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+/-0.3x10(4) 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(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.
Orshal
Julia M
JM
Department of Medicine, Veterans Affairs Medical Center, West Roxbury, Mass, USA.
Khalil
Raouf A
RA
D000818:Animals; D001011:Aorta / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism*; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction; D014664:Vasodilation
D015850:Interleukin-6; D009569:Nitric Oxide; D006152:Cyclic GMP