Endothelin-receptor gene-expression in rat endotoxemia.
OBJECTIVE
The reduced vascular response to endothelin-1 has focused interest onto the regulation of the endothelin-receptor subtypes ET(A) and ET(B) during severe sepsis.


METHODS
Prospective animal trial followed by a controlled cell culture study in the laboratory of the Department of Anesthesiology.


METHODS
Male Sprague-Dawley rats weighing 200-250 g, aortic vascular smooth muscle cell line A7r5.


METHODS
Rats were injected with lipopolysaccharide to induce severe experimental endotoxemia. ET(A)/ET(B) receptor gene expression was investigated by specific RNase protection assay, and abundance of tumor necrosis factor alpha was determined in the lung and kidney. Aortic vascular smooth muscle cells were incubated with the proinflammatory cytokines interleukin-1beta, tumor necrosis factor alpha, and interferon gamma or with the nitric oxide donor S-nitroso- N-acetylpenicillamine to investigate the regulation of ET(A) receptor gene expression during severe inflammation.


RESULTS
ET(A)/ET(B) receptor gene expression was markedly downregulated in the lung but was unchanged in the kidney during endotoxemia. ET(A) receptor gene expression was downregulated in aortic vascular smooth muscle cells by tumor necrosis factor alpha but not by interleukin 1beta, interferon gamma, or nitric oxide. In vivo there seems to be a correlation between the tissue concentration of tumor necrosis factor alpha and gene expression of ET(A) receptors in the lung and kidney.


CONCLUSIONS
Our data show that sepsis causes downregulation of ET(A) receptors at the level of gene expression, and provide correlative evidence that this effect can be mediated by tumor necrosis factor alpha. This downregulation of ET(A) receptors possibly contributes to the attenuated vascular response to endothelin-1 in the pulmonary circulation.
Bucher
Michael
M
Department of Anesthesiology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany. michael.bucher@klinik.uni-regensburg.de
Taeger
Kai
K
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019446:Endotoxemia / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000235:genetics*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D014409:Tumor Necrosis Factor-alpha; D026423:S-Nitroso-N-Acetylpenicillamine; D007371:Interferon-gamma