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Molecular Pharmacology

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Abstract

Regulation of airway muscarinic cholinergic receptor subtypes by chronic anticholinergic treatment.

P A Witt-Enderby, H I Yamamura, M Halonen, J Lai, J D Palmer and J W Bloom
Molecular Pharmacology March 1995, 47 (3) 485-490;
P A Witt-Enderby
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H I Yamamura
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M Halonen
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J Lai
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J D Palmer
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J W Bloom
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Abstract

Anticholinergic agents are commonly used as bronchodilators for patients with airway obstructive diseases. The effects of chronic anticholinergic therapy on airway function and bronchial responsiveness are not known, but data from clinical studies suggest the possibility of adverse effects. We demonstrated in rabbits that, after atropine treatment for 4 weeks, the efficacy (maximum contraction) of in vitro methacholine-induced contraction of mainstem bronchi was increased [control (untreated), 1.0 +/- 0.1 g; atropine-treated, 1.6 g +/- 0.2 g; p = 0.04]. However, there was no significant change in the potency (EC50) of methacholine-induced contraction. Chronic atropine treatment increased the maximum density (Bmax) of muscarinic receptors in the airways, as determined by radioligand binding studies with tritiated quinuclidinyl benzilate. Individual muscarinic receptor subtypes were measured using antibodies selective for the m1-m5 subtypes. Of the subtypes detected in rabbit tracheal smooth muscle (m2, m3, and m4), only the m2 and m3 muscarinic receptor subtypes were significantly up-regulated compared with control, after chronic atropine treatment. Because cholinergic agent-mediated contraction of smooth muscle has been shown to be mediated by m3 muscarinic receptors, the atropine-induced increase in the methacholine response in airway smooth muscle appears to be the result of the up-regulation of m3 muscarinic cholinergic receptors. Such a mechanism may explain the clinical observations that chronic anticholinergic therapy for asthmatic patients is associated with an increase in bronchial responsiveness and that continuous versus "on demand" anticholinergic bronchodilator therapy may cause an accelerated decline in ventilatory function.

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Molecular Pharmacology
Vol. 47, Issue 3
1 Mar 1995
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Abstract

Regulation of airway muscarinic cholinergic receptor subtypes by chronic anticholinergic treatment.

P A Witt-Enderby, H I Yamamura, M Halonen, J Lai, J D Palmer and J W Bloom
Molecular Pharmacology March 1, 1995, 47 (3) 485-490;

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Abstract

Regulation of airway muscarinic cholinergic receptor subtypes by chronic anticholinergic treatment.

P A Witt-Enderby, H I Yamamura, M Halonen, J Lai, J D Palmer and J W Bloom
Molecular Pharmacology March 1, 1995, 47 (3) 485-490;
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