EFFECTS OF VASOACTIVE INTESTINAL POLYPEPTIDE ON ANTIGEN-INDUCED BRONCHOCONSTRICTION AND THROMBOXANE RELEASE IN GUINEA-PIG LUNG

1 Exogenous vasoactive intestinal polypeptide (VIP) infused into the pulmonary artery of isolated and ventilated lungs of guinea-pigs decreased, in a dose-dependent fashion (1.0-10.0 nmol), airway resistance and thromboxane B2 (TXB2, the stable hydrolysis product of TXA2) release in the perfusion medium. Prostacyclin (PGI2) synthesis, as reflected by the release of its stable hydrolysis product 6-oxo-PGF1alpha, was unaffected. Pretreatment with the 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) m) did not modify the bronchodilatory effect of VIP or its inhibitory action on TXB2 release. 2 Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 +/- 0.10 ng min-1 (mean +/- s.e.mean) in the first 2 min to an average of 0.58 +/- 0.10 ng min-1 in the following 15-20 min. 3 Antigen challenge with ovalbumin (0.1%) in sensitized lungs caused an anaphylactic reaction in 45% of tested lung, concomitant with a 5 fold increase in both VIP and TXB2 release. Tetrodotoxin pretreatment (10(-6) m) reduced basal VIP release by > 80% and abolished the VIP increase observed during anaphylaxis, without modifying TXB2 release or the bronchoconstrictor response. 4 Indomethacin (10(-6) M) inhibited TXB2 synthesis and release by > 90%, delayed the bronchoconstrictor response and blunted the increased VIP release during lung anaphylaxis, without influencing basal VIP release. 5 The 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) m) blunted the increase of TXB2 and VIP release from guinea-pig lung and attenuated the bronchoconstrictor response following ovalbumin challenge. 6 The administration of exogenous VIP as a continuous infusion (10(-8) m) attenuated the bronchoconstriction and the release of cyclo-oxygenase metabolites following antigen challenge. 7 Acetylcholine (10(-6)-10(-5) m) infused into the pulmonary artery induced a dose-dependent bronchoconstriction not associated with enhanced VIP or TXB2 release. 8 The TXA2 mimetic U-46619 (0.1 - 1.0 nmol) caused dose-dependent increases in airway resistance, concomitant with an up to 10 fold increase in VIP release. VIP inhibited arachidonate-induced in vitro aggregation of washed rabbit platelets in a dose-dependent manner over a dose range 10(-8)-10(-6) M. Despite the antiaggregatory effect of VIP, TXB2 and PGE2 synthesis was reduced only to a minor extent, and there was no redirection of arachidonate metabolism from TXA2 to PGE2, indicating that VIP does not act as a TX synthase inhibitor in vitro. 9 We conclude that VIP may play a role in regulating bronchial smooth muscle reactivity in lung anaphylaxis by inhibiting the synthesis and release of TXA2, a potent vasoactive and bronchoconstrictor agent. TXA2, on the other hand, strongly enhances neuronal VIP release.