Inhibitors of phosphodiesterase IV (PDE IV) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high-affinity rolipram binding site.
In this report, we describe the ability of selective inhibitors of phosphodiesterase (PDE) isozymes to increase aminopyrine accumulation in rabbit isolated gastric glands. Aminopyrine accumulation in the presence of histamine was increased by the nonselective PDE inhibitor isobutylmethylxanthine (EC50 = 4.8 microM) and by two selective PDE IV inhibitors, rolipram and Ro 20-1724 (EC50 = 0.013 and 0.07 microM, respectively) but not by selective PDE III inhibitors (siguazodan and SK&F 94120) or by a selective PDE V inhibitor (zaprinast). These results suggest that PDE IV is an important regulator of acid secretion in response to histamine. One of the more fascinating properties of PDE IV is the expression of a high-affinity binding site for [3H]-rolipram in addition to cAMP catalytic activity. Although agents that inhibit PDE IV catalytic activity also appear to bind to the high-affinity rolipram-binding site, the rank-order potencies of compounds for these two effects are poorly correlated. Also, certain pharmacological actions of PDE IV inhibitors appear to be related to an interaction with this binding site. In this study, we observed that the ability of PDE IV inhibitors to enhance acid secretion was not associated with their ability to inhibit PDE IV catalytic activity but did show a strong correlation with their ability to compete for [3H]-rolipram binding. Furthermore, we were able to detect [3H]-rolipram binding sites in gastric glands that had characteristics similar to those of the [3H]-rolipram binding sites in rat brain microsomes and human recombinant PDE IV.
Barnette
M S
MS
Department of Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Grous
M
M
Cieslinski
L B
LB
Burman
M
M
Christensen
S B
SB
Torphy
T J
TJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003994:Bucladesine / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011760:Pyrrolidinones / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D020889:Rolipram
D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D000632:Aminopyrine; D003994:Bucladesine; D006632:Histamine; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram