Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
Br J Pharmacol ; 155(1): 93-102, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18536753

ABSTRACT

BACKGROUND AND PURPOSE: Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen-derived radicals and proteases causing damage. EXPERIMENTAL APPROACH: We studied the serine protease inhibitor aprotinin in an in vivo rabbit model of 1 h of myocardial ischaemia followed by 3 h of reperfusion (MI+R). Aprotinin (10,000 Ukg(-1)) or its vehicle were injected 5 min prior to the start of reperfusion. KEY RESULTS: Myocardial injury was significantly reduced with aprotinin treatment as indicated by a reduced necrotic area (11+/-2.7% necrosis as percentage of area at risk after aprotinin; 24+/-3.1% after vehicle; P<0.05) and plasma creatine kinase activity (12.2+/-1.5 and 17.3+/-2.3 IU g(-1) protein in aprotinin and vehicle groups, respectively, P<0.05). PMN infiltration (assessed by myeloperoxidase activity) was significantly decreased in aprotinin-treated animals compared to vehicle (P<0.01). Histological analysis also revealed a substantial increase in PMN infiltration following MI+R and this was significantly reduced by aprotinin therapy (44+/-15 vs 102+/-2 PMN mm2 in aprotinin vs vehicle-treated animals, P<0.05). In parallel in vitro experiments, aprotinin inhibited neutrophil-endothelium interaction by reducing PMN adhesion on isolated, activated aortic endothelium. Finally, immunohistochemical analysis illustrated aprotinin significantly reduced myocardial apoptosis following MI+R. CONCLUSIONS AND IMPLICATIONS: Inhibition of serine proteases by aprotinin inhibits an inflammatory cascade initiated by MI+R. The cardioprotective effect appears to be at least partly due to reduced PMN adhesion and infiltration with subsequently reduced myocardial necrosis and apoptosis.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Aprotinin/pharmacology , Myocardial Reperfusion Injury/prevention & control , Myocardium/immunology , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Serine Proteinase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Cell Adhesion/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Endothelial Cells/immunology , Hemodynamics/drug effects , Leukocyte Count , Male , Myocardial Reperfusion Injury/immunology , Myocardial Reperfusion Injury/physiopathology , Myocardium/pathology , Necrosis , Neutrophils/immunology , Rabbits , Time Factors
2.
Br J Pharmacol ; 153(8): 1678-85, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18332863

ABSTRACT

BACKGROUND AND PURPOSE: The Na(+)/H(+) exchange (NHE) inhibitor cariporide is known to ameliorate ischaemia/reperfusion (I/R) injury by reduction of cytosolic Ca(2+) overload. Leukocyte activation and infiltration also mediates I/R injury but whether cariporide reduces I/R injury by affecting leukocyte activation is unknown. We studied the effect of cariporide on thrombin and I/R induced leukocyte activation and infiltration models and examined P-selectin expression as a potential mechanism for any identified effects. EXPERIMENTAL APPROACH: An in vivo rat mesenteric microcirculation microscopy model was used with stimulation by thrombin (0.5 micro ml(-1)) superfusion or ischaemia (by haemorrhagic shock for 60 min) and reperfusion (90 min). KEY RESULTS: Treatment with cariporide (10 mg kg(-1) i.v.) significantly reduced leukocyte rolling, adhesion and extravasation after thrombin exposure. Similarly, cariporide reduced leukocyte rolling (54+/-6.2 to 2.4+/-1.0 cells min(-1), P<0.01), adherence (6.3+/-1.9 to 1.2+/-0.4 cells 100 microm(-1), P<0.01) and extravasation (9.1+/-2.1 to 2.4+/-1.1 cells per 20 x 100 microm perivascular space, P<0.05), following haemorrhagic shock induced systemic ischaemia and reperfusion. The cell adhesion molecule P-selectin showed a profound decrease in endothelial expression following cariporide administration in both thrombin and I/R stimulated groups (35.4+/-3.2 vs 14.2+/-4.1% P-selectin positive cells per tissue section, P<0.01). CONCLUSIONS AND IMPLICATIONS: The NHE inhibitor cariporide is known to limit reperfusion injury by controlling Ca(2+) overload but these data are novel evidence for a vasculoprotective effect of NHE inhibition at all levels of leukocyte activation, an effect which is likely to be mediated at least in part by a reduction of P-selectin expression.


Subject(s)
Guanidines/pharmacology , Inflammation/physiopathology , P-Selectin/drug effects , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sulfones/pharmacology , Animals , Calcium/metabolism , Cell Adhesion/drug effects , Disease Models, Animal , Leukocyte Rolling/drug effects , Leukocytes/drug effects , Leukocytes/metabolism , Male , Mesentery/blood supply , Microcirculation/metabolism , Microscopy , P-Selectin/metabolism , Rats , Rats, Sprague-Dawley , Reperfusion Injury/drug therapy , Reperfusion Injury/physiopathology
3.
Cardiovasc Surg ; 11(1): 70-4, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12543576

ABSTRACT

PURPOSE: For treatment of univentricular heart, the Fontan operation has been established as the definitive palliation. The current controversy is mainly based on the high incidence of arrhythmias after an intra-atrial lateral tunnel Fontan operation. METHODS: From January 1995 until April 2002, 46 children underwent a Fontan-type operation with or without a small fenestration. In 33 patients (group I) an intracardiac tunnel and in 13 patients (group II) an extracardiac conduit procedure was performed. PRINCIPAL FINDINGS: There was no perioperative mortality. All patients showed postoperative a significant increase of arterial oxygen saturation, from 76 to 86% after surgery with fenestration, or to 90.5% without fenestration respectively. In patients with fenestration procedure, the saturation rose to 90% after closure of fenestrations 9 to 12 months after operation. CONCLUSIONS: Modified Fontan operations can be performed in normothermia on the beating heart with acceptable mortality. The extracardiac conduit Fontan procedure has the benefits of less surgical injury and a higher intraoperative flexibility.


Subject(s)
Fontan Procedure/methods , Heart Defects, Congenital/surgery , Adolescent , Adult , Cardiopulmonary Bypass , Child , Child, Preschool , Female , Follow-Up Studies , Fontan Procedure/adverse effects , Humans , Infant , Intraoperative Period , Male , Oxygen/blood
4.
J Heart Valve Dis ; 10(3): 410-4, 2001 May.
Article in English | MEDLINE | ID: mdl-11380110

ABSTRACT

BACKGROUND AND AIM OF THE STUDY: Magnetic resonance (MR) imaging is used in an increasing number of patients, and not only after cardiac valve replacement. However, ferromagnetic biomedical implants are often considered a contraindication for MR imaging because of the potential hazards with respect to their movement, dislodgement, or heating effects during the procedure. The purpose of this study was to assess ferromagnetism, attraction forces, heating effects, and artifacts associated with prosthetic heart valve implants. METHODS: Seventeen common heart valve prostheses (12 mechanical, five biological) were examined in vitro using a high-field-strength 1.5 Tesla (T) MR system. Attractive forces, temperature changes and the amount of artifacts were assessed by applying turbo-spin and gradient-echo sequences. RESULTS: The maximal calculated corresponding ferromagnetic force was (0.22 x 10(-3) N) in the static magnetic field. The temperature changes ranged from 0 to 0.5 degrees C maximum. Artifacts produced by the presence of the heart valve prostheses were less evident using a spin-echo sequence than a gradient-echo sequence. CONCLUSION: MR imaging exerted no significant force on the examined heart valve prostheses, and did not result in significant biological relevant temperature increase. None of the associated artifacts is considered to pose a substantial risk on MR imaging. MR procedures performed with a 1.5 T MR system can be applied safely in patients with heart valve prostheses evaluated in this study.


Subject(s)
Bioprosthesis , Heart Valve Diseases/pathology , Heart Valve Diseases/surgery , Heart Valve Prosthesis , Magnetic Resonance Imaging , Materials Testing , Artifacts , Ferric Compounds , Hot Temperature , In Vitro Techniques , Prosthesis Design , Stress, Mechanical
5.
J Leukoc Biol ; 67(1): 26-33, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10647994

ABSTRACT

A novel synthetic phosphorothioate analog of oleoyl lysophosphatidic acid LXR-1035 was studied for its ability to modulate leukocyte-endothelial cell interactions using intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME elicited a significant, time-dependent increase in leukocyte rolling, adherence, and transmigration compared to control rats superfused with Krebs-Henseleit solution. However, superfusion of the rat mesentery with 300 nM LXR-1035 consistently attenuated 65-87% of the L-NAME-induced leukocyte rolling, adherence, and transmigration, without altering systemic blood pressure or mesenteric venular shear rate. Similar results were also obtained in rats subjected to 90 min of hemorrhage followed by 90 min of reperfusion. Resuscitation from hemorrhage increased significantly the number of rolling, adherent, and transmigrated leukocytes in the rat mesenteric microcirculation. However, superfusion of the rat mesentery with LXR-1035 markedly attenuated the leukocyte-endothelium interaction occurring after hemorrhage and reinfusion by 75+/-12%. Immunohistochemical localization of P-selectin expression on mesenteric venular endothelium was significantly increased after exposure to L-NAME and after hemorrhage-reinfusion, which was significantly attenuated by LXR-1035 (P<0.05). In addition, treatment of isolated rat neutrophils with 300 nM LXR-1035 significantly attenuated leukotriene B4-induced up-regulation of CD18 (P<0.05). Our data clearly demonstrate that LXR-1035 can potently inhibit the recruitment of leukocytes in the mesenteric rat microvasculature by attenuating cell-surface expression of adhesion molecules.


Subject(s)
Cell Adhesion Molecules/metabolism , Endothelium, Vascular/pathology , Leukocytes/pathology , Lysophospholipids/pharmacology , Animals , Cell Adhesion/drug effects , Endothelium, Vascular/metabolism , Leukocytes/metabolism , Lysophospholipids/chemistry , Male , Mesentery/blood supply , Rats , Rats, Sprague-Dawley , Venules/pathology
6.
Arterioscler Thromb Vasc Biol ; 19(12): 2894-900, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10591666

ABSTRACT

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert beneficial effects in coronary artery and cerebrovascular diseases. We examined the effects of simvastatin on leukocyte-endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 microg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) significantly increased leukocyte rolling from 12+/-2 to 60+/-8 leukocytes per minute, increased adherence to the mesenteric endothelium from 1.8+/-0.5 to 17+/-1.2 leukocytes per 100 microm of venular length, and raised leukocyte transmigration from 2.5+/-1.0 to 10+/-2 leukocytes per perivessel area (P<0.01). Similar results were obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with simvastatin (25 microg per rat IP) significantly attenuated L-NAME-stimulated leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100 microm (P<0.01); and leukocyte transmigration, to 3.5+/-1.5 leukocytes per perivessel area (P<0.01). Similar results were obtained in thrombin-superfused mesenteries. Moreover, immunohistochemical analysis demonstrated significantly increased P-selectin expression on the mesenteric venular endothelium after superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was significantly attenuated by simvastatin. These results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte-endothelial cell interactions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selectin expression on the microvascular endothelium. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects besides their well-known lipid-lowering action.


Subject(s)
Anticholesteremic Agents/pharmacology , Endothelium, Vascular/cytology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Leukocytes/cytology , Simvastatin/pharmacology , Vasculitis/drug therapy , Animals , Blood Pressure , Cell Communication/drug effects , Cell Movement/immunology , Cholesterol/blood , Endothelium, Vascular/immunology , Endothelium, Vascular/metabolism , Enzyme Inhibitors/pharmacology , Glucose/pharmacology , Hemostatics/pharmacology , Leukocytes/immunology , Male , Mesenteric Veins/cytology , Mesenteric Veins/immunology , Microscopy/methods , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , P-Selectin/analysis , P-Selectin/metabolism , Rats , Rats, Sprague-Dawley , Thrombin/pharmacology , Tromethamine/pharmacology , Vasculitis/immunology , Vasculitis/metabolism , Venules/chemistry , Venules/cytology , Venules/metabolism
7.
Gen Pharmacol ; 33(6): 487-98, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10647774

ABSTRACT

Recent evidence indicates that chronic hyperhomocysteinemia, which is found in from 9 to 15% of the general population, is an independent risk factor for the development of atherosclerosis. We sought to elucidate the mechanism by which exposure of the vascular wall to high levels of homocysteine initiates this inflammatory reaction. We examined the acute effect of homocysteine on endothelial dysfunction in isolated rat arteries and on microcirculatory leukocyte-endothelium interaction in vivo. Intravital microscopy of rat mesenteric venules was performed by superfusing the mesentery with increasing concentrations of homocysteine (1-5 mmol/l). There was a significant concentration- and time-dependent increase in leukocyte rolling, adherence, and extravasation compared with control rats superfused with Krebs-Henseleit solution (p < 0.01). Moreover, immunohistochemical staining demonstrated significantly increased P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression on intestinal venules after homocysteine superfusion. In contrast, mesenteric superfusion with the nitric oxide donor 4-hydroxymethyl-furazan-3-carboxylic acid oxide (CAS1609, 1 micromol/l) significantly attenuated homocysteine-induced leukocyte rolling, adherence, and transmigration to control levels (p < 0.01). CAS1609 also attenuated both P-selectin and ICAM-1 expression on mesenteric venules and decreased CD18 expression on isolated leukocytes. Superior mesenteric arteries incubated with 5 mmol/l homocysteine developed significant (p < 0.01) endothelial dysfunction (i.e., impaired relaxation to endothelium-dependent dilators). Acute hyperhomocysteinemia induces endothelial dysfunction, characterized by a loss of endothelium-derived nitric oxide, leading to an inflammatory state. This state results in increased leukocyte rolling, adherence, and transmigration by upregulation of cell adhesion molecules. Our data suggest that hyperhomocysteinemia inhibits the important homeostatic role of nitric oxide in preventing endothelial dysfunction.


Subject(s)
Endothelium, Vascular/drug effects , Homocysteine/pharmacology , Leukocytes/drug effects , Nitric Oxide/physiology , Animals , CD18 Antigens/analysis , Down-Regulation , Endothelium, Vascular/physiology , Immunohistochemistry , In Vitro Techniques , Intercellular Adhesion Molecule-1/analysis , Leukocytes/physiology , Male , Mesenteric Arteries/drug effects , Oxadiazoles/pharmacology , P-Selectin/analysis , Rats , Rats, Sprague-Dawley
SELECTION OF CITATIONS
SEARCH DETAIL
...