© 1997 American Heart Association, Inc.
Articles |
Inhibition of Inducible Nitric Oxide Synthase Restores Endothelium-Dependent Relaxations in Proinflammatory Mediator-Induced Blood Vessels
From Zentrum der Anästhesiologie (P.K.) and Zentrum der Physiologie, (J.B., R.B., V.B.S.-K.), Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Correspondence to V.B. Schini-Kerth, Ph.D., Zentrum der Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. E-mail busse{at}merlin.add.uni-frankfurt.de.
Abstract Endothelium-dependent relaxations
mediated by nitric oxide (NO) are attenuated in arteries exposed to
proinflammatory mediators. Because proinflammatory mediators stimulate
the expression of the inducible NO synthase (iNOS) in vascular cells,
the role of iNOS-derived NO in the impaired
endothelium-dependent relaxation was examined in
arterial ring preparations. Exposure of rabbit carotid
arteries to interleukin-1 ß (IL-1 ß; 100 U/mL for 7 hours) and
porcine coronary arteries to a combination of tumor necrosis
factor-
(1000 U/mL), interferon-
(500 U/mL), and
lipopolysaccharide (10 µg/mL) for 15 hours (conditions that
are associated with iNOS expression) markedly attenuated relaxations to
receptor-dependent agonists, whereas those to the calcium ionophore
A23187 and sodium nitroprusside were virtually unchanged. The impaired
relaxation was not associated with a reduced level of the constitutive
endothelial NOS (cNOS) but was accompanied by a reduced
formation of biologically active NO as assessed in a bioassay system.
The attenuated relaxation of carotid arteries to acetylcholine was not
affected by superoxide dismutase and was neither found in arteries
exposed to IL-1 ß for only 15 minutes nor in IL-1 ß-treated
arteries for 7 hours followed by a 17-hour incubation period without
the cytokine. Furthermore, no impaired relaxation was found in
rings exposed to IL-1 ß in combination with either cycloheximide or
N--tosyl-L-lysine chloromethyl ketone or
pyrrolidine dithiocarbamate, treatments that prevent iNOS expression.
In addition, selective inhibition of iNOS with
S-methylisothiourea (10 µmol/L) completely restored
acetylcholine-induced relaxations.
These findings indicate that the continuous generation of NO induced by proinflammatory mediators plays a major role in the inhibition of endothelium-dependent relaxation, most likely by impairing a step in the signal transduction cascade that links activation of endothelial receptors to the calcium-calmodulin-dependent activation of NOS.
Key Words: nitric oxide • inducible NOS • constitutive NOS • isolated blood vessels • bioassay system
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