Abstract 416: Inhibition of Metabolism of Endogenous AEA and 2-AG Reduces Ang II Induced Uterine Artery Contraction at Early Pregnancy in a Transgenic Model of Preeclampsia

Abstract

Recent evidence of interactions between the renin-angiotensin and the endocannabinoid systems suggests a regulatory role for endogenous cannabinoids (ECs) in modulating Ang II vascular responses. Endogenous levels of the ECs, AEA and 2-AG, are controlled by the hydrolytic enzymes FAAH and MAGL, respectively. We investigated the role of AEA and 2-AG as modulators of Ang II contraction in uterine arteries (UA) in a transgenic pregnant rat, in which the female expressing human angiotensinogen (AGT) is mated to the male with human renin (REN), producing a preeclamptic pregnancy. Uterine arteries were isolated from pregnant transgenic h AGTx h REN rats at 7 days of gestational age (n=4). Arterial segments were mounted in a wire myograph for determinations of isometric tension (DMT USA, 620M). Concentration response curves to Ang II (10 -11 -10 -8 M) were performed in control conditions and after preincubation with enzyme inhibitors: URB597 (FAAH) or JZL184 (MAGL) at 10 -6 M. Data were fitted to a dose response curve, maximal responses (Ang II MAX ) were expressed as percent of maximal response to 75 mM KCl (% K MAX ) and sensitivity as pD 2 (pD 2 = -Log [EC 50 ]). Inhibition of FAAH attenuated both maximal response and sensitivity (Ang II MAX 76±9 vs 105±3, p<0.05; pD 2 8.7±0.09 vs 9.1±0.04, p<0.05) and inhibition of MAGL lowered Ang II sensitivity (Ang II MAX 83±15; pD 2 8.8±0.01, p<0.05), Figure. Thus, by inhibiting the enzymes involved in breakdown of ECs, we demonstrate a functional EC system in the UA that counteracts Ang II contraction. Whether the buffering capacity of the EC system is altered in this model of preeclampsia relative to normal pregnancy is under investigation.