Ia. Jagroop et Dp. Mikhailidis, Doxazosin, an alpha(1)-adrenoceptor antagonist, inhibits serotonin-inducedshape change in human platelets, J HUM HYPER, 15(3), 2001, pp. 203-207
Patients with peripheral vascular disease or diabetes mellitus tend to have
elevated circulating levels of naturally occurring platelet agonists like
serotonin (5 hydroxytryptamine; 5-HT). This bioamine can induce platelet sh
ape change (PSC) an early phase of platelet activation, which is essentiall
y aspirin resistant. in addition, 5-HT exerts other harmful effects (eg sti
mulating vascular smooth muscle proliferation and inducing vasoconstriction
in atheromatous coronary vessels). The aim of this study was to determine
whether doxazosin inhibits 5-HT-induced PSC. Doxazosin is a long acting alp
ha (1)-adrenoceptor antagonist, used in the treatment of essential hyperten
sion and/or benign prostatic hyperplasia (BPH). platelet rich plasma (PRP)
was prepared from healthy volunteers (n = 8; five males and three females w
ith a median age of 32 years, range: 26-57). Agonists (5-HT, 0.06-0.5; ADP,
0.1-0.2 mu mol/l or U46619, a TXA(2) analogue, 0.025-0.05 mu mol/l) were a
dded to PRP and aliquots were removed at specific time points for median pl
atelet volume (MPV) measurement (using a high-resolution channelyser). The
MPV was used as an indicator of PSC. PRP was also incubated with doxazosin
(final concentration: 0.33 muM, a concentration similar to therapeutic plas
ma levels) prior to the addition of each of the above-mentioned agonists. D
oxazosin significantly inhibited (P = 0.007 and P = 0.008, at 30 sec and 60
sec, respectively) the 5-HT-induced increase in MPV. Doxazosin did not sig
nificantly inhibit ADP- or U46619-induced PSC. The inhibitory effect of dox
azosin seems to be specific to platelet 5-HT2 receptors, since there was no
effect on ADP- or U46619-induced PSC. This inhibition of platelet activati
on may be an additional, clinically relevant, advantage. Future in vivo stu
dies should consider assessing the effect of doxazosin on BHT-induced plate
let activation.