Impaired beta-adrenergic receptor activation of adenylyl cyclase in airway smooth muscle in the basenji-greyhound dog model of airway hyperresponsiveness.

C. Emala, C. Black, C. Curry, M. A. Levine, C. A. Hirshman

    Research output: Contribution to journalArticle

    Abstract

    Previous studies in human asthmatics have suggested a defect in the beta-adrenergic pathway leading to cyclic adenosine monophosphate (cAMP) generation. Although these studies have suggested normal or increased numbers of beta-adrenergic receptors, limitations in the quantity of tissue available have not allowed further delineation of the biochemical or molecular mechanisms of human asthma. The basenji-greyhound (BG) dog model of nonspecific airway hyperreactivity displays similarities to human asthma, and altered functional response to beta-adrenergic agonists has been previously shown in airway tissue from this model. We have now correlated this functional impairment in beta-adrenergic response with a decreased generation of cAMP in response to isoproterenol. Organ bath studies and adenylyl cyclase assays of trachealis muscle revealed impaired responses to isoproterenol in the BG dog as compared with control dogs. Pretreatment of muscle strips from BG dogs with isoproterenol had no effect on subsequent dose-response curves to methacholine (pD2 = 7.17 +/- 0.13, 7.34 +/- 0.12, and 7.14 +/- 0.17 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively), while muscle strips from mongrel dogs had a significant shift in methacholine responses after isoproterenol pretreatment (pD2 = 7.91 +/- 0.23, 7.48 +/- 0.29, and 6.98 +/- 0.33 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively). Adenylyl cyclase activity in response to isoproterenol was 54% in the BG trachealis membranes as compared with mongrels. Functional and biochemical responses to forskolin, NaF, prostaglandin, and dibutyryl cAMP, and the quantity of G,alpha were similar in the BG and control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

    Original languageEnglish (US)
    Pages (from-to)668-675
    Number of pages8
    JournalAmerican Journal of Respiratory Cell and Molecular Biology
    Volume8
    Issue number6
    StatePublished - Jun 1993

    Fingerprint

    Receptors, Adrenergic, beta
    Isoproterenol
    Adenylyl Cyclases
    Smooth Muscle
    Muscle
    Chemical activation
    Dogs
    Cyclic AMP
    Methacholine Chloride
    Muscles
    Adrenergic Agents
    Asthma
    Tissue
    Adrenergic beta-Agonists
    Colforsin
    Baths
    Prostaglandins
    Assays
    Membranes
    Defects

    ASJC Scopus subject areas

    • Cell Biology
    • Molecular Biology
    • Pulmonary and Respiratory Medicine

    Cite this

    Impaired beta-adrenergic receptor activation of adenylyl cyclase in airway smooth muscle in the basenji-greyhound dog model of airway hyperresponsiveness. / Emala, C.; Black, C.; Curry, C.; Levine, M. A.; Hirshman, C. A.

    In: American Journal of Respiratory Cell and Molecular Biology, Vol. 8, No. 6, 06.1993, p. 668-675.

    Research output: Contribution to journalArticle

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    abstract = "Previous studies in human asthmatics have suggested a defect in the beta-adrenergic pathway leading to cyclic adenosine monophosphate (cAMP) generation. Although these studies have suggested normal or increased numbers of beta-adrenergic receptors, limitations in the quantity of tissue available have not allowed further delineation of the biochemical or molecular mechanisms of human asthma. The basenji-greyhound (BG) dog model of nonspecific airway hyperreactivity displays similarities to human asthma, and altered functional response to beta-adrenergic agonists has been previously shown in airway tissue from this model. We have now correlated this functional impairment in beta-adrenergic response with a decreased generation of cAMP in response to isoproterenol. Organ bath studies and adenylyl cyclase assays of trachealis muscle revealed impaired responses to isoproterenol in the BG dog as compared with control dogs. Pretreatment of muscle strips from BG dogs with isoproterenol had no effect on subsequent dose-response curves to methacholine (pD2 = 7.17 +/- 0.13, 7.34 +/- 0.12, and 7.14 +/- 0.17 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively), while muscle strips from mongrel dogs had a significant shift in methacholine responses after isoproterenol pretreatment (pD2 = 7.91 +/- 0.23, 7.48 +/- 0.29, and 6.98 +/- 0.33 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively). Adenylyl cyclase activity in response to isoproterenol was 54{\%} in the BG trachealis membranes as compared with mongrels. Functional and biochemical responses to forskolin, NaF, prostaglandin, and dibutyryl cAMP, and the quantity of G,alpha were similar in the BG and control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)",
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