REGULATION OF AIRWAY MUSCARINIC CHOLINERGIC RECEPTOR SUBTYPES BY CHRONIC ANTICHOLINERGIC TREATMENT

Anticholinergic agents are commonly used as bronchodilators for patien ts with airway obstructive diseases. The effects of chronic anticholin ergic therapy on airway function and bronchial responsiveness are not known, but data from clinical studies suggest the possibility of adver se effects. We demonstrated in rabbits that, after atropine treatment for 4 weeks, the efficacy (maximum contraction) of in vitro methacholi ne-induced contraction of mainstem bronchi was increased [control (unt reated), 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 (EC(50)) of me thacholine-induced contraction. Chronic atropine treatment increased t he maximum density (B-max) of muscarinic receptors in the airways, as determined by radioligand binding studies with tritiated quinuclidinyl benzilate. Individual muscarinic receptor subtypes were measured usin g antibodies selective for the m1-m5 subtypes. Of the subtypes detecte d in rabbit tracheal smooth muscle (m2, m3, and m4), only the m2 and m 3 muscarinic receptor subtypes were significantly up-regulated, compar ed with control, after chronic atropine treatment. Because cholinergic agent-mediated contraction of smooth muscle has been shown to be medi ated 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 m echanism may explain the clinical observations that chronic anticholin ergic therapy for asthmatic patients is associated with an increase in bronchial responsiveness and that continuous versus ''on demand'' ant icholinergic bronchodilator therapy may cause an accelerated decline i n ventilatory function.