THE BETA(2)-ADRENERGIC RECEPTOR AGONIST FORMOTEROL REDUCES MICROVASCULAR LEAKAGE BY INHIBITING ENDOTHELIAL GAP FORMATION

beta(2)-Adrenergic receptor agonists inhibit the increase in vascular permeability produced by a variety of inflammatory mediators. The anti-edema effect of beta(2)-agonists is assumed to result from a direct action on endothelial cells, but such a mechanism has not been demonstrated in vivo. The aim of this study was to determine whether beta(2)-agonists exert their anti-edema effect by inhibiting the formation of endothelial gaps at sites of plasma leakage. Vascular permeability in the rat trachea was increased by electrical stimulation of the vagus nerve or by intravenous injection of substance P (5 mu g/kg iv). Plasma leakage was quantified by using Monastral blue and Evans blue as tracers. Endothelial gaps were made visible for light microscopy by staining the borders of endothelial cells with silver nitrate. The experiments showed that the selective beta(2)-agonist formoterol, which is known to have anti-edema effects, reduced the plasma leakage produced by either stimulus. The effect was dose dependent, with a formoterol dose of 10 mu g/kg iv producing maximal reduction of Monastral blue leakage (64+/-14%). The amounts of extravasation of Monastral blue and Evans blue were closely correlated (r(2)=0.76, P < 0.01). After the injection of substance P, there were 15.3+/-1.0 gaps/endothelial cell in postcapillary venules of vehicle-pretreated rats, but only 5.0+/-0.2 gaps/cell in formoterol-pretreated (10 mu g/kg iv) rats. This 68% reduction in the number of endothelial gaps was accompanied by a 70% reduction in Monastral blue leakage. The average diameter of the gaps (1.2 mu m) was the same in both groups. We conclude that beta(2)-agonists reduce plasma extravasation by reducing the number but not the size of endothelial gaps.