(Stroke. 1999;30:2191-2196.)
© 1999 American Heart Association, Inc.
Original Contributions |
Vascular Effects of Lipopolysaccharide Are Enhanced in Interleukin-10–Deficient Mice
From the Departments of Internal Medicine (C.A.G., D.J.B., F.M.F.) and Pharmacology (F.M.F), Cardiovascular Center, University of Iowa College of Medicine, Iowa City.
Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242-1081.
Background and Purpose—The role in blood vessels of interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is not known. Using mice with targeted deletion of the gene for IL-10 (IL-10-/-), we examined the hypothesis that IL-10 is a major modulator of the vascular effects of lipopolysaccharide (LPS).
Methods—We examined in vitro responses of carotid arteries obtained from wild-type (129/SvEv or C57BL/6; IL-10+/+) and IL-10–deficient mice 6 hours after injection of a relatively low dose of LPS (10 µg).
Results—Contraction of the carotid artery in response to U46619 was impaired in IL-10–deficient mice treated with LPS compared with LPS-treated controls. After LPS, U46619 (0.03 and 0.1 µg/mL) contracted the carotid artery by 0.11±0.02 (mean±SEM) and 0.38±0.03 g in wild-type (n=10) and 0.03±0.01 and 0.19±0.03 g in IL-10–deficient (n=8) mice (P<0.05 versus control). Aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), had no significant effect on contraction of the carotid artery from LPS-treated control mice but restored contraction of the carotid artery in response to U46619 in IL-10–deficient mice to levels seen in wild-type mice. Similar findings were obtained when phenylephrine was used as a vasoconstricting agent. These findings indicate that LPS produces much greater impairment of contractile responses of the carotid artery in IL-10–deficient mice than in control mice. Impaired contractile function was eliminated by aminoguanidine, suggesting that expression of iNOS is enhanced in arteries from IL-10–deficient mice. In carotid arteries from animals injected with LPS, reverse transcription–polymerase chain reaction (RT-PCR) products for iNOS were found more frequently in IL-10–deficient mice than in wild-type mice. RT-PCR products for iNOS were not present in arteries from vehicle-treated animals (IL-10–deficient or wild-type mice).
Conclusions—This is the first evidence that endogenous IL-10 is a major determinant of the effects of LPS on vascular tone. The results suggest that impaired constrictor responses of the carotid artery after LPS in IL-10–deficient mice are mediated by enhanced expression of iNOS.
Editorial Comment
Cardiovascular Sciences, DuPont Pharmaceuticals Company, Wilmington, Delaware
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