Fleck E: Regulation of the angiotensin receptor subtypes in cell cultures, animal models and human diseases. Eur Heart J

With the development of subtype specific angiotensin II (Ang II) receptor antagonists and their introduction into the treat-ment of heart failure and hypertension, the regulation of the Ang II receptor with its subtypes AT, and Ang T2 gains clinical importance. In cell cultures, the number of surface AT, is clearly down-regulated by Ang II exposure. Down-regulation can be due to reversible internalization, to phosphorylation and to reduced synthesis and involves protein kinase C and phos-pholipase C mediated pathways. In this respect, the AT, behaves as a typical G-protein coupled receptor. Aldosterone, cAMP, norepinephrine and extracellular glucose concentrations can contribute to AT, regulation. There are very few data regarding the regulation of the subtype AT2, indicating modulation by a number of growth fac-tors and by Ang II. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT,AandAT,B are differentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experi-ences, the AT,, in the adrenals, was up-regulated by Ang II infusion and down-regulated by angiotensin converting enzyme inhibitors (ACEI) or Ang II receptor antagonists. Differing effects were observed in other organs. In humans, a number of studies seeking an association between Ang II levels, Ang II receptor regulation and physiologi-cal events have been conducted in platelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regulation and pregnancy-induced hypertension has been described