Enhancement of endotoxin-induced vascular hyporeactivity to phenylephrine in the thoracic aortas of Mg-deficient rats ex vivo.
Since endotoxin lethality is enhanced by Mg deficiency in animals, we determined whether endotoxin-induced vascular hyporeactivity to phenylephrine (PE) is enhanced in Mg-deficient rats. Normal and Mg-deficient adult male Wistar rats were injected with Escherichia coli 011: B4 lipopolysaccharide (1 or 5 mg/kg, i.p.). Six h later, rings prepared from their thoracic aortas showed severe hyporeactivity to PE. This was more pronounced in the Mg-deficient rats, and was reversed by in vitro treatment with a highly selective inducible nitric oxide (NO) synthase inhibitor, 1400 W, or a highly selective soluble guanylyl cyclase inhibitor, ODQ. However, reversal required high doses of both inhibitors in Mg-deficient rats. Endotoxemia for 6 h was associated with elevated serum interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha levels, and strong TNF receptor mRNA expression in the abdominal aortas, which were significantly greater in the Mg-deficient rats. Treatment of the thoracic aortas, isolated from control and Mg-deficient rats before endotoxic challenge, with IL-1beta or TNF-alpha for 6 h in vitro caused hyporeactivity to PE, but its severity did not differ significantly between the two groups. These results suggest that high serum IL-1beta and TNF-alpha levels, and increased TNF receptor production in the vascular tissue, contribute to vascular hyporeactivity to PE in endotoxemia, and to its enhancement in Mg-deficient rats, via NO/cGMP signaling.
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D001596:Benzylamines / Q000494:pharmacology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000276:immunology; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008275:Magnesium Deficiency / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D010069:Oxadiazoles; D011810:Quinoxalines; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D010656:Phenylephrine