REGULATION OF ANGIOTENSIN II (AII) MEDIATED AUTONOMIC RESPONSES DURING DEVELOPMENT. † 391

Studies in adults suggest that circulating AII acts via central AT₁ receptors within the area postrema (AP), an area which lacks a blood-brain barrier, to effect autonomic control of cardiovascular function. We previously demonstrated that despite similar initial plasma AII levels, inhibition of the renin-angiotensin system with enalaprilat alters arterial baroreflex function in newborn but not third trimester fetal sheep, suggesting that the influence of endogenous AII on autonomic function is attenuated during fetal life. To investigate mechanisms regulating this differential response to AII, we first used Northern blot analysis to characterize maturational changes in ovine AP AT₁ mRNA levels, and second, studied ontogenic changes in functional activation of AII receptors by measuring the intracellular calcium response to AII in AP neurons in culture. AT₁ mRNA levels were lowest early in fetal life and increase to adult levels late in gestation. No differences were seen between late term fetuses and newborns. Using microscopic image digital analysis of Fura-2 loaded single neurons, we found 11 of 24 cells (46%) from newborns (3-7 d of age) had a marked increase in [Ca²⁺]_i in response to AII (10^-6M) whereas 0/27 neurons from fetuses (130 d gestation [term 145 d]) responded (p<0.05). These results suggest that the lack of influence of AII on autonomic function in the mature fetus is related to maturational changes in the ability of AII to activate AP neurons. This developmental effect is not related to differences in AT₁ mRNA levels, but may be secondary to changes in receptor expression or signal transduction mechanisms. Table

Table 1