We previously showed that CGP 42112 (an angiotensin type 2 [AT2] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT2, a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT1) and AT2, in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT1antagonist that selectively simulates AT2stimulation) and the effect of Ang II plus PD 123319 (an AT2antagonist that selectively simulates AT1stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT2, in a similar manner to that found with CGP 42112. Stimulation of AT1significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT2stimulation significantly inhibited TH enzyme activity, whereas AT1stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT1was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT2on TH enzyme activity, indicating that the stimulatory effect of AT2may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT2stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT1stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT2reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT1stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT1and AT2have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.