Ileal luminal nitric oxide synthase inhibitors and E. coli lipopolysaccharide effects in the anesthetized rat.
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 microM), a relatively selective inducible NO synthase (iNOS) inhibitor, or N(G)-nitro-L-arginine (NOLARG, 50 or 500 microM), 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 H20 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 microM, 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 microM, 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 microM intraluminal AMGU and NOLARG. Luminal NOx secretion also increased in control animals. This increase was blocked by 500 microM NOLARG but not AMGU. Luminal 500 microM NOLARG increased blood pressure, but AMGU did not. Luminal 500 microM 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 microM 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.
Mailman
David
D
Biology and Biochemistry Department, University of Houston, Houston, Texas 77204, USA.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004926:Escherichia coli; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D007082:Ileum / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014867:Water / Q000378:metabolism
D006146:Guanidines; D008070:Lipopolysaccharides; D014867:Water; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine