Therapeutic potential of platelet-activating factor antagonism in the management of myocardial infarction.
BACKGROUND
Antagonists of platelet-activating factor (PAF) reduce myocardial postischemia reperfusion injury when given before the onset of ischemia. However, the effects of PAF antagonists when administered at a clinically modelled time (during ischemia but before reperfusion) are controversial. Moreover, the extended survival (eight day) and the characteristics of scar formation after treatment with PAF antagonists have not been investigated.


OBJECTIVE
To determine the therapeutic potential of PAF antagonist TCV-309 for the treatment of regional myocardial ischemia-reperfusion injury; and to determine the effects of TCV-309 on cardiovascular recovery, evolution of scar formation and survival eight days after a myocardial infarction treated with reperfusion.


METHODS
Swine underwent regional myocardial ischemia for 60 mins by ligation of the left anterior descending coronary artery, followed by reperfusion for eight days. The treated group (n=7) received PAF antagonist TCV-309 (0.1 mg/kg) 45 mins after ligation; the untreated group (n=7) received vehicle only.


RESULTS
Untreated animals experienced significantly (P<0.001) lower systemic arterial blood pressure during the reperfusion period than animals treated with TCV-309. Furthermore, untreated animals required significantly more (P<0.01) antiarrhythmic and inotropic support. Only two of seven animals in the untreated group survived, which was significantly different (P<0.05) from the six of seven treated animals that survived for eight days. Morphometric analyses did not show differences between groups in the characteristics of scar formation following reperfusion for eight days.


CONCLUSIONS
PAF antagonist TCV-309 improves survival and reduces cardiovascular dysfunctions associated with regional myocardial ischemia reperfusion injury when administered at a clinically modelled time.
Loucks
E B
EB
University of British Columbia, Vancouver Hospital and Health Sciences Centre, Vancouver, Canada.
Qayumi
A K
AK
Godin
D V
DV
English
J C
JC
Lim
S P
SP
Al Mahmeed
T
T
Gul
S
S
D000818:Animals; D005260:Female; D007546:Isoquinolines / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D011897:Random Allocation; D013552:Swine; D044005:Tetrahydroisoquinolines; D013997:Time Factors
D007546:Isoquinolines; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; D044005:Tetrahydroisoquinolines; C067430:TCV 309