Inhibitory effect of D1-like and D3 dopamine receptors on norepinephrine-induced proliferation in vascular smooth muscle cells

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; the activation of the alpha-adrenergic receptor induces vasoconstriction, whereas the activation of dopamine receptor induces vasorelaxation. We hypothesize that the D-1-like receptor and/or D-3 receptor also inhibit alpha(1)-adrenergic receptor-mediated proliferation in vascular smooth muscle cells (VSMCs). In this study, VSMC proliferation was determined by measuring [H-3] thymidine incorporation, cell number, and uptake of 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT). Norepinephrine increased VSMC number and MTT uptake, as well as [3H] thymidine incorporation via the alpha(1)-adrenergic receptor in aortic VSMCs from Sprague-Dawley rats. The proliferative effects of norepinephrine were attenuated by the activation of D-1-like receptors or D-3 receptors, although a D-1-like receptor agonist, fenoldopam, and a D-3 receptor agonist, PD-128907, by themselves, at low concentrations, had no effect on VSMC proliferation. Simultaneous stimulation of both D-1-like and D-3 receptors had an additive inhibitory effect. The inhibitory effect of D-3 receptor was via protein kinase A, whereas the D-1-like receptor effect was via protein kinase C-zeta. The interaction between alpha(1)-adrenergic and dopamine receptors, especially D-1-like and D-3 receptors in VSMCs, could be involved in the pathogenesis of hypertension.