THE EFFECT OF HYPOFIBRINOGENEMIA AND FIBRINOLYSIS ON SKELETAL-MUSCLE FUNCTION AFTER ISCHEMIA AND REPERFUSION

Isometric contraction to direct supramaximal tetanic stimulation of the anterior tibialis (AT) muscle was measured in 50 New Zealand White rabbits after ischemia and reperfusion. Ischemia was produced unilaterally by collateral ligation and temporary inflow control until AT muscle function decreased to <5% of contralateral (control) AT muscle and the ischemic interval was recorded. Reperfusion was carried out in one of the following ways: group I (n = 20), release of vascular clamps (blood reperfusion [BR]); group II (n = 10), release of vascular clamps and simultaneous intraarterial administration of 50,000 units of urokinase (urokinase reperfusion [UR]); group III (n = 10), release of vascular clamps and simultaneous administration of 50,000 units of urokinase and 28 mg (5 units) of purified rabbit plasminogen (urokinase plasminogen reperfusion [UPR]); and group IV (n = 10), animals defibrinated to <50 mg/dl with ancrod prior to ischemia and received BR (ancrod blood reperfusion [ABR]). During reperfusion, function was recorded every 60 min for 2 hr. Recovery of experimental muscle function is expressed as the percentage of contralateral control limb function. The mean ischemic interval (means ± SEM), to achieve <5% of contralateral control limb function, was 206.7 ± 9.9, 209.5 ± 16.6, 221.7 ± 12.5, and 272.0 ± 14.2 min for animals in groups I-IV, respectively. The mean experimental muscle function (means ± SEM) following the ischemic interval was 3.2 ± 0.8, 4.5 ± 1.4, 4.4 ± 1.2, and 3.3 ± 1.0 for groups I-IV, respectively. The difference in the ischemia time to reach <5% of control function in between the control (group I) rabbits and the animals which received ancrod (group IV) is statistically significant (P < 0.01). After 2 hr of reperfusion, the mean muscle function was 25.5 ± 6.4 for controls (BR), 60.4 ± 18.6 for group II (UR), 72.7 ± 10.3 for group III (UPR), and 42.4 ± 9.7 for group IV (ABR). Both groups II (UR) and IlI (UPR) are statistically significant when compared to the unmodified blood reperfusion group (P < 0.05 and P < 0.01, respectively). We conclude that urokinase infusion during reperfusion improves the recovery of skeletal muscle function after ischemia. This effect is further enhanced by the addition of substrate (plasminogen), suggesting that fibrinolysis is responsible for this effect. Defibrination with ancrod increased the tolerance of skeletal muscle to ischemia but did not significantly improve its function compared to that of unmodified blood. These experiments suggest that manipulations of the fibrinogen/fibrin system may play an important role in the tolerance of skeletal muscle to ischemia and recovery of contractile function following reperfusion. © 1994 Academic Press. All rights reserved.