Phosphodiesterase type 4 that regulates cAMP level in cortical neurons shows high sensitivity to rolipram.
To characterize the role of phosphodiesterase type 4 (a cAMP-specific and rolipram-sensitive phosphodiesterase) among phosphodiesterases in the regulation of the intracellular cAMP level in cortical neurons, we investigated the effects of phosphodiesterase inhibitors on the intracellular cAMP levels in primary cultured rat cortical neurons. Selective inhibitors of phosphodiesterase type 4 and type 2 significantly enhanced beta-adrenoceptor-mediated cAMP increase. Selective inhibitors of phosphodiesterase type 1, type 3 and type 5/6 had no effect on the cAMP level. Rolipram enhanced the beta-adrenoceptor-mediated cAMP increase in cortical neurons, astrocytes and vascular smooth muscle cells at different minimum effective concentrations (10, 100 and 1000 nM, respectively). These findings indicate that phosphodiesterase type 4, showing a high-sensitivity to rolipram, plays a major role in regulating cAMP in the cortical neurons, and that rolipram at low doses enhances the intracellular cAMP increase in the cortical neurons selectively.
Yamashita
N
N
Drug Discovery, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
Yamauchi
M
M
Baba
J
J
Sawa
A
A
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram
D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D020889:Rolipram; D007545:Isoproterenol