title: Bradykinin stimulates tissue plasminogen activator release in human vasculature.
abstract: Bradykinin stimulates tissue plasminogen activator (tPA) release in isolated perfused animal tissues. The present study tests the hypothesis that bradykinin increases tPA release in humans through local effects on the vasculature. Graded doses of sodium nitroprusside (0.8 to 3.2 micrograms/min), acetylcholine (ACh) (7.5 to 60 micrograms/min), and bradykinin (100 to 400 ng/min) were administered intra-arterially in random order in 10 salt-depleted (10 mmol/d of Na) normotensive volunteers. None of the drugs altered mean arterial pressure or heart rate. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in FBF, although ACh was less potent than either nitroprusside or bradykinin (maximum FBF 7.5+/-2.4 versus 10.0+/-1.5 and 11.9+/-2.1 mL. 100 mL-1. min-1, respectively). Bradykinin caused a significant, dose-dependent increase in venous (effect of dose F=9. 9, P=0.028 by ANOVA), but not arterial (F=0.154, P=0.92) tPA antigen in the infused arm. Thus, net tPA release increased significantly in response to bradykinin (50.6+/-13.3 at the highest dose versus 0. 9+/-0.4 ng. 100 mL-1. min -1 at baseline, P=0.014). In contrast, bradykinin did not affect plasminogen activator inhibitor antigen. Neither nitroprusside nor ACh altered plasma levels of tPA or plasminogen activator inhibitor antigen. Bradykinin increased tPA release across the forearm in the absence of systemic effects. This effect could not be attributed to changes in blood flow because doses of equivalent potency of the vasodilator nitroprusside did not increase tPA. These data demonstrate that bradykinin stimulates tPA release in the human vasculature.
authors.affiliation: Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville Veterans Administration Medical Center, Nashville, TN, USA. nancy.brown@mcmail.vanderbilt.edu
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
authors.forename: J V
authors.initials: JV
authors.lastname: Gainer
authors.forename: C M
authors.initials: CM
authors.lastname: Stein
authors.forename: D E
authors.initials: DE
authors.lastname: Vaughan
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology*; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage / Q000494:pharmacology*; D004039:Diet, Sodium-Restricted; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology; D005542:Forearm / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007261:Infusions, Intra-Arterial; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000097:blood*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D014665:Vasodilator Agents; D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine; D001920:Bradykinin