The plasminogen activator system modulates sympathetic nerve function

Sympathetic neurons synthesize and release tissue plasminogen activator (t-PA). We investigated whether t-PA modulates sympathetic activity. t-PA inhibition markedly reduced contraction of the guinea pig vas deferens to electrical field stimulation (EFS) and norepinephrine (NE) exocytosis from cardiac synaptosomes. Recombinant t-PA (rt-PA) induced exocytotic and carrier-mediated NE release from cardiac synaptosomes and cultured neuroblastoma cells; this was a plasmin-independent effect but was potentiated by a fibrinogen cleavage product. Notably, hearts from t-PA–null mice released much less NE upon EFS than their wild-type (WT) controls (i.e., a 76.5% decrease; P < 0.01), whereas hearts from plasminogen activator inhibitor-1 (PAI-1)–null mice released much more NE (i.e., a 275% increase; P < 0.05). Furthermore, vasa deferentia from t-PA–null mice were hyporesponsive to EFS (P < 0.0001) but were normalized by the addition of rt-PA. In contrast, vasa from PAI-1–null mice were much more responsive (P < 0.05). Coronary NE overflow from hearts subjected to ischemia/reperfusion was much smaller in t-PA–null than in WT control mice (P < 0.01). Furthermore, reperfusion arrhythmias were significantly reduced (P < 0.05) in t-PA–null hearts. Thus, t-PA enhances NE release from sympathetic nerves and contributes to cardiac arrhythmias in ischemia/reperfusion. Because the risk of arrhythmias and sudden cardiac death is increased in hyperadrenergic conditions, targeting the NE-releasing effect of t-PA may have valuable therapeutic potential.