INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM MODIFIES RECEPTOR LOCALIZATION AND EXPRESSION IN DEVELOPING RAT HINDBRAIN

SÁNCHEZ SI, FUENTES LB AND CIUFFO GM

Ouro Preto, Brasil

Congreso; Intnl Symposium on Vasoactive Peptides; 2008

Soc

Several evidences suggest that Ang II plays an important role in the complex process of  organogenesis. The aim of the present study was to evaluate if inhibition of the RAS system during pregnancy produce abnormalities in hindbrain development. In the rat, cerebellum development lasts for 20 days after birth. In a previous paper we performed a study on receptor localization on cerebellum and brainstem on 2-week old animals (Arce ME et al., Regul. Pept. 99, 2001, 53-60). We studied the localization of Ang II receptors by autoradiography during hindbrain development in offspring of pregnant rats treated with Ang II and antagonists (Losartan, PD123319). Pups were analyzed at two different ages, PND0 and PND8. The present study demonstrates changes at the histological level and on receptor localization and expression in animals born from mothers treated with Ang II, Losartan or PD123319 (1.0 mg/kg/day) during late pregnancy (GD13-GD21). Although treatments lasted for one week before birth, we observed important effects on hindbrain development both at the histological and receptor localization level in PND8 animals. These observations indicated that the damage continued even when there was no longer exposure to the drugs. In PND0 animals, two levels were analyzed (P60 and P69) and three levels were analyzed fin PND8 animals (Bregma equivalent –9.30,-9.80 and –11.0). In PND0 animals, few structures can be identified, such as g7 (genu facial nucleus), IC (inferior colicullus), SC (Superior colicullus), icp (inferior cerebellar peduncle), IO (inferior olive). Increased binding of the AT2 subtype was observed in Ang II- treated and PD123319-treated animals, associated to SC, IO and cerebellar nucleus. At the histological level, also an abnormal structure was observed. Increased AT2 Ang II receptor expression was observed by RT-PCR, in Ang II- treated and PD123319-treated animals with respect to control animals. PND8 animals exhibited a histological structure more advanced. However, alterations were observed for all treatments. Increased binding of the AT2 subtype was observed in Ang II-treated and PD123319-treated animals, associated to SC, IO, cerebellar area 2 and several brainstem nucleus. Increased binding correlates with increased receptor expression by RT-PCR. Thus, the lack of receptor stimulation during prenatal period by means of pharmacological blockade leads to an altered structure of developing hindbrain. These observations confirm previous assumptions that in development Ang II exerts a stimulatory effect through AT1 receptors that might be counterbalanced by AT2 receptors, which promote apoptosis and growth inhibition. This work was supported by grants from CONICET, PICT 01-9759 (ANPCYT) and Universidad Nacional de San Luis, Argentina.