Inhibitory effects of bromocriptine on vascular smooth muscle cell proliferation

Bromocriptine (BC), an ergot alkaloid with wide therapeutic use in humans, has been shown to inhibit proliferation of several abnormally hyperproliferative cells in vivo and in vitro. In the present study, direct effects of BC on mitogen-stimulated proliferation of rat vascular smooth muscle cells (VSMC) (A7r5 cells) and human aortic smooth muscle cells (HAOSMC) were examined in vitro. Twenty-four hour proliferative responses of quiescent A7r5 cells and HAOSMC to a variety of mitogens in the presence or absence of BC were determined by quantifying the incorporation of 3H-thymidine into DNA. BC at 1 microM inhibited the responses of A7r5 cells to various concentrations of fetal calf serum (FCS) by 50-70% without affecting the ED50 of FCS (2%). BC dose dependently inhibited the proliferation of A7r5 cells and HAOSMC stimulated by 2% FCS, with 52% inhibition at 1 and 0.1 microM, respectively. BC at 1 microM also completely inhibited the maximal mitogenic responses of A7r5 cells to prolactin, platelet-derived growth factor, insulin-like growth factor, and phorbol mysterate acetate (PMA), and BC at 1 microM completely inhibited the mitogenic response of HAOSMC to PMA. BC is a dopamine D2 agonist, a noradrenergic alpha 2 agonist, and an .alpha 1 antagonist, but the inhibitory effects of BC on A7r5 cell proliferation could not be mimicked by the specific D2 agonists, LY162502 and LY171555; the alpha 2 agonist, clonidine; or the alpha 1 antagonist, WB-4101. Neither dopamine nor the D2 agonist, LY162502, could inhibit HAOSMC proliferation induced by FCS. The PMA-induced stimulation of protein kinase C (PKC), a positive regulator of mitogenesis, could be completely blocked in A7r5 cells and HAOSMC by 1 and 0.1 microM BC, respectively. However, FPCS (2%)-induced activation of PKC in A7r5 cells and HAOSMC could only be blocked by 61 and 19% by BC (1 microM for A7r5 cells and 0.1 microM for HAOSMC), respectively. Given the existing evidence that BC reduces the severity of several other pathological conditions, such as insulin resistance, inflammation, and hyperlipidemia, which potentiate vascular disease, the current findings further suggest that BC use in the treatment of atherosclerosis and/or restenosis deserves further investigation.