Nitric oxide causes hyporeactivity to phenylephrine in isolated perfused livers from endotoxin-treated rats.
Systemic vascular hyporeactivity to vasoconstrictors has been described in rats following endotoxin administration. Inducible nitric oxide synthase (iNOS) expression is known to occur in the liver in endotoxemia, but consequences of iNOS induction on hepatic hemodynamics are unknown. The reactivity of the hepatic circulation to phenylephrine was tested in perfused livers from normal rats and rats previously injected with endotoxin (20 mg/kg ip). In control rats (n = 5), phenylephrine-induced portal pressure increases were similar in livers perfused with Krebs-Henseleit-bicarbonate (KHB) buffer, KHB plus the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mM), or KHB plus the substrate for NO synthesis, L-arginine (1 mM). In contrast, livers from endotoxin-treated rats (n = 5) exhibited a marked reduction in the vasoconstrictive response to phenylephrine (14.6 vs. 55.1% in livers from control rats, P < 0.05). Perfusion with L-NMMA restored the phenylephrine response, and the L-NMMA effect was reversible with L-arginine. Perfusate NO2-/NO3- and guanosine 3',5'-cyclic monophosphate (cGMP) levels were increased in endotoxin-treated rats and significantly reduced by L-NMMA perfusion. In control livers, the NO donor S-nitroso-N-acetyl-DL-penicillamine blocked the portal pressure increase after phenylephrine administration. These results suggest that rat hepatic circulation takes part in the systemic vascular hyporeactivity to vasoconstrictors observed in endotoxemia and that NO is involved in this hyporeactivity to phenylephrine.
Department of Surgery, University of Pittsburgh, Pennsylvania 15261.
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Billiar
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology*; D011168:Portal System / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D026423:S-Nitroso-N-Acetylpenicillamine; D014325:Tromethamine / Q000494:pharmacology; D014661:Vasoconstriction; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine
D004731:Endotoxins; C074097:Krebs-Henseleit solution; D014665:Vasodilator Agents; D014325:Tromethamine; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D010396:Penicillamine; D005947:Glucose