Inhibition of glucagon-stimulated glycogenolysis by S-nitroso-N-acetylpenicillamine.
Rat liver is known to contain both a nitric oxide-stimulated guanylate cyclase and a cGMP-stimulated cAMP-phosphodiesterase. To evaluate the possible function of this system, the effect of the nitric oxide generating compound S-nitroso-N-acetylpenicillamine on glycogenolysis was evaluated in isolated rat hepatocytes. S-nitroso-N-acetylpenicillamine (1.0 mM) inhibited glucagon-stimulated glycogenolysis by 15%, but had no effect on basal rates of glycogenolysis. Inhibition of hepatocyte glycogenolysis by S-nitroso-N-acetylpenicillamine was associated with accumulation of cGMP (1.5 pmol/2.0 x 10(6) cells/2 min.). Exogenous 8-Br-cGMP (1.0 mM) inhibited hepatocyte glucagon-stimulated glycogenolysis by a magnitude similar to that observed with S-nitroso-N-acetylpenicillamine. S-nitroso-N-acetylpenicillamine had no effect on phenylephrine-stimulated glycogenolysis, but inhibited 8-bromo-cAMP-stimulated glycogenolysis by 15%. These observations suggest that S-nitroso-N-acetylpenicillamine inhibits cAMP-mediated stimulation of glycogenolysis at a site distal to adenylate cyclase. In summary, hepatocyte glucagon-stimulated glycogenolysis was inhibited to a small, but significant, degree by S-nitroso-N-acetylpenicillamine. This inhibition is consistent with a nitric oxide mediated stimulation of guanylate cyclase and consequent stimulation of cAMP-phosphodiesterase activity. Nitric oxide may contribute to altered carbohydrate homeostasis under pathophysiologic conditions.
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106-4981.
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Vetter
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005934:Glucagon / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005947:Glucose / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D014665:Vasodilator Agents / Q000494:pharmacology*
D008112:Liver Glycogen; D014665:Vasodilator Agents; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D005934:Glucagon; D010396:Penicillamine; D006152:Cyclic GMP; D005947:Glucose