Sodium/hydrogen exchange inhibition with cariporide reduces leukocyte adhesion via P-selectin suppression during inflammation.
OBJECTIVE
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.


METHODS
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).


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
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.
Buerke
U
U
Department of Internal Medicine III, Martin Luther-University, Halle Saale, Germany.
Pruefer
D
D
Carter
J M
JM
Russ
M
M
Schlitt
A
A
Prondzinsky
R
R
Makowski
J
J
Rohrbach
S
S
Niemann
B
B
Schulze
C
C
Dahm
M
M
Vahl
C-F
CF
Werdan
K
K
Buerke
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology*; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008643:Mesentery / Q000098:blood supply; D008833:Microcirculation / Q000378:metabolism; D008853:Microscopy; D019007:P-Selectin / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*
D006146:Guanidines; D019007:P-Selectin; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D002118:Calcium