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 gene rating 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 glycogenolys is by a magnitude similar to that observed with S-nitroso-N-acetylpeni cillamine. S-nitroso-N-acetylpenicillamine had no effect on phenylephr ine-stimulated glycogenolysis, but inhibited 8-bromo-cAMP-stimulated g lycogenolysis by 15%. These observations suggest that S-nitroso-N-acet ylpenicillamine inhibits cAMP-mediated stimulation of glycogenolysis a t a site distal to adenylate cyclase. In summary, hepatocyte glucagon- stimulated glycogenolysis was inhibited to a small, but significant, d egree by S-nitroso-N-acetylpenicillamine. This inhibition is consisten t with a nitric oxide mediated stimulation of guanylate cyclase and co nsequent stimulation of cAMP-phosphodiesterase activity. Nitric oxide may contribute to altered carbohydrate homeostasis under pathophysiolo gic conditions.