Effects of phosphodiesterase 3,4,5 inhibitors on hepatocyte cAMP levels, glycogenolysis, gluconeogenesis and susceptibility to a mitochondrial toxin.
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.
Graduate Department of Pharmaceutics, Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Mohammad
M
Abdollahi
Tom S
TS
Chan
Vangala
V
Subrahmanyam
Peter J
PJ
O'Brien
D000409:Alanine / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D005632:Fructose / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014118:Toxins, Biological / Q000633:toxicity*
D008112:Liver Glycogen; D010726:Phosphodiesterase Inhibitors; D014118:Toxins, Biological; D005632:Fructose; D000242:Cyclic AMP; D000409:Alanine