OS056. Angiotensin II sensitivity and endothelial dysfunction afterexperimental preeclampsia

Women who suffered from preeclampsia (PE) have an increased risk for cardiovascular and renal diseases later in life. Although the exact mechanisms underlying this relationship are unknown, they may relate to an increased sensitivity to angiotensin II (Ang-II) and endothelial dysfunction during a preeclamptic pregnancy, which may persist after PE. Recently, we showed vascular hypersensitivity to Ang-II and disturbed endothelial cell function in experimental PE in rats as compared to healthy pregnant rats.

To study whether vascular hypersensitivity to Ang-II and endothelial dysfunction persist postpartum in experimental PE.

In this ongoing study, we thus far included non-pregnant rats (NP;n=9), formerly healthy pregnant rats (HP;n=9) and formerly experimental preeclamptic rats (PE; infusion of a low dose endotoxin; n=16). Six weeks after pregnancy, animals from each group were treated with Ang-II (osmotic minipump; 200ng/kg/min;NP: n=5;HP: n=6;PE: n=8) or were sham treated (NP: n=4;HP: n=3;PE: n=8). Blood pressure was measured in all rats one day before and weekly after Ang-II or sham treatment (for three weeks). At termination, the aortas of sham operated rats were obtained. Aortic rings (2mm) were mounted for isotonic measurement of vasotonus. Endothelium-dependent acetylcholine- (ACh) mediated vasodilation was studied in phenylephrine-preconstricted rings in the presence of vehicle, N(G)-nitro-L-arginine methyl ester, indomethacin or both, followed by full concentration response curves for ACh (10(-8)M-10(-4)M). Ang-II sensitivity was assessed by obtaining full concentration response curves (10(-10)M-10(-6)M). AT-1 and AT-2 receptor sensitivity was determined by administration of Ang-II in the presence of the AT-1 receptor blocker losartan, or the AT-2 receptor blocker PD123319.

Our results indicate no difference in mean (±SD) systolic blood pressure (SBP) between the three groups six weeks after delivery (NP: 129(±7);HP: 127(±9);PE: 123(±10)mmHg;p=0.248). However, after three weeks of Ang-II treatment, a trend was found towards a stronger increase in SBP in PE rats as compared to HP rats (45.7(±18.9)% vs 63.4(±20.1)% respectively;p=0.081). Although we found no differences in in-vitro Ang-II sensitivity between the three groups, NP rats showed a trend towards an increased sensitivity of the AT-2 receptor to Ang-II compared to both groups of formerly pregnant rats. Total ACh-mediated endothelial relaxation was not different between the three groups. However, contribution of both NO and EDHF components to ACh-mediated relaxation seemed decreased in both groups of formerly pregnant rats as compared to the NP rats.

These preliminary data suggest that healthy rats that suffered from preeclampsia during pregnancy have increased in-vivo sensitivity to Ang-II postpartum as compared to rats with an uncomplicated pregnancy. Whether these differences are related to in-vitro- changes in Ang-II sensitivity or changes in endothelial function remains to be established.