Published Online
on January 5, 2004

A more recent version of this article appeared on February 1, 2004

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Submitted on September 30, 2003
Revised on November 3, 2003

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

Julia M. Orshal and Raouf A. Khalil^*

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

^* To whom correspondence should be addressed. E-mail: raouf_khalil{at}hms.harvard.edu.

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 (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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