Attenuation by nitrosothiol NO donors of acute intestinal microvascular dysfunction in the rat.
1. The effects of the nitric oxide (NO) donors, S-nitroso-glutathione (SNOG) and S-nitroso-N-acetyl-penicillamine (SNAP), on the acute intestinal microvascular dysfunction induced by NG-nitro-L-arginine methyl ester (L-NAME) in combination with low doses of endotoxin were investigated in the anaesthetized rat. 2. Administration of L-NAME (5 mg kg-1, s.c.) concurrently with E. coli lipopolysaccharide (LPS, 3 mg kg-1, i.v.) provoked the leakage of radiolabelled albumin in the ileum and colon, as a measure of microvascular damage, determined 1 h after challenge. 3. Intravenous infusion of SNOG or SNAP (1-10 micrograms kg-1 min-1) dose-dependently attenuated the microvascular leakage induced by L-NAME and LPS. 4. Infusion of the lowest doses of SNOG or SNAP (1 microgram kg-1 min-1, i.v.) that significantly reduced the albumin leakage, did not affect the increase in blood pressure in response to L-NAME in LPS-treated rats. Higher doses of SNOG or SNAP (5-10 micrograms kg-1 min-1, i.v.) dose-dependently reduced this increase in blood pressure. 5. In control studies, intravenous infusion of glutathione (10 micrograms kg-1 min-1) or N-acetyl-penicillamine (10 micrograms kg-1 min-1) had no effect on microvascular leakage in the ileum and colon induced by LPS and L-NAME. 6. Pretreatment with rabbit anti-rat neutrophil serum (0.4 ml kg-1, i.p., 4 h before challenge), which reduced the neutrophil count in peripheral arterial blood, also inhibited the microvascular leakage in the ileum and colon. 7. The protective effects of the nitrosothiol NO donors in this model may reflect, in part, modulation of neutrophil interactions within the microcirculation or actions on endothelial cell integrity, in addition to any local vasodilator action.
László
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Wellcome Foundation Ltd, Langley Court, Beckenham, Kent.
Whittle
B J
BJ
Moncada
S
S
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects; D003106:Colon / Q000098:blood supply* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004731:Endotoxins / Q000633:toxicity; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007082:Ileum / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010396:Penicillamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D026422:S-Nitrosoglutathione; D014665:Vasodilator Agents / Q000494:pharmacology*
D004731:Endotoxins; D009603:Nitroso Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D005978:Glutathione; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester