Pancreatic Blood Flow Research Articles

Inorganic nitrite stimulates pancreatic islet blood flow and insulin secretion

Reactive nitrogen and oxygen species have been proposed to be involved in control of insulin release from the pancreatic β cell. Recent evidence suggests that the supposedly inert anions nitrate and nitrite are metabolized in blood and tissues to form nitric oxide (NO) and other bioactive nitrogen oxides. Here we present evidence for a novel stimulatory role of nitrite in influencing pancreatic islet physiology via a dual mechanism, involving both indirect enhancement (through microcirculation redistribution) and direct insulinotropic effects on the β cell. In rats, intraperitoneal injection of sodium nitrite increased pancreatic islet blood flow by 50% and serum insulin concentrations by 30%, while whole pancreatic blood flow and glycemia remained unaffected. Nitrite also dose dependently enhanced insulin secretion from rat β cells in vitro under nonstimulatory glucose concentrations. This effect was not mimicked by nitrate and was abolished by the guanylyl cyclase (GC) inhibitor ODQ and the NO scavenger cPTIO. It was also mimicked by a cyclic GMP agonist (8-CPT-cGMP) and a classical NO donor (NONOate). Interestingly, a reactive oxygen species scavenger (vitamin E analog, Trolox) abolished the insulin secretion induced by nitrite. We conclude that nitrite exerts dual stimulatory effects on pancreatic islet function, including enhancement of islet blood flow and subsequent insulin secretion in vivo and direct stimulation of insulin release in vitro. The insulinotropic effect of nitrite is cGMP-dependent and involves formation of reactive nitrogen and oxygen species.

Two‐week treatment with the β3‐adrenoceptor antagonist SR59230A normalizes the increased pancreatic islet blood flow in type 2 diabetic GK rats

The Goto-Kakizaki (GK) rat, a type 2 diabetes model, has increased pancreatic islet and white adipose tissue (WAT) blood flow, and this can be normalized by acute administration of SR59230A, a β₃ -adrenoceptor antagonist. We now implanted osmotic pumps which allowed a constant release of saline or SR59230A (0.6 mg/kg × day) for 2 weeks. A decrease in islet blood flow was seen also after 2 weeks of continuous SR59230A treatment in the GK rat. However, no improvement in glucose tolerance was seen in the GK rats. Neither did SR59230A affect insulin secretion from isolated islets in vitro. WAT blood flow was not affected by the 2-week SR59230A treatment. Thus, the increased islet blood flow seen in the GK rat can be normalized for up to 2 weeks, which opens the possibilities for further studies on the long-term functional role on the islet blood flow increase in this type 2 diabetes model.

Early intervention with liraglutide improves glucose tolerance without affecting islet microcirculation in young Goto–Kakizaki rats

Liraglutide, an analog of glucagon-like peptide-1 (GLP-1), is an effective anti-diabetic agent with few side effects. Since native GLP-1 exerts vascular effects, we investigated changes in pancreatic islet blood flow using a non-radioactive microsphere technique, as well as insulin concentration and glucose tolerance after 17day treatment with liraglutide in 6-week-old Goto–Kakizaki (GK) rats. Compared to saline-treated control GK rats, liraglutide limited body weight gain, decreased glycemia, improved glucose tolerance and lowered serum insulin concentration. Neither pancreatic or islet blood flow, nor pancreatic insulin content, was affected by liraglutide treatment. We conclude that early intervention with liraglutide decreases glycemia and improves glucose tolerance, thus halting the natural progression towards diabetes, without affecting islet microcirculation or pancreatic insulin content in young female GK rats.

GLP-1, exendin-4 and C-peptide regulate pancreatic islet microcirculation, insulin secretion and glucose tolerance in rats

GLP-1 (glucagon-like peptide 1) and its mimetic exendin-4 are used against Type2 diabetes. C-peptide has also proven promising to enhance insulin action. Since insulin secretion in vivo can be rapidly tuned by changes in islet microcirculation, we evaluated the influence of GLP-1, exendin-4 and C-peptide on pancreatic IBF (islet blood flow), and dynamic changes in insulin secretion and glycaemia in the rat. Adult male Wistar rats were divided into four groups given intravenous saline, GLP-1, exendin-4 or C-peptide respectively and administered either saline or 30% glucose. Furthermore, we investigated the effect of intravenous infusion of different doses of exendin-4 into either the femoral vein or the portal vein on islet microcirculation. A non-radioactive microsphere technique was adopted to measure the regional blood flow. Both GLP-1 and exendin-4 prevented the glucose-induced PBF (pancreatic blood flow) redistribution into the islets. Infusion of exendin-4 into the portal vein did not alter pancreatic islet microcirculation, while infusion of exendin-4 into femoral vein significantly decreased basal IBF. C-peptide increased basal IBF and the proportion of IBF out of total PBF, but did not affect the islet microcirculation after glucose administration. GLP-1, exendin-4 and C-peptide stimulated insulin secretion and significantly decreased glycaemia. Blocking NO formation did not prevent the decreased IBF and post-load glycaemia evoked by exendin-4, but further decreased IBF and KBF (kidney blood flow) and increased basal glycaemia. Blocking the vagus nerve enhanced pancreatic IBF and further decreased post-load glycaemia and KBF and increased basal glycaemia. The vascular modulatory effect on pancreatic islet microcirculation described herein, with subsequent effects on in vivo insulin secretion and glycaemia, might be one of the mechanisms underlying the anti-diabetic actions of GLP-1 and its long acting mimetic exendin-4, as well as that of C-peptide.

Relationships between the islets blood flow, nitric oxide, insulin, and cytosolic calcium in rat pancreatic islets: Effects of DPP-IV inhibitor vildagliptin

The aim of the present study was to evaluate the relationships between the islets blood flow, nitric oxide, insulin, and cytosolic calcium in rat pancreatic islets, using dipeptidyl peptidase-IV (DPP-IV) inhibitor vildagliptin. For measuring pancreatic and islets blood a non-radioactive microsphere technique was used. Vehicle pre-treatment of glucose administered diabetic rats had decrease pancreatic and islets blood flow as compared with glucose administered normal rats. Blood glucose concentrations were not affected after vildagliptin administration in either diabetic or normal rats (10min after glucose administration). Vildagliptin had no effects on baseline pancreatic or islets blood flow in glucose administered normal rats. Administration of vildagliptin increased both pancreatic and islets blood flow as compared with vehicle treated diabetic rats. Furthermore, diabetic rats showed significant increase in NO and decrease in insulin secretions and vice versa in normal rats. Vildagliptin pre-treatment to both normal and diabetic rats had shown mild decrease in NO, but significantly increased insulin secretions. In addition, vildagliptin itself is able to mobilize intracellular Ca2+ in pancreatic islets both in absence and presence of glucose. From the present study, we conclude following points (A) administration of vildagliptin augmented the blood flow seen in islets of diabetic rats, (B) islets insulin secretions are independent of islets blood flow and NO, (C) vildagliptin inhibited excessive NO production in diabetic rats that prevents the damage to β-cells due to excessive production of peroxynitrite (ONOO−) ions and protects from cytokine-induced suppression of insulin release.

Perfusion Computed Tomography Findings of Autoimmune Pancreatitis

The aim of this study was to clarify the pancreatic blood perfusion in patients with autoimmune pancreatitis (AIP) and the changes after steroid treatment. Perfusion computed tomography was performed in 11 patients with AIP and 12 control subjects. Pancreatic volumetric blood flow (F(V)), volume of distribution (V(D)), and blood transit time τ were determined from a single-compartment kinetic model. Nine patients with AIP were reexamined by perfusion computed tomography after corticosteroid administration. The pancreatic F(V) values of the 11 patients with AIP (82.7/min) were significantly lower than those of control subjects (163.5/min, P = 0.0006). On the other hand, the pancreatic V(D) and τ values were not significantly different between AIP and normal. After steroid treatment, the F(V) values of 9 reexamined patients with AIP (76.2/min) were significantly elevated (109.8/min, P = 0.0391). However, the changes of the values after the treatment differed in degree among individuals. The values of 4 patients were dramatically elevated to greater than 100/min, whereas those of 4 other patients did not improve well. The value of the remaining patient whose initial F(V) value was normal (168.09/min) did not change after the treatment. Pancreatic volumetric perfusion was attenuated in AIP patients. The perfusion was improved after the steroid treatment.

Xenon-Inhalation Computed Tomography for Noninvasive Quantitative Measurement of Tissue Blood Flow in Pancreatic Tumor

The purpose of this prospective study was to demonstrate the ability to measure pancreatic tumor tissue blood flow (TBF) with a noninvasive method using xenon inhalation computed tomography (xenon-CT) and to correlate TBF with histological features, particularly microvascular density (MVD). TBFs of pancreatic tumors in 14 consecutive patients were measured by means of xenon-CT at diagnosis and following therapy. Serial abdominal CT scans were obtained before and after inhalation of nonradioactive xenon gas. TBF was calculated using the Fick principle. Furthermore, intratumoral microvessels were stained with anti-CD34 monoclonal antibodies before being quantified by light microscopy (×200). We evaluated MVD based on CD34 expression and correlated it with TBF. The quantitative TBF of pancreatic tumors measured by xenon CT ranged from 22.3 to 111.4 ml/min/100 g (mean ± SD, 59.6 ± 43.9 ml/min/100 g). High correlation (r = 0.885, P < 0.001) was observed between TBF and intratumoral MVD. Xenon-CT is feasible in patients with pancreatic tumors and is able to accurately estimate MVD noninvasively.

Synergetic Effect of Yihuo Qingyi Decoction ( ) and Recombinant Staphylokinase in Treatment of Severe Acute Pancreatitis of Rats

To investigate the effect of recombinant staphylokinase (r-Sak) and the Chinese medicine Yihuo Qingyi Decoction ((see test) Herbal decoction for severe acute pancreatitis) in the treatment of the severe acute pancreatitis (SAP) in rats, and to observe the synergistic effect of the two.One hundred and sixty-two adult male SD rats with the body mass of 250-280 g were randomly divided into the following 5 groups: sham operation group (n = 18), control group (n = 36), Yihuo Qingyi Decoction treatment group (n = 36), r-Sak treatment group (n = 36), and Yihuo Qingyi Decoction plus r-Sak treatment group (n = 36). The SAP ratmodel was prepared by retrograde injection of 5% sodium taurocholate into the cholangiopancreatic duct. Two days before modeling, Yihuo Qingyi Decoction was intragastrically administrated, and r-Sak was intraperitoneally injected. The survival rate within 18 h after modeling was determined. The pancreatic blood flow, the weight of ascites, and the serum amylase and lipase were investigated at 6 h, 12 h, and 18kh after modeling, and the pancreatic tissue was examined under light microscopy to see its pathological change.The 18 h survival count of group A, B, C, D and E rats was 9, 2, 6, 7 and 8 respectively. After r-Sak and Yihuo Qingyi Decoction intervention, the serum amylase and lipase and the weight of ascites were significantly decreased, especially in group E.18 h after modeling, the level of the serum amylase and lipase and the weight of ascites in group E was 1 100 +/- 118 U x L(-1), 1 000 +/- 150 U x L(-1) and 13.40 +/- 1.80 g respectively, obviously lower than that of group B (P < 0.05). After SAP was induced, the pancreatic blood flow showed a tendency to decrease, but the decrease extent in the treatment groups was smaller than that in the control group. 18h after modeling, the pancreatic blood flow in group B and group E was 30.16 +/- 8.96 mL x 100 g(-1) x min(-1), and 129.10 +/- 42.58 mL x 100 g(-1) x min respectively, there was significant difference (P < 0.05). The pathological change of the pancreatic tissue was alleviated in the treatment groups.Both r-Sak and Yihuo Qingyi Decoction play a beneficial role in the treatment of rat SAP and there is a synergistic effect between the two.

Flow distribution during infusion of UW and HTK solution in anaesthetised rats

Organ transplantation necessitates the use of preservation solutions to maintain the integrity of the organs during retrieval. The aim of this study was to investigate the flow distribution in abdominal organs in rats during acute infusion of preservation solution. Microspheres were used to estimate the distribution of flow in the pancreas, duodenum, ileum, colon, liver, kidneys and lungs in untreated Wistar-Furth rats and in animals with an opened abdominal cavity and catheterised aorta. Some animals were infused by free flow of 5ml of UW, HTK or Ringer solution containing microspheres at a pressure of 100cm H(2)O through an intra-aortic catheter. Opening of the abdominal cavity did not affect any of the organ blood flow values. However, the fraction of total pancreatic blood flow diverted through the islets increased. During infusion of microsphere-containing UW, HTK or Ringer solution, splanchnic and renal organ flow values, represented by microsphere contents, were similar. The fraction of microspheres found in the islets was lower in UW-infused rats. The number of microspheres present in the lungs or liver was very low, suggesting that shunting was negligible. Infusion of HTK and UW solution into anaesthetised rats results in a flow distribution which is similar to that in normal animals in most abdominal organs, but there is a reduction in islet blood perfusion by UW but not HTK solution.

In Vivo Fluorescence Imaging of Blood Flow in Mouse Pancreatic Islets

Diabetes is a disease resulting from changes in pancreatic islets, which are insulin secreting micro-organs within the pancreas. With increased blood glucose, insulin is secreted from beta cells in the islets in a coordinated pulsatile manner. At the same time alpha cell glucagon secretion is inhibited. Mechanisms controlling these processes at the intercellular and at the inter-islet level remain unclear. We suggest that the three-dimensional organization of islet cells and the dynamics of islet blood flow have a role in regulating insulin and glucagon secretion. This is suggested by observation that the density of blood vessels within islets is much greater than in surrounding pancreatic tissue, and that most individual islet cells are adjacent to a blood vessel. As an initial test of our hypothesis, we have developed a high-speed in vivo fluorescence imaging method to track pancreatic blood flow in a living mouse. We are also developing methods necessary to analyze the large amounts of data generated. Using high speed line scan confocal microscopy the method has full frame sub-micron spatial and less than 10 ms temporal resolution. Islets are located within the pancreas by using mice with GFP-labeled beta cells. Blood plasma is labeled with a fluorescent dextran, allowing mapping of vascular dimensions and pathway. Individual blood cells are fluorescently labeled by osmotic shock loading with an Alexa dye, which allows tracking of the blood flow. We present current results for blood flow under different levels of blood glucose in clamping experiments. Our previous qualitative results have suggested that there are differences in blood flow parameters at different glucose levels. Here, a more quantitative analysis of blood flow velocity, any observed changes in vessel dimensions, and changes in blood flow coverage inside and outside islets is presented.

Intra-arterial Targeted Islet-specific Expression of Sirt1 Protects β Cells From Streptozotocin-induced Apoptosis in Mice

Gene therapy provides a promising approach to curing diabetes. However, an effective route for islet-specific targeting has yet to be established. Toward this end, the pancreatic blood circulation system in Balb/c mice was determined by the injection of rhodamine-containing beads. The efficiency of islet targeting was then measured by the injection of adenoviral vectors carrying a green fluorescence gene via the celiac trunk (C.T.). The results showed that >95% of islets and about 60% of β cells within the pancreatic body and tail could be labeled 3 days after surgery. α-Cell labeling was not as efficient, whereas labeling of nonendocrine tissues was barely detectable. For proof of principle, adenoviral vectors carrying a Sirtuin transgene were injected similarly to test the islet protection effect in the streptozotocin (STZ)-induced type 1 diabetic model. The results demonstrated that overexpression of Sirtuin in STZ-treated mice reduced the level of β-cell death and extent of glucose intolerance. This study reports on efficient islet-specific targeting by using adenoviral injection. This procedure could be invaluable to the treatment of diabetes and the study of islet biology.

Hyaluronidase Treatment of Graft Pancreatitis in Rats: Marked Effects on the Blood Perfusion of the Transplanted Pancreas

Hyaluronan is known to accumulate in tissues during inflammatory diseases associated with graft implantation and rejection of organ allografts. The aim was to evaluate whether hyaluronidase treatment affected hyaluronan content and blood perfusion in graft pancreatitis. Syngeneic rat pancreatic-duodenal transplantations were performed. Two days later blood flow measurements were made with a microsphere technique in both grafted and endogenous pancreas in animals treated with daily injections of vehicle or hyaluronidase (20.000 U/kg). Non-transplanted rats served as controls. Also, samples for analysis of hyaluronan and water content were taken. The hyaluronan content of the pancreatic graft was increased after transplantation. Hyaluronidase treatment markedly reduced total pancreatic and islet blood flow in both grafted and endogenous pancreas, whereas duodenum blood flow was unaffected. No blood flow effects were seen in non-transplanted control rats. Hyaluronan content was increased in the grafted pancreas, but hyaluronidase treatment decreased it to levels comparable to those of the endogenous gland. There were no differences in hyaluronan content in the endogenous pancreases of transplanted and non-transplanted rats. Graft pancreatitis after rat pancreas transplantation is associated with an increased hyaluronan content, which can be reduced by treatment with hyaluronidase. Hyaluronidase treatment of the graft recipients effected a 50% reduction in total pancreatic and islet blood flow in the graft, as well as in the endogenous pancreas. The functional importance of this is at present unknown.

Do Statins Beneficially or Adversely Affect Glucose Homeostasis?

The effect of statin treatment on glucose metabolism and the risk of diabetes remains an issue of controversy. Since statins are drugs commonly prescribed for the prevention of cardiovascular disease even in patients with prediabetes or diabetes, it is of great importance to identify the role of statin treatment on glucose homeostasis. In this review, we have scrutinized available data with regard to the effect of every drug of the class on glycemic outcomes. Experimental data describing mechanisms through which these drugs potentially modify the metabolism of carbohydrates have been described. In order to identify statins which may be preferentially used to improve parameters of glycemic control, studies comparing different agents of this class as to their effect on glucose homeostasis have been discussed. According to experimental studies statin lipophilicity as well as the potential to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase should be regarded as prognostic factors of an adverse impact of statin treatment on carbohydrate metabolism. On the other hand, the hypotriglyceridemic capacity, the endothelial-dependent increase in pancreatic islet blood flow, the anti-inflammatory properties along with the capacity of statins to alter circulating levels of several adipokines known to affect glucose homeostasis, including adiponectin, leptin, visfatin and resistin, may beneficially alter glycemic status. In clinical trials, a beneficial, neutral or adverse impact on glycemic control of different populations has been ascribed to various statins. From all drugs of the class pravastatin seems to beneficially affect glucose metabolism and decrease the risk of diabetes. Controversial findings have come to the fore with regard to other statins commonly prescribed in the clinical setting, including rosuvastatin, atorvastatin and simvastatin. More data are needed to clarify the exact role of lovastatin, fluvastatin and the newest statin pitavastatin on carbohydrate metabolism. Comparison trials suggest a potential preferable effect of the hydrophilic statins pravastatin, rosuvastatin and pitavastatin as compared to lipophilic components of the class, including atorvastatin and simvastatin.

Pancreatitis following administration of iodixanol in patients on hemodialysis: a pilot study

We previously described the association of pancreatitis with the use of iodixanol radiocontrast in two patients on hemodialysis. This study was designed to determine whether there might be a causal link. 30 consecutive hemodialysis patients without predisposition for pancreatitis who were undergoing de-clotting and angioplasty of their arteriovenous access were randomly assigned to either iodixanol or iohexol radiocontrast. The demographics and volume of contrast used were similar between the groups. 2 of the 15 patients who received iodixanol developed elevations in serum amylase and lipase as well as signs and symptoms of pancreatitis. No patient who received iohexol developed pancreatitis. The use of iodixanol appears to be associated with pancreatitis in a small population of hemodialysis patients. Although the pathogenesis of iodixanol-induced pancreatitis is unclear, we speculate that it is possibly related to the hyperviscosity of this agent, which may decrease pancreatic blood flow. Larger studies are needed to verify these findings.

Effect of C peptide onpancreatic islet microcirculation in Wistar rats

：Objective To evaluatethe effects of physiological doses of C-peptide on islet microcirculation,bloodglucose,and insulin concentrations.Methods Adult male Wistar rats were divided into twogroups i.v either with C-peptide (75nmoL/kg body wt)or saline (control).Each group wasfurther divided into 2 subgroups using 1 ml saline or 30% glucose.A microsphere techniquewas adopted to measure the pancreatic islet microcirculation.Results Intravenous injectionof C-peptide markedly increased basal islet blood flow[(0.156±flow[(14.33±0.53 vs 9.16±0.64)%,P＜0.01],but did not affect islet microcircuJation after intravenousglucose administration.In IPGT,C-peptide decreased blood glucose at 30 min[(7.9±0.7 vs11.5±0.6) mmol/L,P＜0.01]after glucose challenge and stimulated insulinsecretion(for AUCins(0.120),141.36±15.00 vs 49.78±5.60,P ＜0.01).Conclusion C-peptide inducesredistribution of pancreatic blood flow in favour of islet in normoglycemic rats,andmodulates insulin release in hyperglycaemic rats. Key words: C-peptide; Microshpere technique; Isletmicrocircolation; Intraperitoneal glucose tolerance test

Measurement of canine pancreatic perfusion using dynamic computed tomography: Influence of input–output vessels on deconvolution and maximum slope methods

We investigated whether the prerequisite of the maximum slope and deconvolution methods are satisfied in pancreatic perfusion CT and whether the measured parameters between these algorithms are correlated. We examined nine beagles injected with iohexol (200 mgI kg(-1)) at 5.0 ml s(-1). The abdominal aorta and splenic and celiac arteries were selected as the input arteries and the splenic vein, the output veins. For the maximum slope method, we determined the arterial contrast volume of each artery by measuring the area under the curve (AUC) and compared the peak enhancement time in the pancreas with the contrast appearance time in the splenic vein. For the deconvolution method, the artery-to-vein collection rate of contrast medium was calculated. We calculated the pancreatic tissue blood flow (TBF), tissue blood volume (TBV), and mean transit time (MTT) using both algorithms and investigated their correlation based on vessel selection. The artery AUC significantly decreased as it neared the pancreas (P<0.01). In all cases, the peak time of the pancreas (11.5±1.6) was shorter than the appearance time (14.1±1.6) in the splenic vein. The splenic artery-vein combination exhibited the highest collection rate (91.1%) and was the only combination that was significantly correlated between TBF, TBV, and MTT in both algorithms. Selection of a vessel nearest to the pancreas is considered as a more appropriate prerequisite. Therefore, vessel selection is important in comparison of the semi-quantitative parameters obtained by different algorithms.

Pancreatic perfusion of healthy individuals and type 1 diabetic patients as assessed by magnetic resonance perfusion imaging

Loss of pancreatic beta cell mass and function leads to the development of diabetes mellitus. Currently there is no technical way to non-invasively image islet function and mass. Murine models suggest that islets are highly vascularised organs that make a significant contribution to the total pancreatic blood flow. The current study was undertaken to test with arterial spin labelling (ASL) magnetic resonance imaging if islet mass and/or stimulation of human pancreatic islets by hyperglycaemia can differentially increase whole-pancreas perfusion, thereby distinguishing non-diabetic from type 1 diabetic patients. We assessed pancreatic blood flow using ASL at baseline, during a hyperglycaemia clamp study (glucose at 11 mmol/l) and during recovery to euglycaemia. Seventeen healthy volunteers and seven type 1 diabetic patients were studied. In healthy volunteers we observed no change in pancreatic blood flow during the three phases of the study. A trend for an increase in blood flow was observed in the two control tissues, the liver and kidney. Similarly, there was no significant difference in blood flow during the three stages (baseline, hyperglycaemia and recovery) in diabetic patients and there was no significant difference observed between diabetic patients and normal volunteers. Our data suggest that in humans neither increased demand nor islet mass has a substantial influence on pancreatic perfusion. It is possible, however, that the current state-of-the art imaging technology employed in this study might not be sensitive enough to distinguish between a true effect and noise. ClinicalTrials.gov NCT00280085.

Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the β3-adrenoceptor inhibitor SR-59230A

Previous studies have shown that the Goto-Kakizaki (GK) rat, a nonobese type 2 diabetes model, has an increased white adipose tissue (WAT) and islet blood flow when compared with control rats. The aim of the study was to examine if these increased blood flow values in GK rats could be affected by the beta(3)-adrenoceptor antagonist SR-59230A. We measured organ blood flow with a microsphere technique 10 min after administration of SR-59230A (1 mg/kg body wt), or the corresponding volume of 0.9% NaCl solution (1 ml/kg body wt) in rats anaesthetized with thiobutabarbital. The GK rat had an increased blood flow in all intra-abdominal adipose tissue depots except for the sternal fat pad compared with Wistar-Furth (WF) rats. However, no differences were seen in the blood perfusion of subcutaneous white or brown adipose tissue. The blood flow was also increased in both the pancreas and in the islets in the GK rat compared with WF rats. SR-59230A treatment affected neither WAT nor pancreatic blood flow in WF rats. In GK rats, on the other hand, SR-59230A decreased both WAT and islet blood flow values to values similar to those seen in control WF rats. The whole pancreatic blood flow was not affected by SR-59230A administration in GK rats. Interestingly, the brown adipose tissue blood flow in GK rats increased after SR-59230A administration. These results suggest that beta(3)-adrenoceptors are involved in regulation of blood flow both in islet and in adipose tissue.

Angiotensin II type 1 receptor antagonists prevent glucose‐induced increases in islet blood flow in rats

Objective. Renin‐angiotensin system inhibitors are reported to be beneficial in delaying the onset of diabetes mellitus. Since islet blood hyperperfusion during hyperglycaemia may be detrimental to endothelium in pancreatic islets and eventually lead to β‐cell dysfunction, we studied acute and chronic effects of angiotensin II type 1 receptor blockers (ARB) on islet blood flow before and after glucose load. Material and methods. Islet blood flow was measured using the colour microsphere method in anaesthetized Sprague‐Dawley rats before and 3 min after glucose injection. Results. Olmesartan significantly reduced blood pressure, but did not affect islet blood flow 10 min after its injection. However, pretreatment with olmesartan blunted the glucose‐induced increase in islet blood flow (62 % of control). In rats treated with olmesartan or candesartan for 4 weeks, islet blood flow was not different from untreated control, whereas the glucose‐induced increase in islet blood flow was significantly suppressed in chronically ARB‐treated rats (olmesartan 59 % of control, candesartan 64 % of control, respectively). Acute or chronic treatment with ARB did not change insulin secretion before and in response to glucose load. Pancreatic or duodenal blood flow was not affected by ARB treatment, although acute olmesartan administration reduced pancreatic blood flow after glucose load. Conclusion. ARB appears to suppress the hyperglycaemia‐induced islet hyperperfusion, which may ameliorate haemodynamic stress in pancreatic islets.

Pancreatic Endocrine Tumors: Tumor Blood Flow Assessed with Perfusion CT Reflects Angiogenesis and Correlates with Prognostic Factors1

To prospectively correlate multidetector computed tomographic (CT) perfusion measurement of pancreatic endocrine tumors with tumor microvascular density (MVD) assessed by using histologic techniques and to determine whether perfusion CT parameters differ between tumor grades. Institutional review board approval and informed consent were obtained. Thirty-six patients (15 men, 21 women; mean age, 53 years; range, 18-78 years) with resectable pancreatic endocrine tumors underwent presurgical dynamic perfusion CT. Twenty-eight (78%) of 36 patients were included in the study group; eight were excluded because of artifacts that were not compatible with perfusion postprocessing. Multidetector CT perfusion data were analyzed to calculate tumor and normal pancreatic blood flow, blood volume, mean transit time, and permeability-surface area product. Multidetector CT perfusion parameters were compared with intratumoral MVD by using the Spearman correlation coefficient and with World Health Organization (WHO) classification, tumor size, tumor proliferation index, hormonal profile, and presence of metastases by using Mann-Whitney tests. High correlation (r = 0.620, P < .001) was observed between tumor blood flow and intratumoral MVD. Blood flow was significantly higher (P = .02) in the group of benign tumors (WHO 1) than in the groups of tumors of indeterminate prognosis (WHO 2) or well-differentiated carcinomas (WHO 3). Blood flow was significantly higher in tumors with a proliferation index of 2% or less (P = .005) and in those without histologic signs of microscopic vascular involvement (P = .008). Mean transit time was longer in tumors with lymph node (P = .02) or liver (P = .05) metastasis. Perfusion CT is feasible in patients with pancreatic endocrine tumors and reflects MVD. Perfusion CT measurements are correlated with histoprognostic factors, such as proliferation index and WHO classification.