Doxazosin, an alpha1-adrenoceptor antagonist, inhibits serotonin-induced shape change in human platelets.
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 shape change (PSC) an early phase of platelet activation, which is essentially aspirin resistant. In addition, 5-HT exerts other harmful effects (eg stimulating 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 alpha(1)-adrenoceptor antagonist, used in the treatment of essential hypertension and/or benign prostatic hyperplasia (BPH). Platelet rich plasma (PRP) was prepared from healthy volunteers (n = 8; five males and three females with a median age of 32 years, range: 26-57). Agonists (5-HT, 0.06-0.5; ADP, 0.1-0.2 micromol/l or U46619, a TXA(2)analogue, 0.025-0.05 micromol/l) were added to PRP and aliquots were removed at specific time points for median platelet 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 microM, a concentration similar to therapeutic plasma levels) prior to the addition of each of the above-mentioned agonists. Doxazosin 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 significantly inhibit ADP- or U46619-induced PSC. The inhibitory effect of doxazosin seems to be specific to platelet 5-HT(2) receptors, since there was no effect on ADP- or U46619-induced PSC. This inhibition of platelet activation may be an additional, clinically relevant, advantage. Future in vivo studies should consider assessing the effect of doxazosin on 5-HT-induced platelet activation.
Jagroop
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Department of Molecular Pathology and Clinical Biochemistry, Royal Free and University College Medical School (University of London), Royal Free campus, London, UK.
Mikhailidis
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D000317:Adrenergic alpha-Antagonists / Q000378:metabolism* / Q000627:therapeutic use; D000328:Adult; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology*; D048429:Cell Size / Q000187:drug effects; D017292:Doxazosin / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D012701:Serotonin; D017292:Doxazosin