In vivo and in vitro effects of endotoxin on vascular responsiveness to norepinephrine and signal transduction in the rat.
We investigated, after in vitro and in vivo exposure to gram-negative endotoxin, the altered responsiveness of rat aortic smooth muscle to catecholamines. Two hour exposure of aortic rings from normal rats to 100 ng/ml of Escherichia coli 0111:B4 endotoxin in vitro in an artificial medium supplemented with 5% fetal calf serum at 37 degrees C did not effect the basal and norepinephrine (NE)-stimulated (10 microM, 1 hr, 37 degrees C) phosphoinositide (PI) hydrolysis and isometric contractions induced by graded doses (1 nM to 10.0 microM) of NE. Increasing the incubation time with endotoxin to 18 hr did not alter the basal PI hydrolysis but significantly (P less than 0.05) decreased the NE-induced PI hydrolysis (30% inhibition) and contractile sensitivity to NE (increase of EC50 from 20.0 +/- 3.8 to 156.4 +/- 46.7 nM). Qualitatively similar results were obtained in experiments where rats were injected intravenously with buffer or an LD50 dose (10 mg/kg) of endotoxin. In these ex vivo measurements, only an 18 hr exposure to endotoxin caused significant (P less than 0.001) decreases in basal (58% inhibition) and NE-stimulated (75% inhibition) PI hydrolysis and in NE-induced isometric contractions (increase of EC50 from 11.0 +/- 3.3 to 664.1 +/- 280.0 nM). The results show that the endotoxin-induced hyporeactivity to alpha 1-adrenergic receptor stimulation 1) is markedly dependent on the length of endotoxin exposure, 2) does not require (although may be enhanced by) contact with blood cells and plasma, and 3) is paralleled by a decrease in both basal and NE-stimulated PI hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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Septic Shock Research Program, Naval Medical Research Institute, Bethesda, Maryland 20889-5055.
McKenna
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Williams
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D000818:Animals; D001011:Aorta / Q000187:drug effects; D004195:Disease Models, Animal; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*
D004731:Endotoxins; D010716:Phosphatidylinositols; D009638:Norepinephrine