Evaluation of BM-573, a novel TXA2 synthase inhibitor and receptor antagonist, in a porcine model of myocardial ischemia-reperfusion.
OBJECTIVE
To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A2 synthase inhibitor and receptor antagonist, prevents reperfusion injury in acutely ischemic pigs.


METHODS
Twelve animals were randomly divided in two groups: a control group (n = 6) intravenously infused with vehicle, and a BM-573-treated group (n = 6) infused with BM-573 (10 mg kg(-1) h(-1)). In both groups, the left anterior descending (LAD) coronary artery was occluded for 60 min and reperfused for 240 min. Either vehicle or BM-573 was infused 30 min before LAD occlusion and throughout the experiment. Platelet aggregation induced by arachidonic acid ex vivo measured was prevented by BM-573.


RESULTS
In both groups, LAD occlusion decreased cardiac output, ejection fraction, slope of stroke work--end-diastolic volume relationship, and induced end-systolic pressure-volume relationship (ESPVR) rightward shift, while left ventricular afterload increased. Ventriculo-arterial coupling and mechanical efficiency decreased. In both groups, reperfusion further decreased cardiac output and ejection fraction, while ESPVR displayed a further rightward shift. Ventriculo-arterial coupling and mechanical efficiency remained impaired. Area at risk, evidenced with Evans blue, was 33.2+/-3.4% of the LV mass (LVM) in both groups, and mean infarct size, revealed by triphenyltetrazolium chloride (TTC), was 27.3+/-2.6% of the LVM in the BM-573-treated group (NS). Histological examination and immunohistochemical identification of desmin revealed necrosis in the anteroseptal region similar in both groups, while myocardial ATP dosages and electron microscopy also showed that BM-573 had no cardioprotective effect.


CONCLUSIONS
These data suggest that BM-573 failed to prevent reperfusion injury in acutely ischemic pigs.
Kolh
Philippe
P
Hemodynamic Research Center (HemoLiège), University of Liège, Belgium. philippe.kolh@chu.ulg.ac.be
Rolin
Stéphanie
S
Tchana-Sato
Vincent
V
Pétein
Michel
M
Ghuysen
Alexandre
A
Lambermont
Bernard
B
Hanson
Julien
J
Magis
David
D
Segers
Patrick
P
Masereel
Bernard
B
D'Orio
Vincent
V
Dogne
Jean-Michel
JM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000008:administration & dosage*; D013552:Swine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D017482:Receptors, Thromboxane; D013453:Sulfonylurea Compounds; D013930:Thromboxane-A Synthase