In vivo study of AT(1) and AT(2) angiotensin receptors in apoptosis in ratblood vessels

In vitro experiments suggest that angiotensin II (Ang II) may cause growth via angiotensin type I (AT(1)) receptors and apoptosis via angiotensin type 2 (AT(2)) receptors To answer the question of whether AT(1) or AT(2) recep tor activation could induce apoptosis in the vasculature in vivo, Wistar ra ts were infused for 7 days with Ang II (120 ng . kg(-1) . min(-1) subcutane ously) and treated with the AT(2) receptor antagonist PD 123319 (30 mg . kg (-1) . d(-1) subcutaneously) or the AT(1) receptor antagonist losartan (10 mg . kg(-1) . d(-1) orally). Apoptosis in thoracic aorta was quantified by radiolabeled DNA laddering and by terminal deoxynucleotide transferase-medi ated dUTP nick end-labeling. The expression of p53, bar, bcl-2, and caspase -3, which play critical roles in apoptotic signaling, was examined by Weste rn blot analysis. The mRNA expression of AT(1) and AT(2) receptors was dete rmined by reverse transcription-polymerase chain reaction. The increase in systolic: blood pressure and aortic growth induced by Ang II infusion was c ompletely prevented by losartan alone or losartan given with PD 123319, whe reas PD 123319 resulted in-a greater increase in systolic blood pressure an d aortic growth;than Ang II alone. Radiolabeled DNA laddering showed that A ng II infusion+/-losartan or PD 123319 significantly increased apoptosis (1 47+/-8% 178+/-20%, and 238+/-41%, respectively, P<0.05 compared with contro l). Expression: of bar and active forms of caspase-3 was increased in the A ng II+PD 123319 group, whereas the expression of p53 and bcl-2 was not sign ificantly different in all groups. The expression of AT(1) and AT(2) recept or mRNA was downregulated by losartan and PD 123319, respectively. Thus, wh en AT(1) or AT(2) receptors are stimulated in vivo, apoptosis is enhanced i n the media of blood vessels. In the case of AT(1) receptor stimulation, th is may occur secondary to vascular growth and modulate the latter. Both bar and caspase-3 participate in the pathways of apoptosis triggered by in viv o AT(1) receptor stimulation.