vasoactive-intestinal-peptide and Reperfusion-Injury

Dipeptidyl peptidase 4 (DPP4, DPPIV, CD26, EC 3.4.14.5) was discovered more than four decades ago as a serine protease that cleaves off N-terminal dipeptides from peptide substrates. The development of potent DPP4 inhibitors during the past two decades has led to the identification of DPP4 as a target in the treatment of type 2 diabetes. The favorable effect of DPP4 inhibitors is based on prevention of the in vivo inactivation of the incretin hormone, glucagon-like peptide-1 (GLP-1) by DPP4. Apart from GLP-1, a number of other biologically active peptides are truncated by DPP4. For these peptides, the physiological relevance of their truncation has yet to be fully elucidated. Within the last 10years, DPP4 inhibitors have been employed in several animal models of lung and heart disease, in which injury was induced by an ischemic insult followed by subsequent reperfusion. In this review, we present a state-of-the-art of the ischemia/reperfusion injury (IRI)-related pharmacological actions of DPP4 substrates, including GLP-1, stromal cell-derived factor-1 alpha and vasoactive intestinal peptide. Furthermore, we discuss the large body of experimental work that now provides compelling evidence for the advantageous impact of DPP4 targeting in IRI. However, possible risks as well as underlying mechanisms are yet to be elucidated before translating these promising treatment strategies into clinical practice.

Topics: Animals; Chemokine CXCL12; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoxia; Reperfusion Injury; Vasoactive Intestinal Peptide

Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients.

Topics: Animals; Apoptosis; Caspase 3; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Flow Cytometry; Hepatocytes; Homeostasis; Immune System; Inflammation; Interleukin-10; L-Lactate Dehydrogenase; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Necrosis; Neutrophils; Peroxidase; Reperfusion Injury; Time Factors; Vasoactive Intestinal Peptide

Mesenteric lymph pathway serves as the primary route by which gut injury leads to systemic inflammation and distant organ injury. The inflammation of the intestinal tract is partially mediated by vasoactive intestinal peptide (VIP). Therefore, the aim of this study was to test whether exogenous VIP affects mesenteric lymph pathway during early intestinal ischemia-reperfusion (IIR) injury. Rats were randomized into control, control+VIP, IIR and IIR+VIP groups. The observation of mesenteric lymph flow was carried out by cannulation of mesenteric lymphatics. The distribution of in vivo lymphocyte trafficking was performed by (51)Cr labeled lymphocytes and was measured by γ-counter. Endotoxin concentration was assayed using the limulus test kit and TNF-α level was detected by ELISA. When IIR injury treated with VIP, the volumes of lymph flow increased by 80%, which caused the number of lymphocytes exiting in mesenteric lymphatic increased by 50% while the proportion of (51)Cr-lymphocytes in Peyer's patches, intestinal effector tissues, mesenteric nodes, large intestine, stomach decreased by 58%, 51%, 58%, 63%, 64% respectively at the 6th h after reperfusion following intestinal ischemia. Meanwhile, endotoxin and TNF-α levels in intestinal lymph decreased by 51% and 83%. These results suggest that exogenous VIP ameliorates IIR induced splanchnic organ damage via inhibition of toxic mediators reaching systemic circulation and reinforcement of the effective immune responses in gut-associated lymphoid tissues (GALT).

Topics: Animals; Cell Movement; Drug Evaluation, Preclinical; Endotoxins; Ileum; Lymph; Lymphatic Vessels; Lymphocyte Count; Lymphocytes; Male; Mesenteric Arteries; Mesenteric Vascular Occlusion; Rats; Rats, Wistar; Reperfusion Injury; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Cardiac function is regulated by a balance of sympathetic and parasympathetic transmission. Neuropeptide Y (NPY) and galanin (GAL) released from cardiac sympathetic neurons inhibits parasympathetic transmission in the heart. Sympathetic peptides may contribute to autonomic imbalance, which is characterized by increased sympathetic and decreased parasympathetic transmission and contributes to life threatening cardiovascular pathologies. Several gp130 cytokines are increased in the heart after myocardial infarction (MI), and these cytokines stimulate neuropeptide expression in sympathetic neurons. We used mice whose sympathetic neurons lack the gp130 receptor (gp130(DBH-Cre/lox) mice) to ask if cytokine activation of gp130 regulated neuropeptide expression in cardiac sympathetic nerves after MI. Myocardial infarction decreased NPY mRNA through a gp130 independent mechanism and increased VIP and PACAP mRNA via gp130, while GAL mRNA was unchanged. Immunohistochemistry revealed a gp130-dependent increase in PACAP38 in cells of the stellate ganglion after MI, and PACAP was detected in pre-ganglionic fibers of all genotypes and surgical groups. VIP was identified in a few sympathetic nerve fibers in all genotypes and surgical groups. GAL and PACAP38 were not detected in sham hearts, but peptide immunoreactivity was high in the infarct three days after MI. Surprisingly, peptides were abundant in cells that co-labeled with macrophage markers F4/80 and MAC2, but were not detected in sympathetic axons. PACAP protects cardiac myocytes from apoptosis, and GAL stimulates axon regeneration in addition to inhibiting parasympathetic transmission. Thus, these peptides may play an important role in cardiac and neuronal remodeling after ischemia-reperfusion.

Topics: Animals; Cytokine Receptor gp130; Galanin; Heart; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Ischemia; Myocardium; Neuropeptide Y; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Reperfusion Injury; Sympathetic Nervous System; Vasoactive Intestinal Peptide

Toll-like receptor 4 (TLR4) has attracted a great deal of attention in ischemia-reperfusion (IR) injury in recent years. Vasoactive intestinal peptide (VIP) plays an important role in anti-inflammatory and immunomodulatory activity in several animal models. There are no data available regarding the effect of VIP on TLR4 expression in IR injury in vivo. In the present study, we study the effect of VIP on TLR4 expression in mouse macrophage cell line RAW 264.7 and a mouse partial IR model.. The potential inhibitory effect of VIP on TLR4 mRNA and protein in a mouse macrophage cell line and in a mouse model of partial warm hepatic IR injury was assessed. We also assessed the expression tumor necrosis factor (TNF)-α and interleukin (IL)-6 in this model.. Expression of TLR4 mRNA levels was significantly decreased at 6, 12, and 24 hours after treat with VIP in mouse macrophage cell line RAW 264.7. Expression of TLR4 mRNA, TLR4 protein, alanine aminotransferase, TNF-α, and IL-6 levels were significantly increased in the IR group but significantly decreased in groups pretreated with VIP at a concentration of 5 and 10 nmol. Hematoxylin and eosin staining show apparent edema and necrosis were observed in the IR group, but in the VIP pretreatment group, edema and necrosis in IR modes were reduced.. This study showed that VIP might inhibit TLR4 in vitro and in vivo, and pretreatment with VIP might inhibited TLR4 activation and reduced warm IR injury.

Topics: Alanine Transaminase; Animals; Base Sequence; Blotting, Western; Cell Line; DNA Primers; Immunohistochemistry; Interleukin-6; Liver; Male; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Reperfusion Injury; RNA, Messenger; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

The T cell activation Ag CD26/dipeptidylpeptidase IV (DPP IV) combines co-stimulatory and enzymatic properties. Catalytically, it functions as an exopeptidase, modulating biological activity of key chemokines and peptides. Here we investigated the effect of organ-specific inhibition of DPP IV catalytic activity on ischemia/reperfusion injury after extended ischemia in the mouse model of orthotopic single lung transplantation. C57BL/6 mice were syngeneically, transplanted, grafts were perfused and stored in Perfadex with (treated) or without (control) a DPP IV enzymatic activity inhibitor (AB192). Transplantation was performed after 18h cold ischemia time; following 2-h reperfusion, grafts were analyzed for oxygenation, thiobarbituric acid-reactive substances, histomorphology, and immunohistochemistry was performed for leukocyte Ag 6, myeloperoxidase, hemoxygenase 1, vasoactive intestinal protein (VIP), and real-time PCR for VIP. Treatment with the DPP IV inhibitor AB192 resulted in significant improvement of gas exchange, less lipid oxidation, preservation of parenchymal ultrastructure, reduced neutrophil infiltration, reduced myeloperoxidase expression, increased hemoxygenase 1 expression, pronounced expression of VIP in alveolar macrophages and increased mRNA expression of VIP. Inhibition of intragraft DPP IV catalytic activity with AB192 strikingly ameliorates ischemia/reperfusion injury after extended ischemia. Furthermore, preservation of endogenous intragraft VIP levels correlate with maintaining lung function and structural integrity.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Heme Oxygenase-1; Lung; Lung Transplantation; Male; Mice; Mice, Inbred C57BL; Organophosphonates; Proline; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Transplantation, Homologous; Vasoactive Intestinal Peptide

The inhibitory effect of different reperfusion periods 45 min following hepatic ischemia on the expression of cholecystokinin (CCK) and vasoactive intestinal peptide (VIP) in the jejunum and the effect of salvia miltiorrhiza pretreatment were investigated, and the possible mechanism and implications were explored. Eighty rats were randomly divided into four groups: normal control group (CO group), sham-operated group (SO group), ischemia/reperfusion (I/R) injury group (IR group) and salvia miltiorrhiza pretreatment group (SM group). The rat model of I/R was established by using a non-invasive artery clamp to clip (45 min) or relax the hepatic pedicle. In the SM group, saline (40 mL/kg) and salvia miltiorrhiza injection (6 g/kg) were injected via the tail vein 30 min before clipping the hepatic pedicle. In the SO group only the porta hepatis was dissected after laparotomy without clamping the hepatic pedicle. At 0, 3, 12, 24 and 72 h post-reperfusion, respectively, upper jejunum samples were taken for immunohistochemistry of CCK and VIP. It was found that 0 h after I/R, the expression of CCK and VIP in the upper jejunum was upregulated. With prolongation of the reperfusion period, the expression of CCK and VIP was also increased, reached the peak at the 24th h, and gradually returned to the normal level at the 72nd h after reperfusion. The levels of both CCK and VIP in the SM group were lower than those in the IR group. It is suggested that the digestive tract congestion injury caused by liver ischemia can upregulate the expression of CCK and VIP in the jejunum following reperfusion. Salviae pretreatment can partly reduce the increased expression of CCK and VIP in the jejunum in the same period, which might contribute to the early recovery of gastrointestinal motility.

Topics: Animals; Cholecystokinin; Gastrointestinal Motility; Intestinal Mucosa; Jejunum; Liver; Liver Diseases; Phytotherapy; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Salvia miltiorrhiza; Vasoactive Intestinal Peptide

Enzymatic activity inhibition of CD26/dipeptidylpeptidase IV (CD26/DPP IV) attenuated short-term post-Tx (transplantation) ischemia-reperfusion injury after 18-hr-ischemia. Here, we investigated the effect of intragraft CD26/DPP IV catalytic inhibition on primary graft dysfunction during 7 day post-Tx, following extended ischemia.. A syngeneic rat (LEW [Lewis abstract]) orthotopic lung Tx model was used, grafts exposed to 18 hr cold ischemia before Tx. Controls were flushed and preserved in Perfadex, and harvested after 1 day (CON1) or 7 day (CON7) post-Tx. Investigational groups IN1, IN3, and IN7 grafts were perfused with and stored in Perfadex + inhibitor (AB192) and harvested at 1, 3, and 7 days post-Tx, respectively. Blood gas analysis, peak airway pressure (PAwP), wet/dry weight ratio, myeloperoxidase thiobarbituric acid reactive substances (TBARS), and staining for vasoactive intestinal peptide (VIP) were analyzed.. IN1 versus CON1 showed preserved histology, increased pO2 (P<0.01), lowered PAwP (P<0.01), less edema (P<0.05) and decreased TBARS (P<0.05). Survival was better for IN7 versus CON7 (P<0.01). The course of AB192-perfused grafts from 1 to 7 days displayed improved values for pO2 (P<0.01), PAwP (P<0.01), edema (P<0.05), TBARS (P<0.05), and myeloperoxidase (P<0.05). Compared with controls, VIP was preserved during 18 hr ischemia in alveolar macrophages (P=0.0001) and respiratory epithelial cells (P=0.001).. Perfusion with an inhibitor of CD26/DPP IV enzymatic activity significantly reduced the incidence and severity of pulmonary primary graft dysfunction and enabled recovery after extended ischemia. This is the first report that CD26/DPPIV inhibitor treatment increases local pulmonary VIP levels, which correlate with preserved ventilatory function and pulmonary structural integrity.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Follow-Up Studies; Graft Survival; Heparin; Lung Transplantation; Melatonin; Perfusion; Peroxidase; Rats; Rats, Inbred Lew; Reperfusion Injury; Survival Analysis; Thiobarbituric Acid Reactive Substances; Transplantation, Isogeneic; Vasoactive Intestinal Peptide

Intestinal ischemia as well as mastocytosis occur in patients with inflammatory bowel disease and irritable bowel syndrome. Our aim was to clarify how ischemia with reperfusion (I/R) affects the structure, enteric neurons, and immune cells in the colon. Rats were subjected to colon ischemia for 1 h and reperfused for 1 day up to 20 weeks; sham-operated rats were used as controls. No structural remodeling of the intestinal segment was detected after I/R. The number and distribution of eosinophils were not affected by I/R. Local areas containing numerous mast cells were detected in the muscle layers, the serosa, and in and around the myenteric ganglia 4-20 weeks post ischemia. It was notable that myenteric ganglionic formations within mast-cell-rich areas virtually lacked neurons. Mast cells were rarely found in controls. In conclusion, I/R of the colon attracts mast cells, and death of myenteric neurons occurs in such locations.

Topics: Animals; Cell Death; Cell Movement; Colon; Disease Models, Animal; Enteric Nervous System; Eosinophils; Female; Gastrointestinal Tract; Mast Cells; Muscle, Smooth; Neurons; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors; Vasoactive Intestinal Peptide

Alterations in microvascular perfusion of the intestine after hepatic ischemia/reperfusion have been suggested as an important cause of postoperative septic complications. We therefore investigated small bowel microcirculation and mucosal injury after liver ischemia/reperfusion in a rat model. Furthermore, we analyzed the effects of the regulatory peptides vasoactive intestinal polypeptide and gastrin-releasing peptide for their splanchnic vasoactivity.. Hepatic ischemia was induced by clamping of the left hepatic artery and vein for 40 min, followed by 60 min of reperfusion. The control group was treated similarly, but without clamping of the liver vessels. Ten minutes after clamping of the hepatic vessels, vasoactive intestinal polypeptide or gastrin-releasing peptide, respectively, were continuously infused intravenously in the experimental groups. Small bowel microcirculation and mucosal injury were assessed using intravital microscopy and the Chiu-score, respectively.. The functional capillary density of the small intestine following ischemia and reperfusion of the left hepatic lobe significantly decreased compared to normal controls in both the mucosa and the smooth intestinal muscle. Red blood cell velocity decreased, whereas leukocyte-endothelium adherence, stasis index and the mucosal injury score increased. Administration of vasoactive intestinal polypeptide resulted in an increase of functional capillary density in the mucosa and of the red blood cell velocity and a decrease in the stasis index. The mucosal injury score was significantly higher in reperfused animals without treatment. The application of gastrin-releasing peptide resulted in an isolated increase of the red blood cell velocity. Leukocyte adherences could not be altered by the regulatory peptides.. We conclude that hepatic ischemia/reperfusion injury leads to significant alterations of small bowel microcirculation and mucosal injury. Vasoactive intestinal polypeptide and gastrin-releasing peptide attenuate the damage in a different manner.

Topics: Animals; Gastrin-Releasing Peptide; Hepatic Artery; Intestinal Mucosa; Intestine, Small; Liver; Male; Microcirculation; Rats; Rats, Wistar; Regional Blood Flow; Reperfusion Injury; Vasoactive Intestinal Peptide

Intestinal ischemia impairs gastrointestinal motility. The aims of this study were to investigate the effect of intestinal ischemia on gastrointestinal transit and on the expression of enteric transmitters in the rat, and whether the glutamate N-methyl-d-aspartate receptors influence these effects. Ischemia (1 h), induced by occluding the superior mesenteric artery, was followed by 0 or 24 h of reperfusion. Normal and sham-operated rats served as controls. Serosal blood flow was measured with laser Doppler flow meter. Gastrointestinal transit was measured as time of appearance of a marker in fecal pellets. Immunohistochemistry was used to evaluate the number of neurons immunoreactive for neuronal nitric oxide synthase (NOS) or vasoactive intestinal polypeptide and the density of substance P immunoreactive fibers in the myenteric plexus. The N-methyl-d-aspartate receptors antagonist, (+)-5-methyl-10,11-dihydro-5HT-[a,b] cyclohepten-5,10-imine (MK-801) (1 mg/kg i.v.) or the NOS inhibitor, N-nitro-l-arginine (10 mg/kg i.v.) was administered prior to ischemia. Serosal blood flow was decreased by 70% during ischemia, but it was not altered in sham-operated rats. Gastrointestinal transit was significantly prolonged in ischemic/reperfused rats compared with controls. There was a significant increase in the number of vasoactive intestinal polypeptide and neuronal nitric oxide synthase immunoreactive neurons, and a marked decrease of substance P immunoreactive fibers in ischemia followed by 24 h of reperfusion animals compared with controls. These alterations were not observed in ischemia without reperfusion. A significant delay of gastrointestinal transit and increase of vasoactive intestinal polypeptide neurons were also observed in sham-operated rats. The changes in transmitter expression and gastrointestinal transit in ischemic/reperfused rats were prevented by pre-treatment with the NOS inhibitor, N-nitro-l-arginine or the N-methyl-d-aspartate receptors antagonist, MK-801. This study suggests an involvement of the glutamatergic system and its interaction with nitric oxide in intestinal ischemia/reperfusion. Ischemia/reperfusion might induce local release of glutamate that activates N-methyl-d-aspartate receptors leading to increased production of nitric oxide and adaptive changes in enteric transmitters that might contribute to gastrointestinal dysmotility.

Topics: Analysis of Variance; Animals; Arginine; Dizocilpine Maleate; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Gastrointestinal Motility; Gastrointestinal Transit; Immunohistochemistry; Ischemia; Laser-Doppler Flowmetry; Male; Neural Inhibition; Neuronal Plasticity; NG-Nitroarginine Methyl Ester; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Reperfusion Injury; Time Factors; Vasoactive Intestinal Peptide

To elucidate the action of vasoactive intestinal peptide (VIP) on detorsion injury and the heterogeneity of mast cells in the testes of rats.. Prepubertal male Sprague-Dawley rats were used in six groups. Group 1 was the control group (sham operation); group 2 had 2 hours of torsion; group 3, 2 hours of torsion and 1 hour of detorsion after administration of saline; group 4 had 2 hours of torsion and 4 hours of detorsion after administration of saline; group 5, 2 hours of torsion and 1 hour of detorsion after administration of intraperitoneal VIP (25 ng/kg); and group 6, 2 hours of torsion and 4 hours of detorsion after intraperitoneal VIP. The 2 hours of torsion was created by rotating the right testis 720 degrees in a clockwise direction. VIP (25 ng/kg) was injected intraperitoneally 1 minute before the 1 and 4 hours of detorsion. At the end of the experiment, catalase enzyme activity was measured polarographically, and superoxide dismutase, malondialdehyde, and protein were measured spectrophotometrically. Nitric oxide was measured by capillary electrophoresis in the testicular tissue. Routine histologic examination of testicular mast cells was done under light microscopy; the histochemistry was also analyzed.. Torsion significantly induced oxidative stress, mast cell degranulation, and tissue damage. Detorsion attenuated oxidative stress without any diminution of the histologic damage to the tissue. VIP significantly protected the testicular tissue from detorsion injury. It also inhibited mast cell activity while increasing the heparin content.. VIP can protect testicular tissue from detorsion injury. Heparin-containing mast cells seem to be important mediator cells for this protection.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Catalase; Cytoplasmic Granules; Drug Evaluation, Preclinical; Heparin; Injections, Intraperitoneal; Male; Malondialdehyde; Mast Cells; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spermatic Cord Torsion; Superoxide Dismutase; Testis; Vasoactive Intestinal Peptide

In addition to the primarily affected small bowel, intestinal ischemia and reperfusion (IIR) also leads to a marked decrease in hepatic microcirculation. The aim was to determine the potentially protective effect of the vasoactive hormones vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP) on hepatic microcirculation following IIR.. Using a rat model, three animal groups were subjected to 40 min of intestinal ischemia, two of which were infused with either VIP or GRP (n = 12 each). Following reperfusion, hepatic intravital microscopy was performed. Portal venous perfusion, activities of serum glutamate pyruvate transaminase and alkaline phosphatase, mucosal injury in the small intestine and the expression of antioxidant enzymes glutathione peroxidase, copper-zinc-superoxide dismutase (Cu-Zn-SOD), glutathione reductase and catalase (CAT) in the liver were investigated.. Infusion of either VIP or GRP improved hepatic microcirculation and bile flow when compared with the untreated IIR group. VIP and GRP increased portal venous blood flow during reperfusion. VIP reduced the extent of mucosal damage resulting from IIR. GRP caused a decrease in expression of CAT and Cu-Zn-SOD, whereas VIP simply reduced CAT expression.. This study indicates that vasoactive hormones may attenuate intestinal and hepatic injuries and circulatory disturbances following IIR.

Topics: Animals; Gastrin-Releasing Peptide; Intestinal Mucosa; Intestines; Liver; Male; Microcirculation; Microscopy, Fluorescence; Rats; Rats, Wistar; Reperfusion Injury; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) was tested for its capability to protect the intrinsic nerves of guinea-pig urinary bladder from damage due to anoxia/glucopenia and reperfusion. Guinea-pig detrusor strips were mounted for tension recording in small organ baths and the nerves were subjected to electric field stimulation. VIP (0.3 microM) improved significantly the response of strips to electrical field stimulation either during anoxia/glucopenia or thereafter during reperfusion, as compared to untreated tissues. The antioxidant activity of VIP assessed as its capability to scavenge peroxyl radicals during linoleic acid oxidation corresponded to 6.42+/-0.13 pIC(50) M, i.e. close to the concentration proved to protect strips against the anoxic--glucopenic and reperfusion damage.

Topics: Animals; Dose-Response Relationship, Drug; Electric Stimulation; Female; Free Radical Scavengers; Glucose; Guinea Pigs; Hypoxia; In Vitro Techniques; Lipid Peroxidation; Male; Muscle Contraction; Muscle, Smooth; Peroxides; Reperfusion Injury; Urinary Bladder; Vasoactive Intestinal Peptide

To explore the main pathogenic factors in the development of neuronal death during normothermic reperfusion in rabbits.. Ninety-six New Zealand rabbits were randomly allocated into two groups: group I served as non-ischemic controls; group II served as postischemic normothermic reperfusion models. Complete cerebral ischemia was induced by the four-vessel model for 30 minutes. After ischemia, rabbits in group II were further divided into three subgroups according to the duration of reperfusion: subgroup A, 30 minutes; subgroup B, 180 minutes and subgroup C, 360 minutes. Twenty-eight biochemical parameters in the brain were measured, and neuronal changes were observed by histomorphological assessment. Neurons of 12 regions were differentiated into four types: type A (normal), type B (mildly damaged), type C (severely damaged) and type D (necrotic). Bivariate correlate analysis between the levels of biochemical parameters and the percentages of each type of neurons was carried out.. The main parameters involved in the progressive decrement of type A neurons were VIP, beta-EP, PGI2, T3, T4 and Na+, K(+)-ATPase; in the increment of type B were beta-EP and TXB2; in the increment of type C were GLU and TXB2/PGI2 respectively; in the stepwise increment of percentages of type D neurons were T4, Na+, K(+)-ATPase, GLU, T3 and VIP (P < 0.05).. The main factors involved in the development of neuronal death during postischemic normothermic reperfusion in rabbits include hypermetabolism, deactivation of Na+, K(+)-ATPase, release of excitatory amino acids and disorder of neuropeptides.

Topics: Animals; beta-Endorphin; Brain Ischemia; Cell Death; Female; Male; Neurons; Rabbits; Random Allocation; Reperfusion Injury; Sodium-Potassium-Exchanging ATPase; Thromboxane B2; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) has been reported to have some properties that provide protection from lung injury. Furthermore, its protective effect in cold storage of donor lungs has been confirmed. We examined its effect and the timing of administration in an in vivo rat lung transplantation model.. All lungs were flushed with low-potassium dextran-1% glucose solution, and orthotopic left lung transplantations were performed. Rats were divided into four groups (n = 6). Group I received no preservation or storage. Groups II, III, and IV grafts were stored for 18 hours at 4 degrees C. Group II received no VIP. Group III received VIP (0.1 g/ml) via the flush solution. Group IV recipients received VIP (3 microg/kg) intravenously just after reperfusion. Twenty-four hours after transplantation, the right main pulmonary artery and right main bronchus were ligated, and the rats were ventilated with 100% O2 for 5 minutes. Mean pulmonary arterial pressure, peak airway pressure, blood gas analysis, serum lipid peroxide level, tissue myeloperoxidase activity, and wet-dry weight ratio were measured.. The partial O2 tension values of groups III and IV were better than group II (groups II, III, and IV: 147.4 +/- 71.4, 402.1 +/- 64.8, 373.4 +/- 81.0 mm Hg; p < 0.05). Peak airway pressure was lower in groups III and IV than in group II (groups II, III, and IV: 19.7 +/- 0.8, 16.7 +/- 0.9. and 16.3 +/- 1.0 mm Hg; p < 0.05). Mean pulmonary arterial pressure in group III was lower than group II (groups II and III: 36.3 +/- 3.0 and 22.1 +/- 2.2 mm Hg; p < 0.01). Wet-dry weight ratio in group III was lower than in groups II and IV (group II, III, and IV: 5.2 +/- 0.2, 4.4 +/- 0.2, and 5.2 +/- 0.3; II vs III; p < 0.05, III vs IV; p < 0.01). Serum lipid peroxide levels in groups III and IV were significantly lower (groups II, III, and IV: 2.643 +/- 0.913, 0.455 +/- 0.147, and 0.325 +/- 0.124 nmol/ml; p < 0.01).. VIP ameliorates reperfusion injury in an in vivo rat lung transplantation model. Either administration of VIP via the flush solution or systemically just after reperfusion was associated with improved pulmonary function.

Topics: Airway Resistance; Animals; Blood Pressure; Lung; Lung Transplantation; Male; Organ Preservation; Oxygen; Peroxidase; Pulmonary Artery; Rats; Rats, Inbred F344; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Vasoactive Intestinal Peptide

Infrarenal aortic cross-clamping is associated with remote vascular events, including myocardial infarction and renal insufficiency. The purpose of this study was to determine whether hindlimb ischaemia and reperfusion associated with infrarenal aortic cross-clamping results in the production of vasoactive regulatory neuropeptides. A canine model of infrarenal aortic cross-clamping was used for the study. Serial blood samples were drawn, prior to, at the time of, and serially following placement of the clamp and subsequent release of the clamp and reperfusion. Ischaemia resulted in increased mean(s.e.m.) plasma levels of neuropeptide Y (NPY) (initial 10.0(1.8) pmol/l versus ischaemia 24.7(2.3) pmol/l, P < 0.001) and vasoactive intestinal polypeptide (VIP) (initial 2.53(0.5) pmol/l versus ischaemia, 7.3(1.3) pmol/l, P < 0.05). Reperfusion produced three-fold elevation of VIP (initial 2.5(0.5) pmol/l versus reperfusion 9.6(1.5) pmol/l, P < 0.001), two-fold elevation in the plasma levels of endothelin-1 (initial 1.3(0.1) pmol/l versus reperfusion maximum 2.5(0.3) pmol/l, P < 0.01) and NPY (initial 10.0(0.8) pmol/l versus reperfusion maximum 23.9(2.3) pmol/l, P < 0.001). Ischaemia and reperfusion did not alter calcitonin gene-related peptide (CGRP) (a potent vasodilator) levels. Endothelin-1 (ET-1) plasma levels were also increased following haemorrhagic shock (initial 1.3(0.1) pmol/l versus exsanguination 3.4(0.4) pmol/l, P < 0.001), but not during ischaemia (initial 1.3(0.1) pmol/l versus ischaemia maximum 1.7(0.2) pmol/l, P = 0.7). It was concluded that vasoactive regulatory peptides are released following ischaemia, reperfusion and shock in the canine infrarenal aortic revascularization model and, therefore could contribute to remote vascular events observed with infrarenal aortic cross-clamping.

Topics: Animals; Aorta, Abdominal; Calcitonin Gene-Related Peptide; Dogs; Endothelin-1; Female; Ischemia; Leg; Male; Neuropeptide Y; Radioimmunoassay; Reference Values; Reperfusion Injury; Vasoactive Intestinal Peptide

Topics: Animals; Catalase; Choroid; Female; Ischemia; Lipid Peroxidation; Male; Malondialdehyde; Rats; Reperfusion Injury; Retina; Retinal Vessels; Superoxide Dismutase; Vasoactive Intestinal Peptide