In contrast to other muscarinic agonists, WAL 2014 FU does not induce bronchospasm in laboratory animals. The present investigation was intended to test the hypothesis that this is due to a particular susceptibility of the drug's effect to antagonism by catecholamines, as a result of partial M3-agonism. The tonic activity of the muscarinic agonists, aceclidine, arecoline, carbachol, McN-A-343, RS 86, thiopilocarpine and WAL 2014 FU, was tested in groups of isolated tracheal muscle of the guinea-pig. Susceptibility to functional antagonism by beta-adrenoceptor stimulation was measured by the displacement of the concentration-force curves by 3 microM noradrenaline. Evaluation of the concentration-force relationship revealed differences in potency and intrinsic activity (carbachol-100%) ranging from 114% for arecoline to 36% for thiopilocarpine (WAL 2014 FU-63%). The catecholamine increased the concentration of agonist which induced 5% of the maximum effect achievable (EC05) values fivefold (carbachol) to more than 4,680 fold (thiopilocarpine) (WAL 2014 FU: 2,860 fold). Regression analysis between the intrinsic activity of the seven compounds and the antagonistic effect of noradrenaline revealed a significant correlation (Spearman correlation coefficient (r[s])=-0.79; p=0.036). Inhibition of the effects of endogenous catecholamines by beta-adrenolysis with 50 microM toliprolol increased the maximal contraction induced by 1 mM WAL 2014 FU, but did not affect maximal contraction induced by 30 microM arecoline. Pretreatment with 0.3-1.0 mM dibutyrylcyclic adenosine monophosphate (DBcAMP) shifted the concentration-response curves of arecoline, WAL 2014 FU and thiopilocarpine in a similar manner to noradrenaline. The results exclude an important contribution of adenylate cyclase-coupled M2-receptors to the susceptibility of tracheal contraction by muscarinic agonists to functional antagonism by noradrenaline, but emphasize the importance of intrinsic activity at the M3-receptors. The pronounced susceptibility of WAL 2014 FU-induced contraction to functional antagonism by beta-adrenoceptor activation provides an explanation for the failure of the drug to induce bronchospasm in vivo.

01 May 1997·The Journal of Pharmacology and Experimental Therapeutics

Hippocampal Noradrenaline Release in Awake, Freely Moving Rats Is Regulated by Alpha-2 Adrenoceptors but Not by Adenosine Receptors

Author: Carter, Adrian J.

The ability of the nonselective adenosine receptor antagonist caffeine to influence the concentration of noradrenaline in the central nervous system was investigated, and its effects compared with those of α₂-adrenoceptor modulation.The technique of microdialysis in association with microbore HPLC and electrochem. detection was used to measure the extracellular concentrations of noradrenaline in the hippocampus of awake, freely moving rats.Neither the oral administration of caffeine nor its local perfusion influenced the baseline hippocampal levels of noradrenaline.Furthermore, the levels of noradrenaline were not influenced by local perfusion of the selective adenosine A₁ agonist N⁶-cyclopentyladenosine or by the selective adenosine A₂ agonist CGS 21680.In contrast, the extracellular levels of noradrenaline could be increased by the perfusion of the selective α₂-adrenoceptor antagonist idazoxan and decreased by local perfusion of Ca²⁺-free phosphate buffered saline, a Na⁺-channel blocker, tetrodotoxin, or the selective α₂-adrenoceptor agonist clonidine.The extracellular levels of noradrenaline were stimulated by the local perfusion of different concentrations of K⁺ (10-100 mM).The K⁺-dependent increase in the extracellular levels of noradrenaline was potentiated by local perfusion of idazoxan and inhibited by local perfusion of clonidine.In contrast, neither the oral administration of caffeine nor its local perfusion influenced the K⁺-stimulated increases in hippocampal noradrenaline.Furthermore, local perfusion of N⁶-cyclopentyladenosine or CGS 21680 did not influence the K⁺-stimulated levels of noradrenaline either.These results indicate that baseline and K⁺-stimulated extracellular levels of noradrenaline in the hippocampus of awake, freely moving rats are regulated by α₂-adrenoceptors and not by adenosine receptors.

01 Feb 1997·Life SciencesQ3 · MEDICINE

In vivo consequences of M1-receptor activation by talsaclidine

Q3 · MEDICINE

Article

Author: Walland, A. ; Troeger, W. ; Hammer, R. ; Burkard, St.

The aim of this investigation in anaesthetized dogs was to provide direct evidence for an activation of the sympathetic nervous system by the muscarinic agonist talsaclidine (WAL 2014 FU). Intravenous infusion at a rate of 1 mg/kg/min increased plasma catecholamines and in particular epinephrine, thus indicating a predominant stimulation of the adrenals. Sympathetic activation was also indicated by increases in renal vascular resistance, an effect which was sensitive to alpha-adrenolysis. It is concluded that the sympathetic activation by talsaclidine is due to full agonism at the M1-receptor and the ability to cross the blood-brain barrier. As talsaclidine is less potent and only a partial agonist at M2- and M3-receptors many peripheral actions mediated by these receptor subtypes are functionally antagonized by the concomitant sympathetic activation.

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