RT Journal Article
SR Electronic
T1 Modulation of Sympathetic Activity by Tissue Plasminogen Activator Is Independent of Plasminogen and Urokinase
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 265
OP 273
DO 10.1124/jpet.107.121335
VO 322
IS 1
A1 Ulrich Schaefer
A1 Sandra Vorlova
A1 Takuji Machida
A1 Jerry P. Melchor
A1 Sidney Strickland
A1 Roberto Levi
YR 2007
UL http://jpet.aspetjournals.org/content/322/1/265.abstract
AB 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-PAstop decreased EFS response in WT mice, whereas u-PAstop 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-PAstop 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-PAstop 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. The American Society for Pharmacology and Experimental Therapeutics