tcv-309 and Myocardial-Infarction

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.. 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.. 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.. 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.. PAF antagonist TCV-309 improves survival and reduces cardiovascular dysfunctions associated with regional myocardial ischemia reperfusion injury when administered at a clinically modelled time.

Topics: Animals; Female; Isoquinolines; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Platelet Aggregation Inhibitors; Pyridinium Compounds; Random Allocation; Swine; Tetrahydroisoquinolines; Time Factors

This swine model was designed to elucidate the role of platelet-activating factor in regional myocardial ischemia-reperfusion injury.. In groups 1 and 2 (n = 12 each), the left anterior descending coronary artery was ligated for 60 minutes to induce regional myocardial ischemia followed by 6 hours of reperfusion. Group 1 received the platelet-activating factor antagonist TCV-309 before ischemia, whereas group 2 did not. Group 3 (n = 3) had a sham operation.. Animals in group 2 exhibited significant (p < 0.05) hemodynamic instability and myocardial depression during the reperfusion period. Despite preventive measures, 7 of the 12 animals experienced severe dysrhythmias in the form of atrial and ventricular fibrillation leading to cardiac arrest. In contrast, animals in group 1 in whom the effects of platelet-activating factor were blocked by the specific platelet-activating factor receptor antagonist TCV-309 were hemodynamically stable and had significantly (p < 0.05) better myocardial function. This significant difference in global myocardial function between the groups was observed in the presence of similar morphologic findings and regional myocardial function.. These results suggest that platelet-activating factor has a definite influence on global myocardial dysfunction associated with regional myocardial ischemia-reperfusion injury.

Topics: Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Blood Pressure; Cardiac Output; Cardiac Volume; Disease Models, Animal; Female; Heart Arrest; Hemodynamics; Isoquinolines; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Platelet Activating Factor; Platelet Aggregation Inhibitors; Pyridinium Compounds; Random Allocation; Stroke Volume; Swine; Tetrahydroisoquinolines; Ventricular Fibrillation; Ventricular Function