Histamine is known to increase permeability of venules and to cause formation of gaps between endothelial cells. The permeability increase is transient, lasting only a few minutes during continuous histamine application. In this study, three series of experiments were conducted to test the hypothesis that the transient permeability increase is due to transient formation of endothelial gaps. First, the time course of permeability changes to alpha-lactalbumin during 15 min of 10(-3) M histamine suffusion was determined on single venules in the rat mesentery. With histamine application, permeability increased initially, peaked with an average of fivefold increase around the 3rd min, and then declined toward control. Second, the temporal development of endothelial gaps during histamine treatment was studied with electron microscopy. The fraction of gaps among all junctions increased from 2% at control to 26.5% at 3 min and then decreased toward control. Finally, gap morphology data were obtained from the individual venules whose permeability response to a given period of histamine treatment had been recorded. The temporal development of the gaps was mirrored by that of permeability. Because both permeability and endothelial gaps followed similar developmental patterns during histamine treatment, the result of our study supports the hypothesis that the histamine-induced transient permeability increase is due to transient formation of endothelial gaps.

Blood vessel walls form a selective barrier to the transport of materials between blood and tissue, and the endothelium contributes significantly to this barrier function. The role of the endothelium is particularly important in thin-walled vessels, such as venules, because during tissue inflammation the endothelial junctions widen in localized areas and gaps form, thus compromising the barrier function. The mechanisms of endothelial gap formation are still under question. In this review we describe what is known about the structure of endothelial cell-cell junctions and how this structure can change during inflammation. We then consider two possible mechanisms by which endothelial gaps are formed: active endothelial cell contraction or breakdown of the junctional complex, followed by passive recoil. Using measured values of the mechanical properties of endothelial cells, and the forces to which they are subjected, we calculate that gap formation by breakdown of cellular adhesion, followed by passive recoil, is a feasible mechanism. Finally, since endothelial cell surfaces, including junctions, are coated with a glycocalyx, we consider the question of whether changes in the glycocalyx can markedly increase endothelial permeability. We conclude that gap formation can occur by active contraction or by breakdown of adhesion, depending on the inflammatory mediator, and that the responses of the glycocalyx may also play an important role in the regulation of microvascular permeability.

The response of the endothelial permeability barrier in microvascular networks of the rat mesentery to perfused immune inflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) was examined. TNF-α (12.5 U/ml) treatment did not change albumin permeability, but in combination with IFN-γ (20 U/ml), there was a marked increase in the number of sites of extravascular albumin in postcapillary venules. Endothelial integrity was characterized by cadherin-5 immunoreactivity, which was localized to the continuous intercellular junctions of endothelium in arterioles, capillaries, and venules. Perfusion with the combined cytokines showed that the increased albumin permeability was dose dependent and correlated with the focal disorganization of cadherin-5 at intercellular junctions of venular endothelium. No correlation was found between the increase in albumin permeability and the localization of intravascular leukocytes or extravascular mast cells. These results show that the combination of TNF-α and IFN-γ induces an endothelial phenotype with focal loss of cadherin-5 intercellular adhesion, which, in part, facilitates passage of blood macromolecules and cells to the interstitium.

This blinded, controlled pilot study investigated the effects of Reiki on 46 patients undergoing knee replacement surgery. Of the 3 groups, Reiki, Sham Reiki, and Standard of Care, only the Reiki group showed significant reductions in pain, blood pressure, respiration rate, and state anxiety, which provides evidence for a full-scale clinical study.