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(Hypertension. 2004;43:434.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Reduced Endothelial NO-cGMP–Mediated Vascular Relaxation and Hypertension in IL-6–Infused Pregnant Rats

From Department of Medicine, Veterans Affairs Medical Center, West Roxbury, Mass and Harvard Medical School, Boston, Mass.

Correspondence to Dr Raouf A. Khalil, Harvard Medical School VA Boston Healthcare Research, 1400 VFW Parkway, 3/2B123, Boston, MA 02132. E-mail raouf_khalil{at}hms.harvard.edu

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±0.3x10⁴ N/m²). 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-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.

Key Words: blood pressure • endothelium • nitric oxide • pregnancy

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