Abstract
Some of the effects of bacterial toxins are mediated through the local production of nitric oxide (NO) or its products. This study examined if NO inhibition in the intestinal mucosa had effects on the responses to intravenous lipopolysaccharide (LPS) in anesthetized rats. Aminoguanidine (AMGU, 500 μM), a relatively selective inducible NO synthase (iNOS) inhibitor, or N G-nitro-l-arginine (NOLARG, 50 or 500 μM), a nonselective inhibitor of iNOS and constitutive NOS (cNOS), were perfused through the ileal lumen during intravenous LPS (17 mg/kg) or saline administration. Intestinal H2O transport, NO3 − + NO2 − (NOx) secretion, absorptive site mucosal blood flow (ASBF), blood pressure, plasma [NOx], tissue damage, and blood leukocytes were measured for 4 hr. LPS increased luminal NOx secretion. At 50 μM, luminal NOLARG attenuated the LPS-induced NOx secretion and increased blood pressure. There were no significant changes in lethality, plasma [NOx] or other parameters. At 500 μM, luminal NOLARG converted a nonlethal dose of LPS into a lethal dose, but AMGU did not increase lethality. The LPS-induced luminal NOx secretion was blocked by 500 μM intraluminal AMGU and NOLARG. Luminal NOx secretion also increased in control animals. This increase was blocked by 500 μM NOLARG but not AMGU. Luminal 500 μM NOLARG increased blood pressure, but AMGU did not. Luminal 500 μM NOLARG prevented the LPS-induced increase in plasma [NOx] and the decrease in leukocytes, but AMGU did not. Tissue damage occurred with intravenous LPS plus intraluminal 500 μM NOLARG. It was concluded that luminal AMGU inhibited mucosal iNOS. Luminal NOLARG inhibited mucosal cNOS and iNOS, and cNOS inhibition primed a lethal LPS effect. NOLARG, but not AMGU, was absorbed from the intestine and had systemic effects.
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Mailman, D. Ileal Luminal Nitric Oxide Synthase Inhibitors and E. coli Lipopolysaccharide Effects in the Anesthetized Rat. Dig Dis Sci 47, 190–200 (2002). https://doi.org/10.1023/A:1013200511853
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DOI: https://doi.org/10.1023/A:1013200511853