Doxazosin inhibits proliferation and migration of human vascular smooth-muscle cells independent of alpha1-adrenergic receptor antagonism.
Proliferation and migration of vascular smooth-muscle cells (VSMCs), stimulated by a variety of growth factors, play a critical role in the pathogenesis of vascular diseases. We found unexpectedly that doxazosin, an alpha1-adrenergic-receptor antagonist, inhibits serum-stimulated proliferation of cultured human VSMCs. Subsequent experiments systematically investigated inhibitory effects of doxazosin on mitogenesis stimulated in VSMCs by platelet-derived growth factor (PDGF), epidermal growth factor, and G protein-coupled receptor agonists thrombin and angiotensin II. Doxazosin attenuated the stimulation of DNA synthesis for each of these ligands with median inhibitory concentrations (IC50s) from 0.3 to 1 microM. PDGF-AB (1 nM) increased cell number; doxazosin inhibited this response by 70-80%. Prazosin, a related alpha1-receptor antagonist, had similar but less potent effects on inhibiting mitogenesis in these cells. Doxazosin and prazosin inhibited PDGF-AB-stimulated and insulin-like growth factor (IGF-I)-stimulated migration of VSMCs by approximately 40-50%. These effects of doxazosin were likely unrelated to alpha1-receptor blockade because pretreatment of cells with phenoxybenzamine, an irreversible alpha1 antagonist, did not change the capacity of doxazosin to inhibit of PDGF-stimulated mitogenesis. Also, doxazosin inhibited PDGF-stimulated DNA synthesis in NIH 3T3 cells, which do not express alpha1 receptors. These results suggest that doxazosin is a potent inhibitor of VSMC proliferation and migration through a mechanism unrelated to alpha1-receptor antagonism.
Hu
Z W
ZW
Veterans Affairs Palo Alto Health Care System, Geriatrics, Research, Education, and Clinical Center, California 94304, USA.
Shi
X Y
XY
Hoffman
B B
BB
D016475:3T3 Cells; D058646:Adrenergic alpha-1 Receptor Agonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors
D058646:Adrenergic alpha-1 Receptor Agonists; D000317:Adrenergic alpha-Antagonists; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; C095477:platelet-derived growth factor AB; D007334:Insulin-Like Growth Factor I; D017292:Doxazosin