Evaluation of activated protein C on canine infarct size in a nonthrombotic model of myocardial reperfusion injury

RA Hahn, BR MacDonald, M Chastain, BW Grinnell and PJ Simpson

Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana, USA.

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.

Volume 276, Issue 3, pp. 1104-1110, 03/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

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