Proinflammatory mediators chronically downregulate the formation of the endothelium-derived hyperpolarizing factor in arteries via a nitric oxide/cyclic GMP-dependent mechanism

Endothelium-dependent dilator responses mediated by NO and endothelium-derived hyperpolarizing factor (EDHF) are altered in arteriosclerosis and sepsis. The possibility that proinflammatory mediators that stimulate the expression of inducible NO synthase (NOS II) affect the generation of EDHF was ex...

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Published in:Circulation (New York, N.Y.) N.Y.), 1999-04, Vol.99 (14), p.1878-1884
Main Authors: KESSLER, P, POPP, R, BUSSE, R, SCHINI-KERTH, V. B
Format: Article
Language:English
Subjects:
Animals
Arteries - cytology
Arteries - enzymology
Arteries - metabolism
Atherosclerosis (general aspects, experimental research)
Biological and medical sciences
Biological Factors - biosynthesis
Blood and lymphatic vessels
Cardiology. Vascular system
Cells, Cultured
Cyclic GMP - physiology
Cytochrome P-450 Enzyme Inhibitors
Endothelium, Vascular - cytology
Endothelium, Vascular - enzymology
Endothelium, Vascular - metabolism
Inflammation Mediators - physiology
Medical sciences
Nitric Oxide - physiology
Rabbits
Rats
Swine
Vasodilation - physiology
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Summary:Endothelium-dependent dilator responses mediated by NO and endothelium-derived hyperpolarizing factor (EDHF) are altered in arteriosclerosis and sepsis. The possibility that proinflammatory mediators that stimulate the expression of inducible NO synthase (NOS II) affect the generation of EDHF was examined in isolated arteries. Under combined blockade of NOS and cyclooxygenase, EDHF-mediated relaxation elicited by several agonists was significantly attenuated in rabbit carotid and porcine coronary arteries exposed to cytokines and lipopolysaccharide. The blunted relaxation was coincident with NOS II expression and was prevented by inhibition of NOS II as well as of global protein synthesis. The NO donor CAS 1609 and 8-bromo-cGMP mimicked the proinflammatory mediator effect. In contrast, long-term blockade of endothelial NO generation increased the relaxation in carotid but not in coronary arteries. Proinflammatory mediators reduced the synthesis of EDHF assessed as hyperpolarization of vascular smooth muscle cells elicited by the effluent from bradykinin-stimulated coronary arteries. Proinflammatory mediators induced NOS II expression in cultured endothelial cells and decreased the expression of cytochrome P450 enzymes, which are the most probable candidates for the synthesis of EDHF. Proinflammatory mediators inhibit the formation of EDHF in isolated arteries. This impairment is coincident with NOS II expression in the arterial wall and seems to be mediated through the induced generation of NO, which downregulates the putative EDHF-forming enzyme. Thus, a decreased formation of EDHF may contribute to the endothelial dysfunction in arteriosclerosis and sepsis.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.CIR.99.14.1878