title: Negative inotropic action of denbufylline through interfering with the calcium channel independently of its PDE IV inhibitory activity in guinea pig ventricle papillary muscles.
abstract: The inotropic actions of xanthine derivatives with long alkyl chains were investigated in guinea pig ventricular papillary muscle. A potent and nonselective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine, elicited a positive inotropy and inhibited the negative inotropic effects of calcium channel inhibitors, as did a selective PDE III inhibitor, amrinone, and these effects were canceled by a protein kinase inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89). However, 1,3-di-n-butyl-7-(2'oxopropyl)xanthine (denbufylline) and 1-n-butyl-3-n-propylxanthine (XT-044), which have potent and selective PDE IV-inhibitory activities, showed negative inotropic actions that became more potent in the presence of H-89. Denbufylline abolished the late restoration phase induced by ryanodine. This xanthine derivative attenuated the effects of both the calcium channel acting agents Bay K 8644 and verapamil, without interaction with caffeine and dihydropyridine calcium channel inhibitors, and denbufylline had little direct influence on the specific binding of [(3)H]azidopine and [(3)H]desmethoxyverapamil to cardiac membranes. A nonxanthine PDE IV inhibitor, Ro 20-1724, did not affect the inotropic actions of calcium channel inhibitors. The attenuation by denbufylline or XT-044 of the negative inotropic action of verapamil was not influenced by treatment with H-89. These results suggest that in the ventricular papillary muscle, these xanthine derivatives elicit negative inotropy by acting on a verapamil-sensitive site of the calcium channel without involving their PDE-inhibitory activity.
authors.affiliation: Applied Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Sanae
authors.forename: S
authors.initials: S
authors.lastname: Ohmae
authors.forename: D
authors.initials: D
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Takag
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D003864:Depression, Chemical; D004095:Dihydropyridines / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012433:Ryanodine / Q000494:pharmacology; D013449:Sulfonamides; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D001386:Azides; D015220:Calcium Channels; D004095:Dihydropyridines; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D013449:Sulfonamides; D014970:Xanthines; C043898:denbufylline; D012433:Ryanodine; D002110:Caffeine; C041130:azidopine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide