High capacity for tissue-type plasminogen activator release from vascular endothelium in vivo.

BACKGROUND

Tissue-type plasminogen activator (t-PA) is the key mediator of intravascular fibrinolysis. We showed recently that local administrations both of methacholine (MCH) and of desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) induced a massive local release of t-PA in the human forearm vasculature.

OBJECTIVE

To determine whether the human vascular endothelium could respond to repeated stimulation with the same agonist, and, if so, to further evaluate the releasable endothelial pool of t-PA.

METHOD

Seven young, healthy men participated. MCH and DDAVP were administered as local infusions into the brachial artery. In protocol 1 (n = 3) 2 microg/min MCH was infused for 2 (30 min with a free interval of 20 min). In protocol 2 (n = 4) 70 ng/min DDAVP was infused for 2 (20 min with an interval of 75 min). Dosages and time intervals were based on the different release profiles of the two drugs observed in previous studies. Brachial arterial and venous blood samples were obtained at baseline and throughout infusions. Net release of t-PA was calculated as the product of the arteriovenous concentration gradient and forearm plasma flow.

RESULTS

Forearm blood flow was increased 3-4-fold by MCH and 2-3-fold by DDAVP infusions. During the first and second infusions of MCH, the average amounts of t-PA released were 1600 and 1000 ng/l forearm tissue, respectively. In contrast, DDAVP induced similar t-PA responses during both infusions; the average total releases of t-PA were 2300 and 2400 ng/l tissue, respectively.

CONCLUSION

The results show that the vascular endothelium is responsive to repeated stimulation both with MCH and with DDAVP. The diminished t-PA response to the second MCH infusion can not be explained in terms of depletion of intracellular pools, in view of the large amount of t-PA released by a single infusion of DDAVP. The dynamic pool of t-PA available for release is very large, but further studies are required in order to quantify the releasable endothelial stores.