ffect on both AT1 mRNA expression and AT1 receptor density in cultured VSMC. This inhibitory effect of NE can be prevented by the 1-adrenoreceptor antagonist prazosin, but not by the 2-adrenoreceptor antagonist yohimbine. This is evidence showing that NE negatively regulates AT1 receptor expression in the vascular tissue through an 1-adrenergic receptor-mediated mechanism. In opposition to these positive interactions,results from studies indicate that the sympathetic nervous system negatively regulates the vascular AT1 receptor in vivo and in vitro. For example, it has been shown in brain neuronal cultures of Wistar-Kyoto rats that NE decreases AT1 receptor density and its gene expression. Also, renal denervation or sympathetic blockade with guanethidine increases glomerular ANG II receptor density in normotensive and hypertensive rats, suggesting that the sympathetic nervous system exerts an inhibitory effect on AT1 receptor expression in glomeruli. These studies provide clear evidence for heterologous downregulation of the AT1 receptor by NE. The mechanisms by which NE induces downregulation of the AT1 receptor in the vascular tissue are that NE activates 1-adrenergic receptors and, through modulation of one or more signaling pathways, downregulates AT1 receptor gene expression.support for this come from studies where blockade of the 1-adrenoreceptor with prazosin increases AT1 mRNA levels in the aorta of the rat; this increase does not appear to be an artifact of the effect of DMSO due to preliminary experiments displaying no significant difference in aortic AT1 mRNA levels between DMSO and saline-infused rats, and 2) inhibitory effects of NE on both AT1 mRNA and receptor protein in cultured VSMC were prevented by cotreatment with prazosin but not with the 2-adrenoreceptor antagonist yohimbine. It is possible that yohimbine at 0.1 M may not be sufficient to completely block 2-ad...
