Tachyphylaxis to β-adrenoceptor agonists in guinea pig airway smooth muscle in vivo and in vitro,☆☆

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Abstract

β-Adrenoceptor tachyphylaxis was induced by incubating spirally cut guinea pig tracheas with isoproterenol (2.4 × 10−7 M) for 20 min. This incubation reduced the relaxant effects of catecholamines but not of dibutyryl cyclic AMP, theophylline or sodium nitrite. Tracheas incubated with norepinephrine, phosphodiesterase inhibitors or cyclic nucleotides became tachyphylactic to isoproterenol. Pretreatment with indomethacin prevented induction of tachyphylaxis. Incubation with adenosine, methoxamine or sodium nitrite did not induced β-adrenoceptor tachyphylaxis. When we gave isoprpterenol intramuscularly to guinea pigs, airway sensitivity to aerosolized histamine was unchanged but the toxicity of parenterally administered histamine was increased. A prolonged treatment with isoproterenol reduced airway sensitivity to histamine aerosols; this reduced sensitivity was reversed by indomethacin. Thus, β-adrenoceptor tachyphylaxis may not explain increased toxicity of parenteral histamine after isoproterenol treatment. Elevated levels of cyclic AMP and an increased synthesis of prostaglandins may result in diminished response to β-receptor stimulation.

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      Airway smooth muscle (ASM) acts as the primary effector cell regulating bronchomotor tone. Early studies of β‐adrenergic agonists discovered that short‐term (20 min) incubation of guinea pig tracheas with catecholamines stimulated cAMP production leading to ASM cell relaxation (Douglas et al., 1977). Pharmacological inhibition of PDEs with the nonselective PDE inhibitor, theophylline, further demonstrated that augmentation of cAMP levels evokes ASM relaxation (Newman et al., 1978; Polson et al., 1978; Triner et al., 1977).

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    Supported in part by USPHS grants HL-14534 and HL-14179 from the National Heart and Lung Institute.

    ☆☆

    A preliminary report of this work has been presented (The Physiologist, 15: 197, 1975).

    ∗∗∗

    Present address: Department of Pharmacology, Organon Laboratories, Ltd., Newhouse, Lanarkshire, Scotland.

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