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 p ulmonary artery of isolated and ventilated lungs of guinea-pigs decrea sed, in a dose-dependent fashion (1.0-10.0 nmol), airway resistance an d 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 u naffected. Pretreatment with the 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) m) did not modify the bronchodilatory effect of VIP or its inh ibitory action on TXB2 release. 2 Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 +/- 0.10 n g 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 i n 45% of tested lung, concomitant with a 5 fold increase in both VIP a nd TXB2 release. Tetrodotoxin pretreatment (10(-6) m) reduced basal VI P release by > 80% and abolished the VIP increase observed during anap hylaxis, without modifying TXB2 release or the bronchoconstrictor resp onse. 4 Indomethacin (10(-6) M) inhibited TXB2 synthesis and release b y > 90%, delayed the bronchoconstrictor response and blunted the incre ased VIP release during lung anaphylaxis, without influencing basal VI P release. 5 The 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) m) blunt ed the increase of TXB2 and VIP release from guinea-pig lung and atten uated 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-oxygena se metabolites following antigen challenge. 7 Acetylcholine (10(-6)-10 (-5) m) infused into the pulmonary artery induced a dose-dependent bro nchoconstriction not associated with enhanced VIP or TXB2 release. 8 T he TXA2 mimetic U-46619 (0.1 - 1.0 nmol) caused dose-dependent increas es 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 rang e 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 r edirection of arachidonate metabolism from TXA2 to PGE2, indicating th at 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 reacti vity in lung anaphylaxis by inhibiting the synthesis and release of TX A2, a potent vasoactive and bronchoconstrictor agent. TXA2, on the oth er hand, strongly enhances neuronal VIP release.