Muscarinic M(3) receptor-dependent regulation of airway smooth muscle contractile phenotype.

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Gosens R, Bromhaar MM, Tonkes A, Schaafsma D, Zaagsma J, Nelemans SA, Meurs H

Muscarinic M(3) receptor-dependent regulation of airway smooth muscle contractile phenotype.

Br J Pharmacol. 2004 Mar;141(6):943-50. doi: 10.1038/sj.bjp.0705709. Epub 2004 Mar 1.

PubMed ID

14993104 [ View in PubMed

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Abstract

1. Airway smooth muscle (ASM) cells are known to switch from a contractile to a proliferative and synthetic phenotype in culture in response to serum and growth factors. Phenotype switching in response to contractile agonists, however, is poorly characterised, despite the possible relationship between ASM phenotype and airway remodelling in asthma. 2. To investigate the effects of muscarinic receptor stimulation on ASM phenotype, we used organ-cultured bovine tracheal smooth muscle (BTSM) strips, in which contractile responsiveness, contractile protein expression and proliferation were measured after pretreatment with methacholine. 3. Long-term methacholine pretreatment (8 days) decreased maximal contraction and sensitivity to methacholine as well as to histamine and KCl. This decrease was dose-dependent (pEC(50)=5.2+/-0.1). Pretreatment with the highest concentration of methacholine applied (100 microm) could suppress maximal histamine-induced contraction to 8+/-1% of control. In addition, contractile protein expression (myosin, actin) was downregulated two-fold. No concomitant increase in proliferative capacity was observed. 4. The M(3)/M(2) muscarinic receptor antagonist DAU 5884 (0.1 microm) completely inhibited the observed decrease in contractility. In contrast, the M(2)/M(3) muscarinic receptor antagonist gallamine (10 microm) was ineffective, demonstrating that M(2) receptors were not involved. 5. Pretreatment (8 days) with 60 mm KCl could mimick the strong decreases in contractility. This was completely prevented by pretreatment with verapamil (1 microm). 6. Regulation of contractility was not affected by protein kinase C inhibition, whereas inhibitors of phosphatidyl inositol 3-kinase and p42/p44 mitogen activated protein kinase were partially effective. 7. These results show that long-term methacholine pretreatment (8 days) induces an M(3) receptor-dependent decrease in BTSM contractility without increased proliferative capacity.

DrugBank Data that Cites this Article

Drugs

Methacholine

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Methacholine	Muscarinic acetylcholine receptor M3	Protein	Humans	Yes	Agonist	Details