The Angiotensin AT₁ Receptor Mediates Vasoconstriction in Fetal Umbilical and Systemic Arteries

Abstract 355 Poster Session I, Saturday, 5/1 (poster 145)

Angiotensin II (AII) is an important modulator of fetal organ blood flow and vascular resistance. Two major AII receptor subtypes exist, the AT₁receptor (AT₁R) appears to mediate most cardiovascular actions of AII, whereas the role of the AT₂R is unknown. It has been shown that systemic arteries of term fetal sheep express predominantly AT₂R, while umbilical arteries express AT₁R ( Cox et al, Proc AHA 1995, p.1446), suggesting that AII regulation of fetal blood pressure is primarily mediated by altering umbilical vascular resistance. To determine if systemic arteries in term fetal sheep are sensitive to AII, isometric contraction of fetal renal (RA), mesenteric (MA) and umbilical (UA) arteries in response to AII was studied. Compared with the maximum response seen with KCL (90mM), AII (10^-7 mM) elicited contractile responses of 43±8%, 99±21% and 105±5% for RA, MA and UA respectively, (all n = 4). The AT₁R antagonist losartan (10^-6 mM) slowed the contraction in UA in response to AII but had no effect on maximum contraction; in contrast, losartan abolished contractile responses in RA and MA. Losartan at 10^-5 mM produced partial inhibition of contraction in UA to AII (30±2% of max), while saralasin (non-specific AII receptor antagonist, 10^-5 mM) produced complete inhibition. Neither AT₂R blockade (PD 123319, 10^-7 mM) nor disruption of the endothelium effected the response to AII in any vessel. Tachyphylaxis was more prominent in RA (37±6% contraction with 3rd dose of AII compared with first) than in MA (59±7%) or UA (75±3%). The time-course of the contractile responses also differed among the vessels, exhibiting rapid transient contraction followed by relaxation in RA and MA, while UA displayed a slower and sustained contraction (% of max contractile response at 5 min: 1±0, 3±1, 93±4% for RA, MA and UA respectively). Immunoreactivity for AT₁R was present in endothelium and smooth muscle of the tunica media in both MA and UA (RA not examined). These findings suggest the AT₁R is present and functionally active in fetal systemic arteries and likely contributes to AII regulation of fetal cardiovascular homeostasis. A significant role for the AT₂R in regulating fetal vascular responsiveness to AII could not be demonstrated. Our results are consistent with previous findings that the umbilical circulation displays a greater responsiveness to AII than fetal systemic vasculature. It is unclear if the different character of the contractile response and absence of tachyphylaxis in UA compared with RA and MA is related to differences in AII receptor subtype densities or if other factors, such as differences in signal transduction mechanisms, are involved.