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 (AT(1)) and type 2 (AT(2)) 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 AT(1) and AT(2) 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 AT(1) and AT(2) gene expression during fetal life, and 3) to investigate the role of AT(1) receptor activity on the regulation of AT(1) and AT(2) mRNA levels during fetal cardiac development. Using sheep AT(1) and AT(2) cDNA probes, we demonstrated that cardiac AT(1) gene expression is relatively unchanged during fetal (90-135 d of gestation, term 145 d) and newborn life. In contrast, cardiac AT(2) 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 AT(1) or AT(2) mRNA, but increased adrenal and decreased liver AT(1) mRNA levels. Administration of the AT(1) 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 AT(1) receptor gene expression in the right atrium at 95- and 135-d gestation, and left ventricle at 110-d gestation, cardiac AT(1) and AT(2) mRNA levels were unaltered by AT(1) receptor blockade. In summary, this study demonstrates that cardiac AT(2) but not AT(1) receptor gene expression is regulated by the transition from fetal to newborn life. Neither ANG II nor blockade of AT(1) receptors significantly alter the expression of AT(1) or AT(2) 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.