In this study we examined the desensitization of guinea-pig parenchymal lung strips after excessive stimulation of the histamine H1-receptor. After stimulation with maximal effective concentrations of the selective H1-receptor agonist 2-pyridylethylamine (1 mM) for 30 min, subsequent 2-pyridylethylamine responses were inhibited as shown in a depression of the maximal response with approximately 40%. This desensitization was time- and concentration-dependent. Besides H1-receptor responses, potassium chloride (50 mM)-induced responses were also affected. Treatment of lung strips with 1 mM of 2-pyridylethylamine for 30 min resulted in an inhibition of the potassium-induced contraction with 26.1 +/- 8.7% of the control response. Desensitization of the lung strip preparation could not be prevented by the cyclooxygenase inhibitor indomethacin (20 microM), indicating that the observed inhibition is not due to an elevated production of relaxing prostaglandins. Desensitization was also not dependent on the influx of extracellular calcium. Stimulation of guinea-pig parenchymal lung strips with 1 mM of 2-pyridylethylamine in a calcium-free buffer, supplemented with the calcium chelator EGTA, did not lead to observable contractions. However, desensitization still developed under these conditions. These data indicate that guinea-pig parenchymal lung strips exhibit a desensitized state after prolonged H1-receptor stimulation. Because this effect is not only limited to H1-receptor responses, as KCl effects are reduced as well, it should, at least partly, be explained by an interference with processes which occur distally to the H1-receptor itself.