RELEASE OF NITRIC-OXIDE AND EXPRESSION OF CONSTITUTIVE NITRIC-OXIDE SYNTHASE OF HUMAN ENDOTHELIAL-CELLS - ENHANCEMENT BY A 14-MEMBERED RINGMACROLIDE

A 11-membered ring macrolide, erythromycin, acts not only as an antiba cterial but also as an anti-inflammatory agent. We have previously rep orted that erythromycin modulates neutrophil functions and ameliorates neutrophil-induced endothelial cell damage through the action of cycl ic AMP-dependent protein kinase (PKA) and nitric oxide (NO). We invest igated the effect of erytkromycin on human endothelial cell functions. Erythromycin enhanced intracellular calcium ion concentration ([Ca2+] (i)) of endothelial cells and NO release from endothelial cells. The e nhancement of NO release from endothelial cells by erythromycin was ab olished by addition of EGTA in the medium and was partially reduced by addition of H-89, an inhibitor of PKA. These results suggest that ery thromycin enhances NO release from endothelial cells through the actio n of PKA and [Ca2+](i). In addition, constitutive NO synthase (cNOS) p rotein expression of endothelial cells was dose-dependently enhanced b y treatment with erythromycin, which might also contribute to the enha ncement of NO release from endothelial cells by erythromycin. The effe ct of erythromycin as an anti-inflammatory agent might be partially me diated through the enhancement of NO release from endothelial cells an d the drug might be a useful tool for the investigation of cNOS of end othelial cells.