Abstract-Placental ischemia during pregnancy is associated with increased plasma cytokines such as interleukin-6 (IL-6), which may contribute to increased vascular resistance and hypertension of pregnancy. We tested the hypothesis that an increase in plasma IL-6 during pregnancy is associated with impaired endothelium-dependent relaxation, enhanced vascular contraction, and hypertension. Systolic blood pressure was measured in virgin and pregnant Sprague-Dawley rats non-treated or infused with IL-6 (200 ng/kg per day for 5 days). Isometric contraction was measured in isolated aortic strips, and endothelial nitric oxide (NO) synthase (eNOS) was measured in aortic homogenate using Western blots. Blood pressure was greater in IL-6 -infused (146Ϯ3) than in control pregnant rats (117Ϯ2 mm Hg). In endothelium-intact vascular strips, phenylephrine (Phe) caused greater increase in active stress in IL-6 -infused (maximum: 10.6Ϯ0.6) than in control pregnant rats (maximum: 4.1Ϯ0.3ϫ10 4 N/m 2 ). Acetylcholine (ACh)-induced relaxation of Phe contraction and vascular eNOS protein and nitrite/nitrate production were less in IL-6 -infused than in control pregnant rats.Ϫ5 mol/L), inhibitor of cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in control but not IL-6 -infused pregnant rats. Endothelium removal enhanced Phe-induced stress in control but not in IL-6 -infused pregnant rats. The blood pressure and vascular Phe-induced contraction, ACh relaxation, and eNOS protein were not different between control and IL-6 -infused virgin rats. Thus, an endotheliumdependent NO-cGMP-mediated relaxation pathway is inhibited in systemic vessels of pregnant rats infused with IL-6. The results support a role for IL-6 as a possible mediator of the increased vascular resistance during hypertension of pregnancy. Key Words: blood pressure Ⅲ endothelium Ⅲ nitric oxide Ⅲ pregnancy N ormal pregnancy is associated with reduced systemic vascular resistance and arterial pressure and decreased vascular contraction to vasoconstrictor agonists. 1-3 The hemodynamic and vascular changes observed during normal pregnancy have been attributed, in part, to increased nitric oxide (NO) production by various cells, including vascular endothelial cells. 4 -8 This is supported by reports that the tissue expression and activity of NO synthase are increased during late gestation 9 -11 and that the metabolic production and plasma level of cyclic guanosine 3Ј,5Ј-monophosphate (cGMP), a second messenger of NO and a cellular mediator of vascular smooth muscle relaxation, 12 are increased during pregnancy. 13 In 3% to 5% of pregnancies, a condition called preeclampsia develops, which is characterized by increased intravascular coagulation, proteinuria, increased systemic vascular resistance ,and hypertension. 14 -16 Although preeclampsia is a major cause of maternal and fetal morbidity and mortality, the mechanisms of this disorder have not yet been clearly identified. Because of the difficulty of performing mechanistic...