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Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig. 1989

A L Harris, and M J Connell, and E W Ferguson, and A M Wallace, and R J Gordon, and E D Pagani, and P J Silver
Department of Pharmacology, Sterling Research Group, Rensselaer, New York.

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)

UI MeSH Term Description Entries
D008297 Male Males
D010726 Phosphodiesterase Inhibitors Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. Phosphodiesterase Antagonists,Phosphodiesterase Inhibitor,Phosphoric Diester Hydrolase Inhibitors,Antiphosphodiesterases,Inhibitor, Phosphodiesterase
D011724 Pyridazines Six-membered rings with two adjacent nitrogen atoms also called 1,2-diazine.
D011760 Pyrrolidinones A group of compounds that are derivatives of oxo-pyrrolidines. A member of this group is 2-oxo pyrrolidine, which is an intermediate in the manufacture of polyvinylpyrrolidone. (From Merck Index, 11th ed) Pyrrolidinone,Pyrrolidone,Pyrrolidones
D001980 Bronchi The larger air passages of the lungs arising from the terminal bifurcation of the TRACHEA. They include the largest two primary bronchi which branch out into secondary bronchi, and tertiary bronchi which extend into BRONCHIOLES and PULMONARY ALVEOLI. Primary Bronchi,Primary Bronchus,Secondary Bronchi,Secondary Bronchus,Tertiary Bronchi,Tertiary Bronchus,Bronchi, Primary,Bronchi, Secondary,Bronchi, Tertiary,Bronchus,Bronchus, Primary,Bronchus, Secondary,Bronchus, Tertiary
D005260 Female Females
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000403 Airway Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Airway Resistances,Resistance, Airway,Resistances, Airway
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014132 Trachea The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. Tracheas

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