Reduced endothelial NO-cGMP-mediated vascular relaxation and hypertension in IL-6-infused pregnant rats

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 ( 146 +/- 3) than in control pregnant rats ( 117 +/- 2 mm Hg). In endothelium- intact vascular strips, phenylephrine (Phe) caused greater increase in active stress in IL-6 -infused (maximum: 10.6 +/- 0.6) than in control pregnant rats (maximum: 4.1 +/- 0.3 x 10(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. N-omega-nitro-L-arginine methyl ester (10(-4) mol/L), inhibitor of NOS, or 1H-[1,2,4] oxadiazolo[4,3]quinoxalin- 1-one (10(-5) 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 endothelium-dependent 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.