F018: Reactive hyperaemia releases t-PA in essential hypertensive patients

Background: Tissue plasminogen activator (t-PA), a key controlling factor of fibrinolysis in man, is locally released by endothelial-mediated vasodilators such as bradykinin, substance P or methacholine, thus potentially explaining why defective endothelial-mediated vasomotion may promote thrombotic events in hypertension. However, the significance of data obtained by infusing exogenous compounds at pharmacological concentrations is questionable, and whether that same phenomenon occurs in more physiological conditions is unknown. To test this possibility, we evaluated t-PA release (REL) during reactive hyperaemia (RH), a condition where vasodilatation is produced by several metabolic factors produced in response to the mismatch between oxygen supply and demand. Material & Methods: (Means ± SD): The data were obtained in the right forearm of 11 uncomplicated mild essential hypertensive males (42 ± 9 yrs, 155 ± 12/98 ± 5 mmHg). Forearm blood flow (FBF, strain-gauge plethysmography), arterial (A) and venous (V) t-PA and plasminogen activator inhibitor (PAI)-1 antigen concentrations (ELISA) to derive REL (V-A × FBF), were measured at baseline and 1, 5, 10 minutes after release of i. partial (10-min cuff inflation at the midpoint between systolic and diastolic values, n = 7), and ii. total (10-min cuff inflation at supra-systolic levels, n = 4) ischemia. Results: (Means ± SD or Medians&Range): 1 minute after partial ischemia release, FBF increased from 3.2 ± 1.6 to 18. ± 3 ml/min × dl−1 (p < 0.001), and t-PA REL from 1.4 (−7.4/8.3) to 49 (−38/195) ng/ml × min−1 (p < 0.001) respectively; both parameters normalised thereafter. After total ischemia, FBF went from 4.1 ± 1.1 to 47. ± 3.4 ml/min × dl−1 (p < 0.001), and, correspondingly, t-PA REL increased from 5. (−0.6/19) to 79 (69./171.6) ng/ml × min−1 (p < 0.001, p < 0.04 vs t-PA REL after partial ischemia). PAI-1 REL did not change. Conclusions: RH, a physiological vasodilator response to ischemia, is associated with an immediate, dose-related and selective t-PA release from endothelial cells. Thus, a general relationship seems to exist between local vasomotion and fibrinolytic control in man, possibly as a result of stimulation by endogenous agonists produced in response to blood flow reduction, although vasodilatation per se may also contribute by increasing shear stress.