REGULATION OF THE ANGIOTENSIN RECEPTOR SUBTYPES IN CELL-CULTURES, ANIMAL-MODELS AND HUMAN-DISEASES

With the development of subtype specific angiotensin II (Ang II) recep tor antagonists and their introduction into the treatment of heart fai lure and hypertension, the regulation of the Ang II receptor with its subtypes AT(1) and Ang T-2 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 phospho rylation and to reduced synthesis and involves protein kinase C and ph ospholipase 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 ATI regulat ion. There are very few data regarding the regulation of the subtype A T(2), indicating modulation by a number of growth factors and by Ang I I. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT(1A) and AT(1B) are diff erentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experiences, the AT(1) in the adrenals, was up-regulated by Ang II infusion and down-regulated by an giotensin converting enzyme inhibitors (ACEI) or Ang II receptor antag onists. 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 physiological events have been conducted in p latelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regu lation and pregnancy-induced hypertension has been described. Further, receptor subtype distribution and regulation has been investigated in human heart failure. There is good evidence that the subtype AT(2) is dominant in human hearts and that AT(1) is down-regulated in heart fa ilure. This should further stimulate the search for a physiological ro le for the AT(2) in human hearts.