SummaryA rat model of inflammation was used to investigate the biological effects of thrombin. The thrombin-specific inhibitor Hirulog TM markedly attenuated the carrageenin-induced edema of the paw of the rat. Injection of thrombin into the paw also produced edema. The effect of thrombin was due to activation of its receptor; a thrombin receptor activating peptide (TRAP) reproduced the effects of thrombin in causing edema. TRAP also increased vascular permeability as demonstrated by extravasation of Evans blue and 125I-labeled serum albumin. The release of bioactive amines played an important role in mediating the TRAP-induced edema; the serotinin/histamine antagonist cryproheptadine and the histamine H2 receptor antagonist cimetidine reduced significantly the edema caused by TRAP. Treatment of rats with the mast cell degranulator 48/80 to deplete these cells of their stores of histamine and serotonin abolished completely the ability of TRAP to produce edema. Histochemical examination confirmed that TRAP treatment led to mast cell degranulation. Thus, it has been possible to demonstrate that thrombin acts as an inflammatory mediator in vivo by activating its receptor, which in turn leads to release of vasoactive amines from mast cells.

Coagulation proteases were tested in a rat model of acute inflammation. Subplantar injection of Factor Xa (10-30 g) produced a time-and dose-dependent edema in the rat paw, and potentiated carrageenin-induced edema. In contrast, the homologous protease Factor IXa was ineffective. This

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1 We have investigated the role of ATP-sensitive potassium (K ATP ) channels in an experimental model of a delayed phase of vascular hyporeactivity induced by lipopolysaccharide (LPS) in rats.2 After 24 h, from LPS treatment, in anaesthetized rats the bolus injection of phenylephrine (PE) produced an increase in mean arterial pressure (MAP) signi®cantly (P50.05) reduced in LPS-treated rats compared to the vehicle-treated rats. This reduction was prevented by pre-treatment of rats with glibenclamide (GLB), a selective inhibitor of K ATP channels. 3 GLB administration did not aect the MAP in vehicle-treated rats but produced an increase of MAP in rats treated with LPS. 4 Cromakalim (CRK), a selective K ATP channel opener, produced a reduction of MAP that was signi®cantly (P50.05) higher in LPS-than in vehicle-treated rats. In contrast, the hypotension induced by glyceryl trinitrate (GTN) in LPS-treated rats was not distinguishable from that produced in vehicle-treated rats. 5 Experiments in vitro were conducted on aorta rings collected from rats treated with vehicle or LPS 24 h before sacri®ce. The concentration-dependent curve to PE was statistically (P50.005) reduced in aorta rings collected from LPS-compared to vehicle-treated rats. This dierence was totally abolished by tetraethylammonium (TEA), a non-selective inhibitor of K + channels. 6 CRK produced a relaxation of PE precontracted aorta rings higher in rings from LPS-than in vehicle-treated rats. GLB inhibited CRK-induced relaxation in both tissues, abolishing the observed dierences. 7 In conclusion, our results indicate an involvement of K ATP channels to the hyporesponsiveness of vascular tissue after 24 h from a single injection of LPS in rats. We can presume an increase in the activity of K ATP channels on vascular smooth muscle cells but we cannot exclude an increase of K ATP channel number probably due to the gene expression activation.

An acetylated polypeptide corresponding to residues 2-26 of human lipocortin 1 was synthesized and the anti-inflammatory activity assessed in three models of acute inflammation in rat and mouse. In the carrageenin rat paw oedema test, the peptide produced a maximal inhibition of approximately 41% at the 3 h time point with a 10 gig dose. When rat paw oedema was induced by the injection of venom phospholipase A2, the peptide produced a significant inhibition (31%) at the top dose of 20 gig per paw. In the mouse air-pouch model, systemic treatment with the peptide produced a dramatic reduction in cytokine-induced leukocyte migration with an ID50 of approximately 40 gig per mouse.The N-terminal peptide 2-26 shares the actions of lipocortin 1 in these acute models of inflammation.