Bronchodilating properties of the VIP receptor agonist Ro 25-1553 compared to those of formoterol on the guinea-pig isolated trachea
Introduction
Ro 25-1553 is a 31-amino acid analogue of vasoactive intestinal peptide (VIP) with the amino acid sequence:where Ac=Nα-acetyl (Bolin et al., 1995). Like VIP it has a bronchodilating effect in vitro as well as in vivo but it is more potent and metabolically more stable than the native compound (O'Donnell et al., 1994a). Moreover, Ro 25-1553 has the capacity to inhibit allergen-induced bronchoconstriction and eosinophil influx in the guinea-pig lung (O'Donnell et al., 1994b). Ro 25-1553, like native VIP and the β2-adrenoceptor agonist salbutamol, increases the formation of cyclic AMP as shown in murine splenocytes (Tang et al., 1995). Recently, Ro 25-1553 has been found to be highly selective for the VIP2 (now VPAC2) receptor subclass (Gourlet et al., 1997), and hence designated by the International Union of Pharmacology as a tool for classification of receptors for VIP (Harmar et al., 1998).
We now report on extended studies exploring the relative potency and efficacy of Ro 25-1553 compared to the long-acting β2-adrenoceptor agonist, formoterol. The aims of the investigation were to, (a) estimate the capability to relax strongly contracted airway smooth muscle strips, (b) measure the rate of onset of action and the durability of the relaxing effect, (c) investigate the interaction between Ro 25-1553 and the β2-adrenoceptor agonists, formoterol and salmeterol, and (d) explore, with the aid of a vagus nerve-trachea tube preparation, the ability of Ro 25-1553 to pass the airway epithelium. All experiments were carried out on isolated preparations of guinea-pig trachea.
Section snippets
Animals and organ baths
Male Dunkin–Hartley guinea-pigs (Charles River, Sweden), 200–400 g, were anaesthetized with pentobarbitone and exsanguinated by cutting the subclavian arteries. The trachea, with or without the adhering vagus nerves was dissected out and prepared for measurements as described below. All experiments were performed in water-jacketed organ baths (40 ml) containing oxygenated Krebs solution at 37 °C. The Krebs solution had the following composition in mmol l−1: NaCl 118; KCl 4.7; CaCl2 2.5; MgSO4
Potency and efficacy
Ro 25-1553 caused a concentration-dependent and complete relaxation of the guinea-pig trachea strip preparation contracted with 0.1 μmol l−1 carbachol (Fig. 1). A further increase in smooth muscle tone achieved by increasing the concentration of carbachol to 1 μmol l−1 resulted in a sevenfold shift of the concentration–response curve to the right (P<0.001) but with maximum relaxation maintained. Very similar results were obtained with formoterol (Fig. 1). With the low level of carbachol-induced
Discussion
The present data confirm and extend previous results (O'Donnell et al., 1994a) which show that the VIP receptor agonist Ro 25-1553 potently relaxes airway smooth muscle with an EC50 in the nanomolar range. Our data further show that Ro 25-1553 is 3–7 times less potent than formoterol on a molar base. For both compounds, the concentration–response curves were moved to the right with no depression of the maximum relaxation when the degree of precontraction was increased by carbachol. This
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