title: Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig.
abstract: This study evaluated the relationship between inhibition of the rolipram-sensitive and the CI-930-sensitive low Km cyclic AMP-specific phosphodiesterase (PDE) isozymes (PDE IIIRO and PDE IIIc, respectively) and bronchomotor tone in the guinea pig. Rolipram and CI-930 exhibited biphasic concentration-response relationships for relaxation of carbachol-, histamine- and leukotriene D4-contracted trachea. However, each agent produced a monophasic (sigmoidal) concentration-response curve when tested in the presence of a fixed concentration (3 microM) of the other. The same relationships were observed for inhibition of tracheal peak III PDE isolated via diethylaminoethyl-cellulose chromatography. Whereas CI-930 was approximately equipotent inhibiting PDE IIIc and relaxing rolipram-pretreated trachea, rolipram was substantially more potent (EC50 = 0.02 microM) in relaxing CI-930-pretreated trachea than in inhibiting CI-930-pretreated PDE III (PDE IIIRO, IC50 = 2.6 microM). Among a series of PDE inhibitors, there was a highly significant correlation (r = 0.89, P less than .01) between PDE IIIc inhibition (i.e., PDE III in the presence of rolipram) and rolipram-pretreated tracheal relaxation, but not between PDE IIIRO inhibition and CI-930-pretreated tracheal relaxation (r = 0.23). Nine of the PDE inhibitors used in this study have been reported to displace rolipram from a high-affinity binding site in rat brain. A highly significant correlation between relaxation of CI-930-pretreated trachea and displacement of rolipram binding by these agents was observed (r = 0.97, P less than .0001).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Sterling Research Group, Rensselaer, New York.
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: M J
authors.initials: MJ
authors.lastname: Connell
authors.forename: E W
authors.initials: EW
authors.lastname: Ferguson
authors.forename: A M
authors.initials: AM
authors.lastname: Wallace
authors.forename: R J
authors.initials: RJ
authors.lastname: Gordon
authors.forename: E D
authors.initials: ED
authors.lastname: Pagani
authors.forename: P J
authors.initials: PJ
authors.lastname: Silver
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D014132:Trachea / Q000187:drug effects
chemical_list: D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; C042528:4,5-dihydro-6-(4-(imidazol-1-yl)phenyl)-5-methyl-3(2H)-pyridazinone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram