Relaxant effect of YM976, a novel phosphodiesterase 4 inhibitor, on bovine tracheal smooth muscle.
Effects of 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one (YM976), a novel and selective phosphodiesterase type 4 inhibitor, on tension and adenosine 3',5'-cyclic monophosphate (cAMP) content of bovine tracheal smooth muscle were compared with those of rolipram and theophylline. YM976, rolipram and theophylline relaxed the tracheal preparations contracted with histamine in a concentration-dependent manner. The relaxant effects of YM976 and rolipram were more potent than those of theophylline. These phosphodiesterase inhibitors-induced relaxations were dramatically diminished when tracheal smooth muscle was contracted with methacholine instead of histamine. Pretreatment of the tracheal preparations with YM976 (10 microM) or rolipram (10 microM), but not with theophylline (1 mM), shifted the concentration-response curves for contractile responses to histamine; however, the same procedure failed to affect concentration-response relationships for methacholine-induced contractions. At 1 and 10 microM, both YM976 and rolipram increased the tissues cAMP content. These results suggest that YM976 relaxes tracheal smooth muscle, probably through the cAMP-dependent mechanism.
Moriuchi
Hiroshi
H
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Nakahara
Tsutomu
T
Maruko
Takeshi
T
Sakamoto
Kenji
K
Ishii
Kunio
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000201:enzymology
D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; C414544:YM 976; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4