Influence of endothelium on induction of the L-arginine-nitric oxide pathway in rat aortas.
The role of the endothelium in the onset and persistence of vascular hyporeactivity induced by bacterial lipopolysaccharide (LPS) and the implication of the L-arginine-nitric oxide (NO) pathway in this phenomenon were investigated in rat aortic rings exposed to LPS for different times. LPS (100 ng/ml) induced a decrease in the contractile response obtained by norepinephrine (NE) in rings without endothelium after a delay of 6 h. This delay was reduced to 4 h in the presence of the endothelium and corresponded temporally with the development of relaxation after addition of L-arginine (1 mM). This effect of L-arginine along with hyporeactivity to NE was reversed by both NG-nitro-L-arginine methyl ester (300 microM) and methylene blue (3 microM). The effects of LPS on reactivity, L-arginine-dependent relaxation, and tissue guanosine 3',5'-cyclic monophosphate content were prevented by cycloheximide (100 micrograms/ml) whether present throughout the experiment or added 6 h after LPS. Increasing the concentration of LPS to 1 mg/ml reduced the delay between addition of LPS and response to L-arginine in endothelium-denuded rings to 4 h but was without effect on the delay observed in rings with endothelium. These results demonstrate that the time course of development of hyporeactivity to NE corresponds to that of activation of the L-arginine-NO pathway after LPS challenge as assessed by development of sensitivity to L-arginine. The induction process was accelerated by the presence of the endothelium, which also increased the sensitivity of the preparation to LPS.(ABSTRACT TRUNCATED AT 250 WORDS)
Laboratoire de Pharmacologie Cellulaire et Moléculaire, Centre National de la Recherche Scientifique URA 600, Université Louis Pasteur de Strasbourg, Illkirch, France.
I
I
Fleming
G A
GA
Gray
J C
JC
Stoclet
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009434:Neural Pathways / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019323:omega-N-Methylarginine
D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D003513:Cycloheximide; D006152:Cyclic GMP; D008751:Methylene Blue; D009638:Norepinephrine