Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2004-06, Vol.55 (6), p.R1013-R1023
• Main Authors: ORSHAL, Julia M, KHALIL, Raouf A
• Format: Article
• Language: English
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cytokines; Experimental diseases; Fundamental and applied biological sciences. Psychology; Hypertension; Medical sciences; Motor control and motor pathways. Reflexes. Control centers of vegetative functions. Vestibular system and equilibration; Nitric oxide; Pregnancy; Vertebrates: nervous system and sense organs
• ISSN: 0363-6119; 1522-1490

IL-6 is elevated in plasma of preeclamptic women, and twofold elevation of plasma IL-6 increases vascular resistance and arterial pressure in pregnant rats, suggesting a role of the cytokine in hypertension of pregnancy. However, whether the hemodynamic effects of IL-6 reflect direct effects of the cytokine on the mechanisms of vascular contraction/relaxation is unclear. The purpose of this study was to test the hypothesis that IL-6 directly impairs endothelium-dependent relaxation and enhances vascular contraction in systemic vessels of pregnant rats. Active stress was measured in aortic strips isolated from virgin and late pregnant Sprague-Dawley rats and then nontreated or treated for 1 h with IL-6 (10 pg/ml to 10 ng/ml). In endothelium-intact vascular strips, phenylephrine (Phe, 10-5 M) caused an increase in active stress that was smaller in pregnant (4.2 plus or minus 0.3) than virgin rats (5.1 plus or minus 0.3 x 104 N/m2). IL-6 (1,000 pg/ml) caused enhancement of Phe contraction that was greater in pregnant (10.6 plus or minus 0.7) than virgin rats (7.5 plus or minus 0.4 x 104 N/m2). ACh and bradykinin caused relaxation of Phe contraction and increases in vascular nitrite production that were greater in pregnant than virgin rats. IL-6 caused reductions in ACh- and bradykinin-induced vascular relaxation and nitrite production that were more prominent in pregnant than virgin rats. Incubation of endothelium-intact strips in the presence of N{omega}-nitro-L-arginine methyl ester (10-4 M) to inhibit nitric oxide (NO) synthase, or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10-5 M) to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in nontreated but to a lesser extent in IL-6-treated vessels, particularly those of pregnant rats. Removal of the endothelium enhanced Phe-induced stress in nontreated but not IL-6-treated vessels, particularly those of pregnant rats. In endothelium-denuded strips, relaxation of Phe contraction with sodium nitroprusside, an exogenous NO donor, was not different between nontreated and IL-6-treated vessels of virgin or pregnant rats. Thus IL-6 inhibits endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of virgin and pregnant rats. The greater IL-6-induced inhibition of vascular relaxation and enhancement of contraction in systemic vessels of pregnant rats supports a direct role for IL-6 as one possible mediator of the incre