Cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M 2-like receptors

Abstract

The muscarinic receptor subtype mediating contraction of the guinea pig lung strip preparation was investigated and compared with that in guinea pig tracheal and human peripheral airway (small bronchi) smooth muscle preparations, using a number of subtype selective muscarinic receptor antagonists. It was found that guinea pig lung strip contraction was not mediated by a homogenous class of muscarinic M 3 receptors, in contrast to guinea pig tracheal and human peripheral airway smooth muscle. The affinities of the M 1- and M 3/M 2-selective muscarinic receptor antagonists on the guinea pig lung strip were between 0.35 and 1.94 log units lower than in the M 3 receptor tissues (respective pA 2 values on guinea pig lung strip and trachea: pirenzepine 6.36/6.71, AF-DX 474 6.39/7.11, AQ-RA 721 6.93/7.96, DAU 5884 6.78/8.72, UH-AH 371 7.04/8.20), whereas the affinities of the M 2/M 3-selective antagonists were between 0.63 and 1.97 log units higher (AF-DX 116 6.63/6.00, AQ-RA 741 7.48/6.63, gallamine 5.44/3.47, methoctramine 7.30/5.38). As a result, a good correlation was obtained when pA 2 values from guinea pig lung strip were compared to p K i values towards bovine cardiac muscarinic M 2 receptors, though it was noticed that pirenzepine and the M 3/M 2-selective antagonists showed a closer relationship than the M 2-selective compounds. These results suggest that cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M 2-like receptors, possibly representing a novel subtype or a mixture of M 2 (cardiac) and M 3 (or M 4) subtypes. It remains to be established, however, on what structure in the lung these contractile M 2-like receptors are located and also by which transduction mechanism they produce contraction.