OBJECTIVE This study was undertaken to determine whether stimulation of sympathetic cardiac nerves induces release of the thrombolytic enzyme tissue-type plasminogen activator (t-PA) in the coronary vascular bed. RESULTS Anesthetized pigs were studied in an open chest model. Bilateral vagotomy was performed, and sympathetic cardiac nerves were activated by electrical stimulation (1 and 8 Hz). To evaluate possible mediating effects of increased heart rate and enhanced local blood flow, tachycardia was induced by pacing and hyperemia by local infusion of sodium nitroprusside and clevedipine. Furthermore, to study the effects of alpha- and beta-adrenergic receptor stimulation, phenylephrine and isoprenaline were infused locally. In response to low- and high-frequency sympathetic stimulation, mean coronary net release of total t-PA increased approximately 6- and 25-fold, respectively. Active t-PA showed a similar response pattern. Neither tachycardia nor coronary hyperemia stimulated t-PA release. In contrast, beta-adrenergic stimulation by isoprenaline induced an approximately 6-fold increase in coronary t-PA release, whereas no significant change in release rates occurred in response to alpha-adrenergic stimulation by phenylephrine. CONCLUSIONS Stimulation of cardiac sympathetic nerves induces a marked coronary release of t-PA, and part of this response may be mediated through stimulation of beta-adrenergic receptors.