Characterization of airway and vascular responses in murine lungs

1 We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. 2 Airways: The EC50 (mu M) for contractions of airways in IPL/slices was me thacholine (Mch), 6.1/1.5 > serotonin, 0.7/2.0 > U46619 (TP-receptor agonis t), 0.1/0.06 > endothelin-1, 0.1/0.05. In the IPL, maximum increase in airw ay resistance (R-L) was 0.6, 0.4, 0.8 and 11 cmH(2)O s ml(-1), respectively . Adenosine (less than or equal to 1 mM), bombesin (less than or equal to 1 00 mu M), histamine (less than or equal to 10 mM), LTC4 (less than or equal to 1 mu M), PAF (0.25 mu M) and substance P (less than or equal to 100 mu M) had only weak effects (<5% of Mch) on R-L. 3 Vessels: The EC50 (mu M) for vasoconstriction in the IPL was LTC4, 0.06 > U46619, 0.05 < endothelin-1, 0.02. The maximum increase in pulmonary arter y pressure (PAP) was 11, 41 and 48 cmH(2)O, respectively. At 250 nM, the ac tivity of PAF was comparable to that of LTC4. At 100 mu M only, substance P caused a largely variable increase in PAP. Serotonin, adenosine, bombesin, histamine and Mch had no or only very small effects on PAP. 4 Hyperresponsiveness: In both the IPL and slices, U46619 in subthreshold c oncentrations (10 nM) reduced the EC50 to 0.6 mu M. In the IPL, U46619 rais ed the maximum airway response to Mch 5 fold and the maximum PAF-induced va soconstriction 4 fold. 5 Conclusion: Murine precision-cut lung slices maintain important character istics of the whole organ. The maximum reagibility of murine airways to end ogenous mediators is serotonin < Mch < U46619 < ET-1. The reagibility of th e murine pulmonary vasculature is serotonin < LTC4 approximate to PAF < U46 619 < ET-1. The airway and vessel hyperreactivity induced by U46619 raises the possibility that thromboxane contributes directly to airway hyperrespon siveness in various experimental and clinical settings.