oxadiazoles and Magnesium-Deficiency

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.

Topics: Amidines; Animals; Aorta, Thoracic; Benzylamines; Diet; Dose-Response Relationship, Drug; Enzyme Inhibitors; Escherichia coli; In Vitro Techniques; Injections, Intraperitoneal; Interleukin-1; Lipopolysaccharides; Magnesium Deficiency; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oxadiazoles; Phenylephrine; Quinoxalines; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor; RNA, Messenger; Tumor Necrosis Factor-alpha