Cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M2-like receptors

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 M3 receptors, in contrast to guinea pig tracheal and human peripheral airway smooth muscle. The affinities of the M1- and M3/M2-selective muscarinic receptor antagonists on the guinea pig lung strip were between 0.35 and 1.94 log units lower than in the M3 receptor tissues (respective pA2 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 M2/M3-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 pA2 values from guinea pig lung strip were compared to pK(i) values towards bovine cardiac muscarinic M2 receptors, though it was noticed that pirenzepine and the M3/M2-selective antagonists showed a closer relationship than the M2-selective compounds. These results suggest that cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M2-like receptors, possibly representing a novel subtype or a mixture of M2 (cardiac) and M3 (or M4) subtypes. It remains to be established, however, on what structure in the lung these contractile M2-like receptors are located and also by which transduction mechanism they produce contraction.