The clot-busting power of t-PA—which works by cleaving the proenzyme plasminogen into the active plasmin that then breaks down the clot protein fibrin—is often used to dissolve clots in patients who have had heart attacks or strokes. But treatment with recombinant t-PA has been associated with erratic heartbeats (or arrhythmias)—a common cause of death post–heart attack.

The team now shows that the production of t-PA causes sympathetic nerve endings in the heart to release NE. And NE, which constricts vessels and increases heart rate, is known to trigger arrhythmias. Indeed, mice lacking t-PA produced lower levels of NE and were less likely to develop arrhythmias after ischemic heart injury.

t-PA did not need to cleave plasminogen to induce NE release, but this activity did involve both Ca²⁺-dependent exocytosis and carrier-dependent transport of NE from nerve endings. Exactly how this process gets started remains obscure, in part because plasminogen is thus far the only known t-PA substrate.

Sympathetic nerve endings, which are abundant in vessel walls and heart tissue, may produce t-PA to magnify fibrin breakdown in response to injury. But the secondary release of NE might then contribute to the arrhythmia often associated with therapeutic t-PA.