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Interleukin‐1β Causes Depression of Aortic Contractions in Wild‐Type Mice but Endothelium‐Dependent Enhancement of Contractions in INOS‐Knockout Mice
Author(s) -
Chan Siu L,
Fiscus Ronald R
Publication year - 2002
Publication title -
journal of cardiac surgery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.428
H-Index - 58
eISSN - 1540-8191
pISSN - 0886-0440
DOI - 10.1046/j.1540-8191.2002.101421.x
Subject(s) - phenylephrine , knockout mouse , nitric oxide synthase , nitric oxide , endothelium , medicine , endocrinology , agonist , cytokine , pharmacology , chemistry , receptor , blood pressure
: Studies in animals have indicated that increased production of nitric oxide (NO) from an inducible isoform of nitric oxide synthase (iNOS) contributes to the vascular abnormalities of endotoxin‐ and cytokine‐induced shock. Objective: The aim of this study was to determine if the cytokine interleukin‐1β (IL‐1β) depresses vasocontractions induced by an α‐adrenergic agonist in aortic rings of control C57BL/6J (wild‐type) mice and if mice lacking iNOS gene expression (using iNOS‐knockout mice) completely lacks the vasodepressant effect of IL‐1β. Methods: Thoracic aortas were removed from wild‐type and knockout mice, and setup in isolated organ baths with Krebs solution and 95% oxygen and 5% carbon dioxide. After equilibration, contractions by the α‐adrenergic agonist phenylephrine, over a complete concentration‐response range, were first measured before adding IL‐1β. Rings were then incubated with 100 ng/ml IL‐1β for 2 hr, followed by replacing with fresh Krebs solution every 20 min over another 3 hr. Contractile responses to phenylephrine, over a complete concentration‐response range, were again measured. Results: There was no significant difference between the contractile response to phenylephrine at the beginning and the end of the 5 hr incubation in all of the time controls (i.e. both wild‐type and iNOS‐knockout mouse aortic rings, both with and without endothelium) that were not exposed to IL‐1β. In aortic rings incubated with IL‐1β, contractions induced by phenylephrine were significantly attenuated both in endothelium‐preserved and endothelium‐denuded rings of wild‐type mice. In endothelium‐denuded aortic rings of iNOS‐knockout mice, IL‐1β had no effect on phenylephrine‐induced contractions, indicating a complete lose of the vasodepressant actions of IL‐1β. In contrast, in endothelium‐preserved aortic rings of iNOS‐knockout mice, IL‐1β significantly enhanced the contractions caused by phenylephrine. Conclusions: The present data demonstrate that the IL‐1β−induced depression of vasocontractions in mouse aortic rings is completely dependent on the expression of iNOS and increased production of NO in vascular smooth muscle cells. Aortic rings with intact endothelium but lacking iNOS expression showed enhanced vasocontractions following incubation with IL‐1β. The data suggest that, when iNOS is absent, IL‐1β induced another endothelium‐dependent pathway that potentiates contractile responses of α‐adrenergic agonists. (Supported by a Direct Grant for Research)