The aim of the present investigation was to determine the reasons why the
muscarinic receptor agonist talsaclidine (
WAL 2014 FU, 1-azabicyclo[2.2.2]
octane,3-(2-propynyloxy)-, (R)-,(E)-2-butenedioate) is devoid of bronchospastic effects in anaesthetized guinea pigs but causes
contracture in isolated tracheal muscle from this species. Effects on airway resistance were assessed with a modified Konzett-Rossler method in guinea pigs anaesthetized with
urethane.
Intravenous injection of 1-64 mg/kg talsaclidine did not cause substantial
bronchospasm in control animals. After blockade of beta-
adrenoceptors, the
muscarinic receptor agonist induced dose-dependent
bronchospasm which could be blocked by
atropine. In despinalized animals and in animals with spinal transection, talsaclidine was bronchospastic but ED50 values were higher and maximal effects were smaller than in intact animals after beta-
adrenoceptor blockade. In adrenalectomized guinea pigs, talsaclidine was nearly as bronchospastic as after blockade of beta-
adrenoceptors. In contrast, the
muscarinic ganglion stimulant
McN-A-343, 4-(m-chlorophenylcarbamoyloxy)-2-butyn-trimethyl-ammonium
chloride, (2-32 mg/kg i.v.), which has a
muscarinic receptor profile similar to that of talsaclidine, i.e., full
muscarinic agonism and highest affinity at
muscarinic M1 receptors, partial agonism at
muscarinic M3 receptors, but in contrast to talsaclidine does not penetrate the blood-brain barrier, caused dose-dependent
bronchospasm in control animals. These results indicate that talsaclidine has bronchospastic potential which, however, does not become evident in vivo because of functional antagonism via beta-
adrenoceptors resulting from concomitant activation of the sympathetic nervous system in general and the adrenals in particular. It can be concluded that the unique profile of action of talsaclidine is due to partial agonism at bronchial
muscarinic M3 receptors, a prerequisite for susceptibility to functional antagonism, and to its ability to penetrate the blood-brain barrier readily and to induce sympathetic activation as a result of full agonism at peripheral ganglionic and adrenal as well as central
muscarinic M1 receptors.