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Role of cyclic nucleotide phosphodiesterase isozymes in intact canine trachealis.
Mol Pharmacol. 1991 Mar; 39(3):376-84.MP

Abstract

The role of individual cyclic nucleotide phosphodiesterase (PDE) isozymes in regulating cAMP and cGMP content in intact canine trachealis was examined using isozyme-selective and nonselective PDE inhibitors. The inhibitors used in this study were characterized previously [Mol. Pharmacol. 37:206-214 (1990)] and included: 1) zaprinast, an inhibitor (Ki = 0.1 microM) of the cGMP-specific PDE (cAMP Km = 135 microM; cGMP Km = 4 microM); 2) SK&F 94120, an inhibitor (Ki = 7 microM) of the cGMP-inhibited PDE (cAMP Km = 0.3 microM; cGMP Km = 8 microM); 3) Ro 20-1724, an inhibitor (Ki = 5 microM) of the cAMP-specific PDE (cAMP Km = 4 microM; cGMP Km = 40 microM); and 4) 3-isobutyl-1-methylxanthine (IBMX), a nonselective PDE inhibitor (IC50 = 1-30 microM). In addition to the aforementioned isozymes, canine trachealis contains a Ca2+/calmodulin-stimulated PDE (cAMP Km = 1 microM; cGMP Km = 2 microM) and a GMP-stimulated PDE (cAMP Km = 93 microM; cGMP Km = 60 microM), for which selective inhibitors are not available. Isolated canine trachealis strips were contracted with methacholine and exposed to various concentrations of PDE inhibitors, before being relaxed by the cumulative addition of isoproterenol, an adenylate cyclase activator, or sodium nitroprusside, a guanylate cyclase activator. At the completion of the concentration-response studies, tissues were flash-frozen and assayed for cyclic nucleotide content. Neither isoproterenol-induced relaxation nor cAMP accumulation was altered by zaprinast, but both of these responses were potentiated by pretreatment of tissues with either SK&F 94120 or Ro 20-1724. The effects of SK&F 94120 and Ro 20-1724 were additive, and the combination of SK&F 94120, Ro-1724, and IBMX had no greater effect on the responses to isoproperenol than did either IBMX alone or the combination of SK&F 94120 plus Ro 20-1724. In contrast, zaprinast potentiated sodium nitroprusside-induced relaxation and cGMP accumulation, whereas neither SK&F 94120 nor Ro 20-1724 altered these responses. IBMX produced a greater potentiation than did zaprinast, and the combination of zaprinast and IBMX had a greater effect than either agent alone. The results of this study suggest that the cGMP-inhibited and cAMP-specific PDEs are responsible for cAMP hydrolysis in intact canine trachealis, whereas cGMP hydrolysis is mediated by the cGMP-specific PDE as well as the Ca2+/calmodulin-stimulated PDE and/or the cGMP-stimulated PDE.

Authors+Show Affiliations

Torphy TJ
Division of Pharmacological Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Zhou HL
No affiliation info available
Burman M
No affiliation info available
Huang LB
No affiliation info available

MeSH

3',5'-Cyclic-AMP Phosphodiesterases3',5'-Cyclic-GMP PhosphodiesterasesAdenosineAnimalsCyclic AMPDogsFemaleIsoenzymesIsoproterenolMaleMuscle RelaxationMuscle, SmoothNitroprussidePhosphodiesterase InhibitorsTrachea

Pub Type(s)

Journal Article

Language

eng

PubMed ID

1848659

Citation

Torphy, T J., et al. "Role of Cyclic Nucleotide Phosphodiesterase Isozymes in Intact Canine Trachealis." Molecular Pharmacology, vol. 39, no. 3, 1991, pp. 376-84.
Torphy TJ, Zhou HL, Burman M, et al. Role of cyclic nucleotide phosphodiesterase isozymes in intact canine trachealis. Mol Pharmacol. 1991;39(3):376-84.
Torphy, T. J., Zhou, H. L., Burman, M., & Huang, L. B. (1991). Role of cyclic nucleotide phosphodiesterase isozymes in intact canine trachealis. Molecular Pharmacology, 39(3), 376-84.
Torphy TJ, et al. Role of Cyclic Nucleotide Phosphodiesterase Isozymes in Intact Canine Trachealis. Mol Pharmacol. 1991;39(3):376-84. PubMed PMID: 1848659.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of cyclic nucleotide phosphodiesterase isozymes in intact canine trachealis. AU - Torphy,T J, AU - Zhou,H L, AU - Burman,M, AU - Huang,L B, PY - 1991/3/1/pubmed PY - 1991/3/1/medline PY - 1991/3/1/entrez SP - 376 EP - 84 JF - Molecular pharmacology JO - Mol Pharmacol VL - 39 IS - 3 N2 - The role of individual cyclic nucleotide phosphodiesterase (PDE) isozymes in regulating cAMP and cGMP content in intact canine trachealis was examined using isozyme-selective and nonselective PDE inhibitors. The inhibitors used in this study were characterized previously [Mol. Pharmacol. 37:206-214 (1990)] and included: 1) zaprinast, an inhibitor (Ki = 0.1 microM) of the cGMP-specific PDE (cAMP Km = 135 microM; cGMP Km = 4 microM); 2) SK&F 94120, an inhibitor (Ki = 7 microM) of the cGMP-inhibited PDE (cAMP Km = 0.3 microM; cGMP Km = 8 microM); 3) Ro 20-1724, an inhibitor (Ki = 5 microM) of the cAMP-specific PDE (cAMP Km = 4 microM; cGMP Km = 40 microM); and 4) 3-isobutyl-1-methylxanthine (IBMX), a nonselective PDE inhibitor (IC50 = 1-30 microM). In addition to the aforementioned isozymes, canine trachealis contains a Ca2+/calmodulin-stimulated PDE (cAMP Km = 1 microM; cGMP Km = 2 microM) and a GMP-stimulated PDE (cAMP Km = 93 microM; cGMP Km = 60 microM), for which selective inhibitors are not available. Isolated canine trachealis strips were contracted with methacholine and exposed to various concentrations of PDE inhibitors, before being relaxed by the cumulative addition of isoproterenol, an adenylate cyclase activator, or sodium nitroprusside, a guanylate cyclase activator. At the completion of the concentration-response studies, tissues were flash-frozen and assayed for cyclic nucleotide content. Neither isoproterenol-induced relaxation nor cAMP accumulation was altered by zaprinast, but both of these responses were potentiated by pretreatment of tissues with either SK&F 94120 or Ro 20-1724. The effects of SK&F 94120 and Ro 20-1724 were additive, and the combination of SK&F 94120, Ro-1724, and IBMX had no greater effect on the responses to isoproperenol than did either IBMX alone or the combination of SK&F 94120 plus Ro 20-1724. In contrast, zaprinast potentiated sodium nitroprusside-induced relaxation and cGMP accumulation, whereas neither SK&F 94120 nor Ro 20-1724 altered these responses. IBMX produced a greater potentiation than did zaprinast, and the combination of zaprinast and IBMX had a greater effect than either agent alone. The results of this study suggest that the cGMP-inhibited and cAMP-specific PDEs are responsible for cAMP hydrolysis in intact canine trachealis, whereas cGMP hydrolysis is mediated by the cGMP-specific PDE as well as the Ca2+/calmodulin-stimulated PDE and/or the cGMP-stimulated PDE. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/1848659/Role_of_cyclic_nucleotide_phosphodiesterase_isozymes_in_intact_canine_trachealis_ DB - PRIME DP - Unbound Medicine ER -