-peptide release predicts subsequent modulation of PBF. Disclosure D.C.Simonson: Stock/Shareholder; GI Windows, Phase V Technologies, Inc. M.Taso: Research Support; GE Healthcare Systems. C.Mcgrath: None. S.A.Waldman: None. F.Papadopoulou: None. D.C.Alsop: Other Relationship; GE Healthcare Systems, Hitachi, Ltd., Philips Healthcare, Siemens, UIH America, Research Support; GE Healthcare Systems.

Comparative analysis of two mathematical algorithms for the calculation of computed tomography perfusion parameters in the healthy and diseased pancreas.

BackgroundThe maximum slope (MS) and deconvolution (DC) algorithms are commonly used to post‐process computed tomography perfusion (CTP) data. This study aims to analyze the differences between MS and DC algorithms for the calculation of pancreatic CTP parameters.MethodsThe pancreatic CTP data of 57 patients were analyzed using MS and DC algorithms. Two blinded radiologists calculated pancreatic blood volume (BV) and blood flow (BF). Interobserver correlation coefficients were used to evaluate the consistency between two radiologists. Paired t‐tests, Pearson linear correlation analysis, and Bland–Altman analysis were performed to evaluate the correlation and consistency of the CTP parameters between the two algorithms.ResultsAmong the 30 subjects with normal pancreas, the BV values in the three pancreatic regions were higher in the case of the MS algorithm than in the case of the DC algorithm (t = 39.35, p < 0.001), and the BF values in the three pancreatic regions were slightly higher for the MS algorithm than for the DC algorithm (t = 2.19, p = 0.031). Similarly, among the 27 patients with acute pancreatitis, the BV values obtained using the MS methods were higher than those obtained using the DC methods (t = 54.14, p < 0.001). Furthermore, the BF values were higher with the MS methods than the DC methods (t = 8.45, p < 0.001). Besides, Pearson linear correlation and Bland–Altman analysis showed that the BF and BV values showed a good correlation and a bad consistency between the two algorithms.ConclusionsThe BF and BV values measured using MS and DC algorithms had a good correlation but were not consistent.

Cytokine and Nitric Oxide-Dependent Gene Regulation in Islet Endocrine and Nonendocrine Cells.

While exposure to inflammatory cytokines is thought to contribute to pancreatic β-cell damage during diabetes, primarily because cytokine-induced nitric oxide impairs β-cell function and causes cell death with prolonged exposure, we hypothesize that there is a physiological role for cytokine signaling that protects β-cells from a number of environmental stresses. This hypothesis is derived from the knowledge that β-cells are essential for survival even though they have a limited capacity to replicate, yet they are exposed to high cytokine levels during infection as most of the pancreatic blood flow is directed to islets. Here, mouse islets were subjected to single-cell RNA sequencing following 18-h cytokine exposure. Treatment with IL-1β and IFN-γ stimulates expression of inducible nitric oxide synthase (iNOS) mRNA and antiviral and immune-associated genes as well as repression of islet identity factors in a subset of β- and non-β-endocrine cells in a nitric oxide-independent manner. Nitric oxide-dependent expression of genes encoding heat shock proteins was observed in both β- and non-β-endocrine cells. Interestingly, cells with high expression of heat shock proteins failed to increase antiviral and immune-associated gene expression, suggesting that nitric oxide may be an internal “off switch” to prevent the negative effects of prolonged cytokine signaling in islet endocrine cells. We found no evidence for pro-apoptotic gene expression following 18-h cytokine exposure. Our findings suggest that the primary functions of cytokines and nitric oxide are to protect islet endocrine cells from damage, and only when regulation of cytokine signaling is lost does irreversible damage occur.

Laser speckle contrast imaging for monitoring of acute pancreatitis at ischemia–reperfusion injury of the pancreas in rats

The influence of ischemia–reperfusion (I/R) action on pancreatic blood flow (PBF) and the development of acute pancreatitis (AP) in laboratory rats is evaluated in vivo by using the laser speckle contrast imaging (LSCI). Additionally, the optical properties in norm and under condition of AP in rats were assessed using a modified integrating sphere spectrometer and inverse Monte Carlo (IMC) software. The results of the experimental study of microcirculation of the pancreas in 82 rats in the ischemic model are presented. The data obtained confirm the fact that local ischemia and changes in the blood flow velocity of the main vessels cause and provoke acute pancreatitis.

Utility of perfusion CT in characterizing the pancreatic tumors

Purpose: The aim of this study was to apply perfusion CT (Computed Tomography) technique to various pancreatic masses and to prospectively evaluate the perfusion parameters of pancreatic lesions and to compare these parameters with the parameters of normal pancreatic parenchyma. Materials and Methods: A total of 33 subjects with pancreatic tumors underwent perfusion CT. The perfusion parameters like tBF & pBF (Tumor Blood-Flow and Pancreatic Blood-Flow), tPEI & pBF (Tumor Peak Enhancement Index and Pancreatic Peak Enhancement Index), tTTP & pTTP (Tumor Time to Peak and Pancreatic Time to peak) and tBV & pBV (Tumor Blood-Volume and Pancreatic Blood-Volume) were obtained by placing an ROI (Region of Interest) on the tumor and the normal pancreas respectively. Descriptive statistics of the perfusion values of the tumor and the normal pancreas was tabulated and statistical significance was calculated using Mann Whitney U test. Results: 26 patients had adenocarcinoma, 4 had endocrine tumors, 2 had metastases and 1 had Ewing’s sarcoma. Adenocarcinomas showed significantly lower BF (Blood-Flow), PEI (Peak Enhancement Index) and Blood volume (BV) but significantly higher TTP (Time to Peak) as compared to the normal pancreas (P

In Vivo and In Situ Approach to Study Islet Microcirculation: A Mini-Review.

The pancreas is regarded as consisting of two separate organ systems, the endocrine and exocrine pancreas. While treatment of a disease with either an endocrine or exocrine pathogenesis may affect the function of the entire pancreas, the pancreatic diseases have been treated by clinicians in different medical disciplines, including endocrinologists and gastroenterologists. Islet microcirculation has long been considered to be regulated independently from that of the exocrine pancreas. A new model proposes that pancreatic islet blood flow is integrated with the surrounding exocrine capillary network. This recent model may provide revived or contrasting hypotheses to test, since the pancreatic microcirculation has critical implications for the regulation of islet hormones as well as acinar pancreas functions. In this mini-review, practical applications of in vivo and in situ studies of islet microcirculation are described with a specific emphasis on large-scale data analysis to ensure sufficient sample size accounting for known islet heterogeneity. For in vivo small animal studies, intravital microscopy based on two-photon excitation microscopes is a powerful tool that enables capturing the flow direction and speed of individual fluorescent-labeled red blood cells. Complementarily, for structural analysis of blood vessels, the recent technical advancements of confocal microscopy and tissue clearing have enabled us to image the three-dimensional network structure in thick tissue slices.

Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease.

Non‐alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, being a common comorbidity of type 2 diabetes and with important links to inflammation and insulin resistance. NAFLD represents a spectrum of liver conditions ranging from steatosis in the form of ectopic lipid storage, to inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Macrophages that populate the liver play important roles in maintaining liver homeostasis under normal physiology and in promoting inflammation and mediating fibrosis in the progression of NAFLD toward to NASH. Liver macrophages are a heterogenous group of innate immune cells, originating from the yolk sac or from circulating monocytes, that are required to maintain immune tolerance while being exposed portal and pancreatic blood flow rich in nutrients and hormones. Yet, liver macrophages retain a limited capacity to raise the alarm in response to danger signals. We now know that macrophages in the liver play both inflammatory and noninflammatory roles throughout the progression of NAFLD. Macrophage responses are mediated first at the level of cell surface receptors that integrate environmental stimuli, signals are transduced through multiple levels of regulation in the cell, and specific transcriptional programmes dictate effector functions. These effector functions play paramount roles in determining the course of disease in NAFLD and even more so in the progression towards NASH. The current review covers recent reports in the physiological and pathophysiological roles of liver macrophages in NAFLD. We emphasise the responses of liver macrophages to insulin resistance and the transcriptional machinery that dictates liver macrophage function.

Detection of Circulating Tumor Cells in Resectable Pancreatic Ductal Adenocarcinoma: A Prospective Evaluation as a Prognostic Marker.

Circulating tumor cells (CTCs) are useful biomarkers of many solid tumors, but are infrequently detected in early stage pancreatic ductal adenocarcinomas (PDACs). The first drainage of pancreatic venous blood flow come to portal vein and pass through the liver, and they finally go out for peripheral blood. We thought that comparing CTCs from portal vein and peripheral blood could enable us to understand the clinical meaning of CTCs from each different site in PDACs. Therefore, we aimed to determine 1) whether CTCs could be reliably identified in early stages (operable) of PDACs, 2) if there are any differences in the detected number of CTC in portal vein blood and peripheral blood, and 3) whether CTCs can be sensitive biomarkers for the prognosis of resectable PDAC patients. Newly diagnosed PDAC patients who underwent operation with curative intention between 2013 and 2015 were prospectively enrolled. Blood draws from portal and peripheral vein ran through the microfabricated porous filter, and anti-epithelial cell adhesion molecule (EpCAM) and anti-Plectin-1 antibodies were used for CTC identification. Baseline clinical characteristics, tumor characteristics, treatment, and clinical outcomes were assessed. The clinical stages of the 32 enrolled patients were as follows: IA/IB 1 (3.1%); IIA 9 (28.1%); IIB 17 (53.1%); III 5 (15.6%). Twenty-seven patients (84.4%) received R0 resection, while five patients (15.6%) received R1 resection. EpCAM+ CTCs were detected in 20 portal blood (62.5%) and 22 peripheral blood (68.8%). Plectin-1+ CTCs were identified in 14 portal blood (43.8%) and 16 peripheral blood (50%). Plectin-1-expressing CTCs were picked from CTC platform (microfabricated porous filter) and we could find out all KRAS mutation. Patients with detectable EpCAM+ CTC less than one in peripheral blood showed longer overall survival (OS) compared to patients with detectable CTCs more than one (35.5 months vs. 16.0 months). EpCAM and Plectin-1 successfully identified CTCs at the early stage of PDACs. Also, the number of CTCs could be a prognostic marker for survival in resectable PDACs.

Histopathological changes in the pancreas due to decreased pancreatic blood flow in a canine tachycardia-induced cardiomyopathy model

In dogs, pancreatic acinar cell injury is thought to be caused by decreased pancreatic blood flow due to heart failure. In previous our report, it demonstrated that decreased heart function causes a significant decrease in pancreatic blood flow in heart failure dog model caused by rapid ventricular pacing (RVP). However, the types of histopathological changes remain unclear. We aimed to verify the types of histopathological changes occurring in the pancreatic tissue due to decreased heart function. After RVP for 4 weeks, atrophy of pancreatic acinar cells, characterized by a decrease in zymogen granules, was observed in all areas of the pancreas. In conclusion, the result of this study suggests that attention should be paid to ischemia/hypoperfusion injury in the pancreas.

Vasoactive intestinal peptide in canine portosystemic shunt in the absence of portal hypertension

Background:The congenital portosystemic shunt (PSS) is a common vascular anomaly in dogs. Vasoactive intestinal peptide (VIP) is produced in various organs (including the small intestine, large intestine, and pancreas), leading to abdominal vasodilation, increased blood flow, increased pancreatic blood flow, and promotion of pancreatic endocrine and exocrine secretions. However, there have been no reports on the concentration of VIP in the portal and peripheral veins in canine PSS.Aim:The aim of this pilot study was to evaluate whether dogs with PSS have a different VIP concentration in their portal system in general.Methods:Six dogs with an extrahepatic portosplenic shunt were included in the study. Blood samples were taken from the saphenous and portal veins during PSS ligation surgery with an amerid constrictor, to evaluate and compare the VIP concentration in both samples. VIP was measured using a commercial canine enzyme-linked immunosorbent assay kit.Results:The breeds included Mongrels (n = 2), Norfolk Terriers (n = 1), Miniature Dachshunds (n = 1), and Maltese (n = 2), and their ages were 9.3 ± 6.5 months; the bodyweight was 3.3 ± 0.8 kg. The concentration of VIP in the saphenous vein was 17.75 ± 13.88 pg/ml; on the contrary, the concentration of VIP in the portal vein was 29.7 ± 20.29 pg/ml. There was no significant difference in the VIP concentration between veins.Conclusion:There was no difference in the VIP concentration between the portal and saphenous veins, suggesting a non-association between VIP and the PSS, in the absence of portal hypertension.

CART decreases islet blood flow, but has no effect on total pancreatic blood flow and glucose tolerance in anesthetized rats

Cocaine- and amphetamine-regulated transcript (CART) is a neurotransmitter and hormone, involved in the regulation of e.g. food intake, body weight, reward and addiction, and stress response. CART has also been found to affect insulin secretion and beta cell morphology, both in vivo and in vitro. Furthermore, CART affects regulation of the cardiovascular system and helps to modulate vascular tone. The present study evaluated the local effect of CART on the pancreatic and islet circulation and function. CART (25 μg/h) or saline, combinations of CART and endothelin-A receptor antagonist (BQ123; 100 μg/kg), and glucose (2 g/kg) were intravenously infused in Sprague Dawley rats followed by blood flow measurements using a microsphere technique. Separately, CART-infused animals underwent an intravenous glucose tolerance test (ivGTT). The direct effect of CART on insulin release was investigated using isolated islets from Sprague Dawley rats. CART reduced islet blood flow, without reduction in total pancreatic blood flow. The normal glucose-induced islet blood flow increase was diminished by CART, albeit still present. Simultaneously, CART had no effect on systemic-, intestinal- or renal blood flow. The endothelin-A receptor antagonist BQ123 together with CART had no pancreatic vascular effects. We found that CART has pronounced vascular constrictive actions restricted to the pancreatic islet circulation but had no effect on insulin release neither in vivo nor in vitro. The mechanisms behind the vascular effects are still unknown, but may reflect a direct action on pancreatic blood vessels.

Administration of warfarin accelerates the recovery in ischemia/reperfusion-induced acute pancreatitis.

Acute pancreatitis is associated with activation of coagulation and there is a close relationship between coagulation and the severity of this disease. Administration of anticoagulants such as heparin or acenocoumarol has shown to reduce the severity of acute pancreatitis and accelerate the recovery. The aim of the current study was to determine the impact of warfarin administration on the course of ischemia/reperfusion-induced acute pancreatitis. Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. Vehicle (1 ml/dose) or warfarin (45, 90 or 180 μg/kg/dose in 1 ml of vehicle) were administered intragastrically once a day. The first dose of warfarin was given 24 h after the start of pancreatic reperfusion. The severity of acute pancreatitis was assessed 2, 5, 9 and 14 days after the beginning of pancreatic reperfusion. Treatment with warfarin reduces pancreatic damage and accelerates recovery in histological examination and this effect is accompanied by a faster reduction in serum activity of pancreatic digestive enzymes, lipase and amylase. In addition, warfarin led to an earlier decrease in serum concentration of pro-inflammatory interleukin-1β and plasma level of D-dimer. These effects were associated with an improvement of pancreatic blood flow. We conclude that warfarin exhibits a therapeutic effect in acute pancreatitis evoked by pancreatic ischemia followed by reperfusion.