Effect of a novel PACAP-27 analogue on muscarinic airway responsiveness inguinea-pigs in vivo

A recent study showed that the novel pituitary adenylate cyclase-activating peptide (PACAP)-27 analogue [Arg(15,20,21), Leu(17)]-PACAP-27-Gly-Lys-Arg- NH2 causes sustained airway smooth muscle relaxation in vitro. This study e xamined whether this analogue also has bronchoprotective effects, by inhibi ting muscarinic airway responsiveness in vivo. Total lung resistance was measured in anaesthetized, tracheostomized and ve ntilated guinea-pigs, Increasing doses of acetylcholine were given i.v. onc e before and thereafter repeatedly each hour after intratracheal instillati on of either the PACAP-27 analogue or the clinical beta(2)-agonist bronchod ilator salbutamol, Mean arterial blood pressure (MAP) was monitored to dete ct cardiovascular side-effects. Both the PACAP-27 analogue and salbutamol significantly attenuated the airw ay responsiveness to acetylcholine, The total inhibitory effect of the PACA P-27 analogue (350 nmol) corresponded to that of salbutamol (35 nmol), Titl e inhibitory effect of salbutamol (35 nmol) peaked during the second hour a nd disappeared prior to 5 h after administration. In contrast, the correspo nding effect of the analogue (350 nmol) gradually increased and peaked duri ng the fifth hour after administration, whereas it did not fade during the observation period. Both the PACAP-27 analogue (350 nmol) and salbutamol (3 5 nmol) produced a transient decrease in MAP within 6 min after administrat ion. In conclusion, the novel pituitary adenylate cyclase-activating peptide-27 analogue has bronchoprotective properties, by decreasing muscarinic airway responsiveness in guinea Digs in viva. The time course of its effect is com patible with a more sustained duration of action compared with salbutamol.