Prenatal blockade of Ang II receptors affects neonatal rat hindbrain structure and receptor localization

The development of knock-out mice for Angiotensin II (Ang II) AT(2) receptors, which exhibited altered exploratory behavior, prompted us to investigate the cerebellum and brainstem. We evaluated the effect of stimulation/inhibition of Ang II receptors on hindbrain development, in offspring (postnatal days P0, P8) of pregnant rats treated during late pregnancy (Ang II, Losartan or PD123319, 1 mg/kg/day). Receptor localization by autoradiography showed in P0 and P8 hindbrains, that most structures expressed AT(2) subtype: cerebellar cortex, cerebellar nuclei, genu facial nucleus, inferior colicullus, inferior olive. In the cerebellar cortex, [(125)I]Ang II AT(2) binding was predominant, while low AT(1) binding was observed in adjacent layers of the cerebellar cortex. Blockade of AT(2) receptors with PD123319 increased binding in cerebellar nuclei (p<0.05) and brainstem nuclei at P0, P8, in correlation with increased AT(2) receptor expression by RT-PCR. The enlarged external granular layer (EGL) in PD123319-treated P0 pups contrast with the significant decrease in Ang II binding (p<0.001) in the cerebellar cortex. Blockade of AT(2) receptors during late pregnancy seems to arrest cerebellar cortex development in P0 animals. On the contrary, increased AT(2) binding was observed in cerebellar cortex and DTg nucleus in PD123319-treated P8 animals (p<0.001). Ang II treatment leads to increased binding in the brainstem. In spite of the low doses of Ang II antagonists used, treatments were performed during a time-frame critical for hindbrain development, leading to remarkable effects. The present study makes a contribution to understand the role of Ang II receptors during hindbrain development.