Positive cooperative interaction of quaternary anticholinergics with functional muscarinic receptors in bovine tracheal smooth muscle.

The interaction of quaternary anticholinergics with muscarinic receptors in bovine tracheal smooth muscle strips was investigated because some of these compounds have shown anomalous (biphasic) behaviour in radioligand displacement studies, in contrast to their tertiary analogues. It was found that ipratropium, N-methylscopolamine, oxyphenonium and N-methyldeptropine give Schild plots with slopes significantly greater than unity (up to 2.0) in contrast to 4-DAMP methobromide and thiazinamium, and the tertiary analogues atropine and scopolamine. However, in guinea pig tracheal smooth muscle, ipratropium and N-methyldeptropine behaved as classic antagonists with Schild slopes of unity. The high Schild plot slopes in bovine tracheal smooth muscle could not be solely explained by inadequate equilibration of the antagonists, since increased incubation times (3 or 5 h instead of 30 min) still brought about slopes significantly greater than unity, or by the presence of an atropinesterase in the tissue. However, by using combinations of atropine with ipratropium or oxyphenonium it could be demonstrated that these quaternary antagonists interact with muscarinic M3 receptors in bovine but not in guinea pig tracheal smooth muscle in a positive cooperative fashion.