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 (microM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP-receptor agonist), 0.1/0.06>endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml(-1), respectively. Adenosine (< or =1 mM), bombesin (< or =100 microM), histamine (< or =10 mM), LTC4 (< or =1 microM), PAF (0.25 microM) and substance P (< or =100 microM) had only weak effects (<5% of Mch) on RL. 3. Vessels: The EC50 (microM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.05<endothelin-1, 0.02. The maximum increase in pulmonary artery pressure (PAP) was 11, 41 and 48 cmH2O, respectively. At 250 nM, the activity of PAF was comparable to that of LTC4. At 100 microM 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 concentrations (10 nM) reduced the EC50 to 0.6 microM. In the IPL, U46619 raised the maximum airway response to Mch 5 fold and the maximum PAF-induced vasoconstriction 4 fold. 5.


CONCLUSIONS
Murine precision-cut lung slices maintain important characteristics of the whole organ. The maximum reagibility of murine airways to endogenous mediators is serotonin<Mch<U46619<ET-1. The reagibility of the murine pulmonary vasculature is serotonin<LTC4 approximately = to PAF<U46619<ET-1. The airway and vessel hyperreactivity induced by U46619 raises the possibility that thromboxane contributes directly to airway hyperresponsiveness in various experimental and clinical settings.
Held
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Division of Pulmonary Pharmacology, Research Centre Borstel, Germany.
Martin
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Uhlig
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D006639:Histidine / Q000494:pharmacology; D066298:In Vitro Techniques; D017997:Leukotriene C4 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010477:Perfusion; D010972:Platelet Activating Factor / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016085:Bronchoconstrictor Agents; D019332:Endothelin-1; D010972:Platelet Activating Factor; D014662:Vasoconstrictor Agents; D016210:Methacholine Chloride; D017997:Leukotriene C4; D012701:Serotonin; D013373:Substance P; D006639:Histidine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000241:Adenosine; D001839:Bombesin