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Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig.
J Pharmacol Exp Ther. 1989 Oct; 251(1):199-206.JP

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+Show Affiliations

Department of Pharmacology, Sterling Research Group, Rensselaer, New York.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

2552074

Citation

Harris, A L., et al. "Role of Low Km Cyclic AMP Phosphodiesterase Inhibition in Tracheal Relaxation and Bronchodilation in the Guinea Pig." The Journal of Pharmacology and Experimental Therapeutics, vol. 251, no. 1, 1989, pp. 199-206.
Harris AL, Connell MJ, Ferguson EW, et al. Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig. J Pharmacol Exp Ther. 1989;251(1):199-206.
Harris, A. L., Connell, M. J., Ferguson, E. W., Wallace, A. M., Gordon, R. J., Pagani, E. D., & Silver, P. J. (1989). Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig. The Journal of Pharmacology and Experimental Therapeutics, 251(1), 199-206.
Harris AL, et al. Role of Low Km Cyclic AMP Phosphodiesterase Inhibition in Tracheal Relaxation and Bronchodilation in the Guinea Pig. J Pharmacol Exp Ther. 1989;251(1):199-206. PubMed PMID: 2552074.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig. AU - Harris,A L, AU - Connell,M J, AU - Ferguson,E W, AU - Wallace,A M, AU - Gordon,R J, AU - Pagani,E D, AU - Silver,P J, PY - 1989/10/1/pubmed PY - 1989/10/1/medline PY - 1989/10/1/entrez SP - 199 EP - 206 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 251 IS - 1 N2 - 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) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/2552074/Role_of_low_Km_cyclic_AMP_phosphodiesterase_inhibition_in_tracheal_relaxation_and_bronchodilation_in_the_guinea_pig_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2552074 DB - PRIME DP - Unbound Medicine ER -