Release of nitric oxide and expression of constitutive nitric oxide synthase of human endothelial cells: enhancement by a 14-membered ring macrolide.
A 14-membered ring macrolide, erythromycin, acts not only as an antibacterial but also as an anti-inflammatory agent. We have previously reported that erythromycin modulates neutrophil functions and ameliorates neutrophil-induced endothelial cell damage through the action of cyclic AMP-dependent protein kinase (PKA) and nitric oxide (NO). We investigated the effect of erythromycin on human endothelial cell functions. Erythromycin enhanced intracellular calcium ion concentration ([Ca2+]i) of endothelial cells and NO release from endothelial cells. The enhancement of NO release from endothelial cells by erythromycin was abolished by addition of EGTA in the medium and was partially reduced by addition of H-89, an inhibitor of PKA. These results suggest that erythromycin enhances NO release from endothelial cells through the action of PKA and [Ca2+]i. In addition, constitutive NO synthase (cNOS) protein expression of endothelial cells was dose-dependently enhanced by treatment with erythromycin, which might also contribute to the enhancement of NO release from endothelial cells by erythromycin. The effect of erythromycin as an anti-inflammatory agent might be partially mediated through the enhancement of NO release from endothelial cells and the drug might be a useful tool for the investigation of cNOS of endothelial cells.
Mitsuyama
T
T
Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Hidaka
K
K
Furuno
T
T
Hara
N
N
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004533:Egtazic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004917:Erythromycin / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III; D011651:Pulmonary Artery; D013449:Sulfonamides
D000893:Anti-Inflammatory Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; C071449:H 85; D009569:Nitric Oxide; D004533:Egtazic Acid; D004917:Erythromycin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D001920:Bradykinin; D002118:Calcium