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(Hypertension. 2002;39:142.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Angiotensin II Type 2 Receptor Counter-Regulates Type 1 Receptor in Catecholamine Synthesis in Cultured Porcine Adrenal Medullary Chromaffin Cells

Kazuhiro Takekoshi; Kiyoaki Ishii; Shunsuke Shibuya; Yasushi Kawakami; Kazumasa Isobe; Toshiaki Nakai

From the Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Correspondence to Kazuhiro Takekoshi, MD, Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575, Japan. E-mail K-takemd @md.tsukuba.ac.jp

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 AT₁ antagonist that selectively simulates AT₂ stimulation) and the effect of Ang II plus PD 123319 (an AT₂ antagonist that selectively simulates AT₁ stimulation) 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 AT₁ significantly 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 AT₂ stimulation significantly inhibited TH enzyme activity, whereas AT₁ stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT₁ was 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 AT₂ on TH enzyme activity, indicating that the stimulatory effect of AT₂ may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT₂ stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT₁ stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT₂ reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT₁ stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT₁ and AT₂ have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.

Key Words: receptors, angiotensin II • tyrosine hydroxylase • cyclic GMP • angiotensin antagonist • catecholamines

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