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Evidence of a Local Mechanism for Desmopressin-Induced Tissue-Type
Plasminogen Activator Release in Human Forearm
Ulrika Wall,
Sverker Jern,
Lilian Tengborn, and
Christina Jern
From the Clinical Experimental Research Laboratory, the Department of
Medicine, Heart and Lung Institute, Sahlgrenska University
Hospital/Östra, Göteborg, Sweden; the
Coagulation Centre, the Institute of Internal Medicine, and the
Institute for Clinical Neuroscience, Department of Neurology,
Sahlgrenska University Hospital, Göteborg University,
Göteborg, Sweden.
Systemic administration of desmopressin (DDAVP) induces
increased plasma levels of tissue-type plasminogen activator (t-PA), coagulation factor VIII, and von Willebrand factor (vWF). However, the
mechanisms behind these responses are not known. We tested the
hypothesis that DDAVP acts as a local stimulator of acute endothelial
release of t-PA and vWF independently of central pathways. Healthy,
young, nonsmoking male volunteers were studied. In a first study
(n = 7), DDAVP and placebo were administered as randomized single-blind stepwise intrabrachial artery infusions (0.7, 7.0, and 70 ng/min). In a another subset of subjects (n = 4), a constant-rate DDAVP infusion of 70 ng/min was administered for 20 minutes in the
brachial artery of the nondominant arm with the dominant arm as
control. To rule out that the observed t-PA release was flow-dependent, 4 additional subjects received stepwise intra-arterial infusions of
both DDAVP (7.0, 21, and 70 ng/min) and sodium nitroprusside (SNP; 0.5, 2.5, and 10 µg/min). Brachial venoarterial plasma concentration gradients and forearm plasma flow were used to determine net
release/uptake rates of t-PA and vWF. At baseline, the average net
release rate of t-PA was 6.7 ng/min across the whole forearm vascular
bed, whereas there was no detectable basal release of vWF. Stepwise infusion of DDAVP induced a massive regulated release of t-PA with a
peak after 15 minutes on the highest dose-step (ANOVA; P < .0001). The average maximum net release rate was 178 ng/min, and the
total amount of t-PA released was, on the average, 3,000 ng. The
majority was released in its active form. Constant-rate DDAVP infusion
again markedly increased t-PA release in the infusion arm but had no
effect whatsoever in the control arm. In contrast, DDAVP did not
stimulate a local release of vWF in either study. Central hemodynamics
were unchanged during infusions despite a local vasodilatory response
with DDAVP. Endothelium-independent flow stimulation by SNP did not
elicit any local t-PA release. We conclude that DDAVP induces a massive
acute flow-independent release of t-PA, without the simultaneous
release of vWF, in the human forearm vascular bed. The lack of
a t-PA response in the control arm, as well as the unaltered central
hemodynamics with DDAVP, confirms that the observed regulated t-PA
release is local and independent of central mechanisms.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 529-537
© 1998 by The American Society of Hematology.
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