The sympathetic nervous system plays an important role in the regulation of blood pressure. There is increasing evidence for positive and negative interactions between dopamine and adrenergic receptors; activation of the-adrenergic receptor induces vasoconstriction while activation of dopamine receptor induces vasorelaxation. We hypothesize that the D₁-like receptor and/or D₃ receptor also inhibit-adrenergic receptor-mediated proliferation in vascular smooth muscle cells (VSMCs). In this study, VSMC proliferation was determined by measuring [³H]-thymidine incorporation, cell number, and uptake of 3-(4,5-dimethylthiazol-2-yl)-diphenyl-tetrazolium bromide (MTT). Norepinephrine increased VSMC number and MTT uptake, as well as [³H]-thymidine incorporation via the-adrenergic receptor in aortic VSMCs from Sprague-Dawley rats. The proliferative effects of norepinephrine were attenuated by activation of D₁-like receptors or D₃ receptors, although a D₁-like receptor agonist, fenoldopam, or a D3 receptor agonist, PD128907, by themselves, at low concentrations, had no effect on VSMC proliferation. Simultanenous stimulation of both D₁-like and D₃ receptors had an additive inhibitory effect. The inhibitory effect of D₃ receptor was via protein kinase A, while the D₁-like receptor effect was via protein kinase C. The interaction between-adrenergic and dopamine receptors, especially D₁-like and D₃ receptors in VSMCs, could be involved in the pathogenesis of hypertension.