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.
Schaefer
Ulrich
U
Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Machida
Takuji
T
Vorlova
Sandra
S
Strickland
Sidney
S
Levi
Roberto
R
D000320:Adrenergic Fibers / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004558:Electric Stimulation; D005089:Exocytosis / Q000502:physiology; D017353:Gene Deletion; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009447:Neuroblastoma; D009469:Neuromuscular Junction / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury; D013566:Sympathomimetics / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014649:Vas Deferens / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D013566:Sympathomimetics; D010959:Tissue Plasminogen Activator; D009638:Norepinephrine