Inhibition of Mediator Induced Macromolecular Leakage

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theless they all inhibit macromolecular leakage in postcapil-lary venules, thus emphasizing that in spite of increased blood flow and perfusion pressure in the arterioles that should favor plasma leakage from the venules, the effect of the drug localized to receptors on the endothelial cells of the postcapillary venules is the dominant factor in the regulation of plasma leakage in inflammation. Neutrophil-induced changes in vascular permeability are the result of a complex interaction between adhesive proteins expressed on the surface of leukocytes and endothelial cells, selectins, and integrins, which finally results in the firm adhesion of leukocytes in postcapillary venules. It is possible to interfere with the leukocyte-endothelial cell interaction at different steps. Monoclonal antibodies against adhesion glycopro-teins have been used to elaborate mechanisms of leukocyte rolling and adhesion. Dextran sulfate, and possibly also heparin, acts by neutralizing charged peptides released from the LTB4-activated neutrophil, thereby inhibiting macromolecular leakage by 85 percent. Ropivacain, a local anesthetic with anti-inflammatory properties, may reduce the rolling and firm adhesion of LTB4-stimulated neutrophils and also the macromolecular leakage, see Table II. These effects could be explained by a shedding of selectins on the surface of leukocytes. Studies on neutrophil or leukocyte induced macromolecular leakage illustrate that the final result of inhibitor action is localized to the venular endothe-lial cells in the postcapillary venules. Antioxidants such as ascorbic acid, tocopherol, flavonoids, and SODs may not exert any constriction or dilation, but they may neutralize products released from adhering and activated neutrophils. Asthma and diabetes are today recognized as inflammatory diseases, and asthma drugs, which have been studied in the HCP (b2-adrenoreceptor stimulants, theophylline, glucocor-ticoids, chromoglycate), all have a significant inhibitory effect on histamine-induced macromolecular leakage. The antidiabetic drugs, glibenclamide and gliclazide, may counteract I/R-induced inflammatory effects in the HCP

Pharmacological inhibition of mediator (bradykinin) induced macromolecular leakage in the HCP was first shown with the b2-adrenoreceptor terbutaline. Since then a variety of drugs have been studied for their potential to inhibit plasma leakage in the HCP as listed in Table II. The listed drugs represent different physiological and pharmacological principles as exemplified by selective receptor blockers (mepyramin, HOE 140, theophylline, ketanserin), calcium antagonists (verapamil), glucocorticoids (budes-onide, methylprednisolone, dexamethasone), nitric oxide synthetase (NOS) inhibitors (L-NA, L-NAME, L-NMMA), antioxidants (ascorbic acid, tocopherol, flavonoids), potassium channel blockers (glibenclamide, gliclazid, for treatment of diabetes) and drugs interfering with leukocyte adhesion or activation (antioxidants, prostacyclin, NOS-inhibitors, superoxide dismutase, dextran sulfate).

b2-Adrenoreceptor stimulants (terbutaline, salbutamol) and phosphodiesterase inhibitors (rolipram, milrinone) will cause arteriolar dilation on application to the HCP. Never

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