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Histamine is known to cause a substantial increase in the permeability of venules to both water and proteins. However, this increase is transient, i.e. the initially elevated permeability escapes even during continuous histamine stimulation. This project was designed to identify the mechanisms underlying this permeability-escape phenomenon. The project was conducted in two stages. In the first stage, three series of experiments were performed to test the hypothesis that the permeability-escape phenomenon is due to the reclosure of endothelial gaps. Firstly, the time course of permeability changes to a-lactalbumin during continuous histamine stimulation was obtained from single venules of rat mesentery. It was found that, after the start of histamine treatment, permeability initially increased, peaked around the third minute and then declined towards its control level. Secondly, the temporal development of endothelial gaps during histamine treatment was studied with electron microscopy. The number of gaps underwent a similar development, i.e. an initial increase, peaking at 3 minutes, and a subsequent decrease toward control. Lastly, both permeability and gap morphology were obtained from the same individual venules subjected to different periods of histamine treatment. It was found that the temporal development of the gaps was mirrored by that of permeability. Since both permeability and endothelial gaps followed similar developmental patterns during histamine treatment, the result supports the hypothesis that the permeability-escape phenomenon is due to the reclosure of endothelial gaps. In the second stage, the chemical signal initiating the permeability escape was identified. Specifically, we tested whether histamine's binding to H2 receptors and/or the production of prostacyclin by endothelial cells were involved. The time course of venular permeability changes during histamine stimulation was measured in the presence of H2 receptor antagonist and of prostacyclin synthetase inhibitor, respectively. It was found that, while blocking H2 receptors did not have any effect on the escape of permeability, inhibiting prostacyclin synthesis suppressed or even abolished the permeability-escape phenomenon. Therefore, we concluded that the production of prostacyclin by endothelial cells may serve as one chemical signal to initiate the escape of permeability.

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