The present study was designed to test the hypothesis that an increase in AT1 receptor activity participates in the decline in AT2 mRNA expression associated with fetal maturation (Pediatr Res 38:896904, 1995). To test this hypothesis, we studied eleven pairs of chronically instrumented twin fetal sheep at 95d gestation and seven pairs at 110d gestation (term is 145d). One twin received intravenous infusion of losartan (L) (10mg/kg bolus followed by 20 μg/kg/min for 48 hr) while the other served as a salinetreated control (C). In the 95d animals, no change in heart rate, mean arterial blood pressure (MABP), plasma renin activity (PRA), or aldosterone levels were observed during L infusion. Furthermore, L did not alter AT1 and AT2 mRNA expression in 95d fetuses; AT1 and AT2 mRNA levels were consistent in C and L animals kidney cortex, kidney medulla, liver, and adrenal. In contrast, in 110d fetuses, L decreased MABP from 40.1±1mmHg to 33±1mmHg(p<0.001) while PRA increased from 4.8±1.5 to 9.8±3 ngAI/ml/hr (p<0.05). In addition, L decreased 110d kidney medulla AT1 by 32±12% (p<0.05) and reduced kidney medulla AT2 by 32±14%(p<0.05) mRNA expression. Likewise, adrenal AT2 fell by 14±11%. To determine if these changes in mRNA expression during L were secondary to changes in MABP, three additional sets of 110d twin fetuses were studied; one twin received L while the other twin received L plus phenylephrine to keep MABP from falling. When compared to L fetuses, keeping MABP normal prevented changes in AT1 and AT2 mRNA levels.

In summary, the present results suggest that AT1 receptors do not become physiologically functional before the third trimester of gestation. Changes in AT1 and AT2 receptor mRNA following L in 110d fetuses appear to be related to changes in blood pressure.