title: Hepatic cyclic GMP formation is regulated by similar factors that modulate activation of purified hepatic soluble guanylate cyclase.
abstract: The same factors that regulate the activation of purified hepatic soluble guanylate cyclase by diverse agents possessing distinct requirements for enzyme activation were found to modulate cyclic GMP formation in intact viable hepatic cells. A comparison was made between activation of heme-deficient or heme-reconstituted guanylate cyclase and stimulation of cyclic GMP formation in mouse hepatic slices that were 95% viable and showed no active efflux of cyclic GMP. Heme-dependent activators of guanylate cyclase elicited a greater -fold increase in hepatic cyclic GMP levels in slices from phenobarbital-pretreated than control mice. Brilliant cresyl blue and KCN inhibited both enzyme activation and hepatic cyclic GMP accumulation caused by agents that generate nitric oxide. Hepatic slices from 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated mice, which are known to develop sharp increases in hepatic protoporphyrin IX/heme concentration ratios, showed elevated resting cyclic GMP levels whereas phenobarbital pretreatment produced decreased resting cyclic GMP levels compared to controls. Guanylate cyclase activation by azide required added catalase, and both enzyme activation and hepatic cyclic GMP formation were inhibited by aminotriazole. Enzyme activation by glyceryl trinitrate and NaNO2 required added thiols. Hepatic slices from acetaminophen-pretreated mice showed marked depletion of sulfhydryls and decreased cyclic GMP formation in response to these enzyme activators. Both effects were completely restored by treatment of thiol-depleted mice with N-acetylcysteine. These observations lend support to the general view that information gained from studies on the regulatory properties of purified soluble guanylate cyclase bears a close relationship to studies on regulatory mechanisms that modulate cyclic GMP formation in intact cells.
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000082:Acetaminophen / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D005996:Nitroglycerin / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D010659:Phenylhydrazines / Q000494:pharmacology; D011190:Potassium Cyanide / Q000494:pharmacology; D011339:Probenecid / Q000494:pharmacology; D011524:Protoporphyrins / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine
chemical_list: D010659:Phenylhydrazines; D011524:Protoporphyrins; D011688:Purinones; C030299:phenylhydrazine; D008769:Methylnitronitrosoguanidine; D000082:Acetaminophen; D006418:Heme; D026423:S-Nitroso-N-Acetylpenicillamine; C028025:protoporphyrin IX; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D010396:Penicillamine; C011145:zaprinast; D006152:Cyclic GMP; D011190:Potassium Cyanide; D011339:Probenecid; D015056:1-Methyl-3-isobutylxanthine; D000111:Acetylcysteine; D010634:Phenobarbital