Sodium/hydrogen exchange inhibition with cariporide reduces leukocyte adhesion via P-selectin suppression during inflammation.
Br J Pharmacol
; 153(8): 1678-85, 2008 Apr.
Article
em En
| 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. EXPERIMENTALAPPROACH:
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). KEYRESULTS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonas
/
Trocadores de Sódio-Hidrogênio
/
Selectina-P
/
Guanidinas
/
Inflamação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article