Evaluation of activated protein C on canine infarct size in a nonthrombotic model of myocardial reperfusion injury.
Myocardial infarct size has been measured after 1 hr of mechanical occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with saline, and in dogs infused with activated protein C (aPC) (1mg/kg/hr i.v.). Infusion of aPC during reperfusion produced a sustained doubling of activated partial thromboplastin time and no change in thrombin time at a final plasma parent drug concentration of 1.25 +/- 0.11 mug/ml. aPC infusion did not alter systolic arterial pressure, cardiac rate or the rate pressure product when compared to time-related alterations observed in control dogs. ST-segment deviation and the intensity and duration of cardiac arrhythmias associated with reperfusion of ischemic myocardium also were similar between groups. Resultant infarct sizes were 34.8 +/- 3.9 and 33.2 +/- 6.2% of the left ventricular mass placed at risk of necrosis in control and aPC-treated dogs. respectively. aPC infusion was associated with a small reduction in leukocytosis in response to myocardial ischemic injury, but did not alter the localization of leukocytes within ischemic and infarcted myocardium. In vitro concentrations of aPC (0.3, 1 and 3 mug/ml), comparable to the plasma concentration that inhibited blood coagulation in dogs, did not alter superoxide production or CD11b/CD18-mediated adhesion of chemotactic factor f-Met-Leu-Phe-stimulated neutrophils. Present data indicate that aPC lacks cardioprotectant activity at an infusion rate inhibiting coagulation. Apart from inhibition of thrombin generation, no evidence of an anti-inflammatory effect of aPC was observed.
Hahn
R A
RA
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana, USA.
MacDonald
B R
BR
Chastain
M
M
Grinnell
B W
BW
Simpson
P J
PJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015425:Myocardial Reperfusion; D011486:Protein C / Q000494:pharmacology*; D013997:Time Factors
D011486:Protein C