Effects of phosphodiesterase 3,4,5 inhibitors on hepatocyte cAMP levels, glycogenolysis, gluconeogenesis and susceptibility to a mitochondrial toxin.

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Abdollahi M, Chan TS, Subrahmanyam V, O'Brien PJ

Effects of phosphodiesterase 3,4,5 inhibitors on hepatocyte cAMP levels, glycogenolysis, gluconeogenesis and susceptibility to a mitochondrial toxin.

Mol Cell Biochem. 2003 Oct;252(1-2):205-11. doi: 10.1023/a:1025568714217.

PubMed ID

14577594 [ View in PubMed

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Abstract

Various phosphodiesterase (PDE) 3,4 and 5 inhibitors have been compared with glucagon for their effectiveness at increasing hepatocyte cAMP, glycogenolysis and gluconeogenesis. Preincubation of isolated hepatocytes with PDE 3 and 4 inhibitors (50 microM) for 2 h induced significant increases in cellular cAMP level. The order of effectiveness was: glucagon (78%), V11294A (42%), rolipram (40%), milrinone (36%), CDP-840 (33%), R(0) 20-1724 (31%), papaverine (27%), isobutylmethylxanthine (28%), isoliquiritigenin (25%), theophylline (22%), and amrinone (22%). The PDE 5 inhibitors dipyridamol and sildenafil had only a slight effect on cAMP levels. Glucose formation was increased as a result of increased glycogenolysis in the following order of effectiveness: glucagon (89%), V11294A (63%), rolipram (61%), milrinone (50%), CDP-840 (46%), R(0) 20-1724 (45%), sildenafil (34%), dipyridamol (31%), papaverine (30%), isobutylmethylxanthine (29%), theophylline (20%), amrinone (20%), and isoliquiritigenin (20%). Rolipram and milrinone, selective PDE 4 and PDE 3 inhibitors respectively, stimulated the gluconeogenesis of alanine, lactate + pyruvate, or fructose in hepatocytes isolated from fasted rats. On the other hand, selective cGMP specific phospodiesterase inhibitors, sildenafil and dipyridamol inhibited alanine-induced gluconeogenesis. All PDE inhibitors increased hepatocyte susceptibility to cyanide toxicity (3-4 fold) which was prevented by fructose whereas PDE 5 inhibitors did not significantly increase hepatocyte susceptibility.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amrinone	cAMP-specific 3',5'-cyclic phosphodiesterase 3	Protein	Humans	Yes	Inhibitor	Details
Amrinone	cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) (Protein Group)	Protein group	Humans	Yes	Inhibitor	Details