We have previously demonstrated that collateral development takes place in a swine model of coronary artery occlusion. In this report we have examined the effect of coronary artery occlusion on urokinase and tissue plasminogen activator activity in the myocardium. Urokinase activity was increased four-fold in the ischemic heart compared to sham and unoperated controls. In contrast, the level of tissue plasminogen activator activity remained relatively constant. The increase in urokinase activity was associated with an upregulation of urokinase RNA levels and of the RNAs corresponding to the plasminogen activator inhibitors, PAI I and II. Urokinase has been shown to be an important angiogenic protease both in vivo and in cultured cells. Its increase during collateral development suggests that urokinase may play a role in angiogenesis in the ischemic heart.