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Involvement of reduced sensitivity to Ca 2+ in β‐adrenergic action on airway smooth muscle
Author(s) -
Oguma T.,
Kume H.,
Ito S.,
Takeda N.,
Honjo H.,
Kodama I.,
Shimokata K.,
Kamiya K.
Publication year - 2006
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.2006.02412.x
Subject(s) - isoprenaline , methacholine , contraction (grammar) , forskolin , isometric exercise , muscle contraction , chemistry , endocrinology , trachealis muscle , medicine , muscle relaxation , adrenergic , protein kinase a , rho kinase inhibitor , biophysics , rho associated protein kinase , kinase , calcium , biology , biochemistry , receptor , charybdotoxin , stimulation , lung , respiratory disease
Summary Background It is well known that β‐adrenoceptor agonists (β‐agonists) cause relaxation in airway smooth muscle mediated by a reduction in the concentration of intracellular Ca 2+ ([Ca 2+ ] i ). However, little is currently known regarding whether reduced sensitization to Ca 2+ is involved in the β‐adrenergic relaxation. Objective This study was designed to determine the intracellular mechanisms underlying suppression of Ca 2+ sensitization in β‐adrenergic relaxation (Ca 2+ ‐independent relaxation by β‐agonists). Methods Isometric tension and [Ca 2+ ] i were simultaneously measured in fura‐2‐loaded strips isolated from guinea‐pig tracheal smooth muscles. The relationships between tension and [Ca 2+ ] i were examined in the inhibitory action of isoprenaline (ISO) and other cAMP‐related agents against methacholine‐induced contraction. Results The concentration‐inhibition curve for ISO against methacholine in tension was significantly dissociated from the curve for ISO in [Ca 2+ ] i . In ISO‐induced relaxation, a reduction in tension was significantly greater than that in [Ca 2+ ] i. This phenomenon was mimicked by other cAMP‐related agents: forskolin and dibutyryl‐cAMP. In contrast, the inhibitory action of SKF‐96365, a non‐selective inhibitor of Ca 2+ channels, was associated with that in [Ca 2+ ] i . In the presence of Rp‐cAMPS, an inhibitor of protein kinase A (PKA), ISO caused an equivalent relaxation with less reduction in [Ca 2+ ] i . The effects of ISO were not affected by Y‐27632, an inhibitor of Rho‐kinase, or by bisindolylmaleimide, an inhibitor of protein kinase C. ISO failed to inhibit contraction elicited by calyculin A, an inhibitor of myosin phosphatase. Conclusion β‐Adrenergic action antagonizes not only Ca 2+ mobilization but also Ca 2+ sensitization in methacholine‐induced contraction. The cAMP/PKA‐independent, G s ‐direct action is more potent in Ca 2+ ‐independent relaxation by β‐agonists than the cAMP/PKA‐dependent pathway. Moreover, myosin phosphatase is a fundamentally affected protein in the reduced response to Ca 2+ mediated by β‐agonist. Our results may provide evidence that this Ca 2+ desensitization is a novel target for a reliever medication using rapid‐acting β‐agonists in acute asthma management.