ONTOGENY AND REGULATION OF CARDIAC ANGIOTENSIN TYPE-1 AND TYPE-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 developme ntally regulated, although factors modulating these receptors have not been well investigated. The present study was designed 1) to characte rize the ontogeny of cardiac AT(1) and AT(2) gene expression during th e last third trimester of gestation in fetal sheep and newborn lambs, 2) to determine the influence of ANG II on modulating cardiac AT(1) an d AT(2) gene expression during fetal life, and 3) to investigate the r ole of AT(1) receptor activity on the regulation of AT(1) and AT(2) mR NA levels during fetal cardiac development. Using sheep AT(1) and AT(2 ) cDNA probes, we demonstrated that cardiac AT(1) gene expression is r elatively unchanged during fetal (90-135 d of gestation, term 145 d) a nd newborn life. In contrast, cardiac AT(2) mRNA expression was high d uring 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 level s 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 live r AT(1) mRNA levels. Administration of the AT(1) receptor antagonist l osartan (1.2 mg kg(-1) h(-1)) significantly decreased arterial blood p ressure in fetuses at 110- and 135-d, but not 95-d gestation. Except f or increased AT(1) receptor gene expression in the right atrium at 95- and 135-d gestation, and left ventricle at 110-d gestation, cardiac A T(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) r eceptor gene expression is regulated by the transition from fetal to n ewborn life. Neither ANG II nor blockade of AT(1) receptors significan tly alter the expression of AT(1) or AT(2) mRNA in the fetal heart. En dogenous ANG II also appears to significantly contribute to the mainte nance of blood pressure homeostasis during the final third of gestatio n in fetal lambs.