A novel dual-agonist challenge model in guinea pigs for assessment of individual and combined muscarinics antagonists and b ₂ adrenoceptor agonists bronchodilator efficacy

The guinea pig broncoconstriction model has been shown to be predictive for both muscarinics receptor antagonist and b 2 -adrenoceptor agonist efficacy in humans. Here we describe a novel in vivo model of bronchoconstriction in guinea pigs, stimulated by two different agonists, histamine and methacholine. This dual-agonist challenge model can be used to assess the potency of both M 3 antagonists and b 2 -adrenoceptor agonists individually and in combination. This can be extended to investigate compounds with dual activity: M uscarinic receptor a ntagonists and β 2 - a drenoceptor a gonists (MABA). Following administration of test compounds three separate bronchoconstrictor challenges were given to each animal: The β 2 potency was assessed after challenging guinea pigs with histamine. Methacholine challenge in the same animal allowed assessment of combined in vivo potency at both β 2 and M 3 receptors. Finally, the potency of the compounds at M 3 receptor alone was assessed using methacholine challenge in the presence of propranolol. No significant difference in between single- and dual-challenge model was observed for the both M 3 antagonists and b 2 -adrenoceptor agonists tested with regards to in vivo potency or duration of action, therefore validating our approach. In addition to reducing number of animals used, this approach allowed us to assess individual and combined potency and duration of action for both M 3 antagonists and b 2 -adrenoceptor agonists in single animal. This novel bronchoconstriction model provides a robust mechanism for the future testing of MABA compounds.