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CARDIOVASCULAR

Modulation of Sympathetic Activity by Tissue Plasminogen Activator Is Independent of Plasminogen and Urokinase

Department of Pharmacology, Weill Cornell Medical College, New York, New York (U.S., T.M., R.L.); and Laboratory of Neurobiology and Genetics, Rockefeller University, New York, New York (S.V., J.P.M., S.S.)

Sympathetic neurons synthesize, transport, and release tissue-type plasminogen activators (t-PAs) and urinary-type plasminogen activators (u-PAs). We reported that t-PA enhances sympathetic neurotransmission and exacerbates reperfusion arrhythmias. We have now assessed the role of u-PA and plasminogen. Neurogenic contractile responses to electrical field stimulation (EFS) were determined in vasa deferentia (VD) from mice lacking t-PA (t-PA^-/-), plasminogen activator inhibitor-1 (PAI-1^-/-), plasminogen (plgn^-/-), u-PA (u-PA^-/-), and wild-type (WT) controls. Similar levels of t-PA were present in VD and cardiac synaptosomes of WT, PAI-1^-/-, plgn^-/-, and u-PA^-/- mice, whereas t-PA was undetectable in t-PA^-/- tissues. EFS responses were potentiated and attenuated in VD from PAI-1^-/- and t-PA^-/- mice, respectively, but indistinguishable from WT responses in VD from plgn^-/- and u-PA^-/- mice. Moreover, t-PA inhibition with t-PA_stop decreased EFS response in WT mice, whereas u-PA_stop did not. VD responses to ATP, norepinephrine, and K⁺ in t-PA^-/-, PAI-1^-/-, plgn^-/-, and u-PA^-/- mice were similar to those in WT, whereas t-PA_stop did not modify VD responses to norepinephrine in WT, t-PA^-/-, and PAI-1^-/- mice, indicating a prejunctional site of action for t-PA-induced potentiation of sympathetic neurotransmission. Indeed, K⁺-induced norepinephrine exocytosis from cardiac synaptosomes was potentiated in PAI-1^-/-, attenuated in t-PA^-/- and not different from WT in u-PA^-/- and plgn^-/- mice. Likewise, ATP exocytosis was decreased in t-PA^-/- and attenuated by t-PA_stop in WT mice. Thus, t-PA-induced enhancement of sympathetic neurotransmission is a prejunctional event associated with increased transmitter exocytosis and independent of u-PA and plasminogen availability. This novel t-PA action may be a potential therapeutic target in hyperadrenergic states.

Address correspondence to: Dr. Roberto Levi, Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021. E-mail: rlevi{at}med.cornell.edu