The effects of doxazosin on platelet aggregation, platelet adhesion and blood coagulation in cynomolgus monkeys.
The effect of doxazosin, a selective alpha-1 adrenergic inhibitor, on hemostasis was investigated in 9 cynomolgus monkeys. During 12 weeks of doxazosin treatment (1 mg/kg per day), serum lipids, lipoprotein cholesterols, blood coagulation, platelet aggregation and template bleeding times were measured and compared with predrug values. In addition, platelet adhesion to cultured human umbilical vein endothelial cells (HUVEC) in the presence or absence of doxazosin was evaluated. Platelet aggregation was also determined in monkeys following chronic oral exposure to aspirin (162 mg/day). Doxazosin administration was associated with significant reductions in serum total cholesterol (TC) (-16%) and low density lipoprotein cholesterol (LDL-C) (-23%), while high density lipoprotein cholesterol (HDL-C) levels increased 66%. Doxazosin did not alter any parameters of blood coagulation measured; however, bleeding times were increased significantly (33%) in doxazosin-treated animals. Although collagen-stimulated platelet aggregation was not influenced by either chronic doxazosin or aspirin treatment, the maximal extent of ADP-stimulated platelet aggregation was significantly reduced (-26% and -18%, respectively) compared with the control monkeys. Platelets from untreated control animals displayed reductions in the extent of ADP-stimulated aggregation of 13% and 23%, respectively, when incubated in vitro with 200 and 300 micrograms/ml of doxazosin. Additionally, the decrease in aggregation response of platelets obtained from doxazosin-treated monkeys was accompanied by a rapid reversal of platelet aggregation. Adhesion to HUVEC by platelets isolated from doxazosin-treated animals was significantly decreased; however, adhesion was not altered when platelets from untreated control animals were incubated with HUVEC in the presence of doxazosin. Thus, the ex vivo and in vitro studies reported in this communication suggest that doxazosin administration to nonhuman primates is associated with beneficial alterations in plasma lipids, platelet aggregation, bleeding times and platelet adhesion to endothelial cells, parameters which are thought to influence risk of cardiovascular disease in both animals and humans.
Weiner
E J
EJ
Department of Clinical Sciences, University of Massachusetts, Lowell 01854.
Stucchi
A F
AF
Foxall
T L
TL
Shwaery
G T
GT
Yoganathan
S
S
Nicolosi
R J
RJ
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*
D008078:Cholesterol, LDL; D008055:Lipids; D017292:Doxazosin