Ontogeny and regulation of cardiac angiotensin types 1 and 2 receptors during fetal life in sheep.

Previous studies have shown that the expression of cardiac angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors are developmentally regulated, although factors modulating these receptors have not been well investigated. The present study was designed 1) to characterize the ontogeny of cardiac AT1 and AT2 gene expression during the last third trimester of gestation in fetal sheep and newborn lambs, 2) to determine the influence of ANG II on modulating cardiac AT1 and AT2 gene expression during fetal life, and 3) to investigate the role of AT1 receptor activity on the regulation of AT1 and AT2 mRNA levels during fetal cardiac development. Using sheep AT1 and AT2 cDNA probes, we demonstrated that cardiac AT1 gene expression is relatively unchanged during fetal (90-135 d of gestation, term 145 d) and newborn life. In contrast, cardiac AT2 mRNA expression was high during fetal development and decreased rapidly after birth. Continuous i.v. infusion of ANG II (9.5 nM/h) for 24 h, which raised ANG II levels from 84+/-9 to 210+/-21 pg/mL had no effect on the expression of cardiac AT1 or AT2 mRNA, but increased adrenal and decreased liver AT1 mRNA levels. Administration of the AT1 receptor antagonist losartan (1.2 mg kg(-1) h(-1)) significantly decreased arterial blood pressure in fetuses at 110- and 135-d, but not 95-d gestation. Except for increased AT1 receptor gene expression in the right atrium at 95- and 135-d gestation, and left ventricle at 110-d gestation, cardiac AT1 and AT2 mRNA levels were unaltered by AT1 receptor blockade. In summary, this study demonstrates that cardiac AT2 but not AT1 receptor gene expression is regulated by the transition from fetal to newborn life. Neither ANG II nor blockade of AT1 receptors significantly alter the expression of AT1 or AT2 mRNA in the fetal heart. Endogenous ANG II also appears to significantly contribute to the maintenance of blood pressure homeostasis during the final third of gestation in fetal lambs.