Angiotensin (Ang) II has an important role in the vascular smooth muscle cell (VSMC) proliferation and migration and subsequently in the development of vascular diseases, whereas dopamine has the opposite effect. Previous studies have shown an interaction between dopamine and AT(1) receptors in the kidney. The dopamine D(4) receptor is expressed in arteries and has an inhibitory effect on VSMC proliferation. We hypothesized that the D(4) receptor, through its interaction with the AT(1a) receptor, may have an inhibitory effect on Ang II-mediated VSMC proliferation and migration, which could have a pivotal role in hypertension-induced vascular remodeling. In the current study, we found that Ang II markedly induced the proliferation and migration of A10 cells, which was inhibited by the D(4) receptor agonist PD168077. The activation of the D(4) receptor by PD168077 inhibited AT(1a) receptor expression in a concentration- and time-dependent manner. These effects were attenuated by silencing the D(4) receptor with a D(4) receptor-targeting small interfering RNA. The D(4) receptor-mediated inhibition of AT(1) receptor function involved protein kinase A (PKA). The activation of the D(4) receptor by PD168077 increased PKA activity in A10 cells, and the presence of a PKA inhibitor (PKA inhibitor 14-22, 10(-7) mol l(-1) per 24 h) blocked the inhibitory effect of the D(4) receptor on AT(1) receptor expression and function. The inhibitory effect of the D(4) receptor on AT(1) receptor expression and function was preserved in VSMCs (primary culture) from spontaneously hypertensive rats relative to VSMCs from Wistar-Kyoto rats. In conclusion, our data provide insight into the regulatory role of the D(4) receptor on AT(1a) receptor expression and function in VSMCs and suggest that targeting the action of the D(4) receptor may represent an effective therapeutic approach for the treatment of cardiovascular diseases.