In vivo and in vitro effects of endotoxin on vascular responsiveness to norepinephrine and signal transduction in the rat
Suba, E.A.; McKenna, T.M.; Williams, T.J.
Circulatory Shock 36(2): 127-133
1992
ISSN/ISBN: 0092-6213 PMID: 1316243 Document Number: 404815
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.degree. C did not effect the basal and norepinephrine (NE)-stimulated (10 .mu.M, 1 hr, 37.degree. C) phosphoinositide (PI) hydrolysis and isometric contractions induced by graded doses (1 nM to 10.0 .mu.M) of NE. Increasing the incubation time with endotoxin to 18 hr did not alter the basal PI hydrolysis but significantly (P < 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 < 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. This latter finding suggests that .alpha.1-adrenergic hyporesponsiveness may be due to impairment by endotoxin of PI hydrolysis that is the initial response of the membrane transduction system of vascular smooth muscle membrane. The data are consistent with either a marked decrease in receptor number and/or a postreceptor impairment.