Erythromycin inhibits ATP-induced intracellular calcium responses in bovine tracheal epithelial cells.
Erythromycin (EM) therapy is known to decrease airway secretion in chronic inflammatory airway diseases such as diffuse panbronchiolitis. Airway secretion is regulated by intracellular Ca2+ concentration ([Ca2+]i). To elucidate the intracellular site of action of EM in airway epithelium, we examined the effect of EM on Ca2+ dynamics in cultured bovine tracheal epithelial cells using fura-2. EM per se did not cause any change in [Ca2+]i. Adenosine triphosphate (ATP; 10(-4) M) induced a biphasic [Ca2+]i increase, consisting of a transient response followed by a sustained response. Pretreatment of cells with EM had little effect on the ATP-induced transient Ca2+ response but substantially reduced the sustained response in a dose-dependent manner. Clarithromycin, another 14-membered ring macrolide, likewise showed the inhibitory effect, but ampicillin and cephasolin did not. Uridine triphosphate (UTP; 10(-4) M) induced a biphasic [Ca2+]i increase similar to ATP, and the UTP-induced sustained Ca2+ response was also inhibited by EM. In Ca2+-deficient medium (1 mM ethyleneglycol-bis-(beta-aminoethyl ether)-N, N'-tetraacetic acid [EGTA]) or in the presence of La3+, the sustained Ca2+ response disappeared, suggesting that EM may inhibit Ca2+ influx induced by P2u purinoceptor stimulation. In single-cell Ca2+ image analysis, low concentration of ATP (10(-6) M) induced Ca2+ oscillations, which were also inhibited by EM. The disappearance of [Ca2+]i oscillations after addition of EM was similar to that after addition of EGTA. These results suggest that EM may decrease Ca2+-dependent airway secretion by inhibiting agonist-stimulated Ca2+ influx.
Kondo
M
M
First Department of Medicine and Second Department of Physiology, Tokyo Women's Medical College, Tokyo, Japan.
Kanoh
S
S
Tamaoki
J
J
Shirakawa
H
H
Miyazaki
S
S
Nagai
A
A
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D004917:Erythromycin / Q000494:pharmacology*; D005453:Fluorescence; D016257:Fura-2 / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007811:Lanthanum / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*; D014544:Uridine Triphosphate / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004917:Erythromycin; D007811:Lanthanum; D000255:Adenosine Triphosphate; D014700:Verapamil; D002118:Calcium; D016257:Fura-2; D014544:Uridine Triphosphate