Compensation of muscarinic bronchial effects of talsaclidine by concomitant sympathetic activation in guinea pigs

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.