Beta-lactam antibiotics inhibit agonist-stimulated platelet calcium influx
Burroughs, S.F.; Johnson, G.J.
Thrombosis and Haemostasis 69(5): 503-508
1993
ISSN/ISBN: 0340-6245 PMID: 8322272 Document Number: 419758
beta-lactam antibiotics cause platelet dysfunction with reversible agonist-receptor inhibition, irreversible (14C)-penicillin binding, and inhibition of agonist-stimulated elevation in cytosolic Ca-2+ ((Ca-2+)-i, occurring after 24 h exposure in vitro and after in vivo treatment. We investigated beta-lactam antibiotic-induced inhibition of rises in (Ca-2+)-i stimulated by thrombin, sodium arachidonate or A23187 to determine whether Ca-2+ influx or intracellular release was primarily affected. The mean rise in (Ca-2+)-i, measured with fura-2-AM, was inhibited 43.7-84.1% by penicillin when the extracellular Ca-2+ concentration ((Ca-2+)-e) was 1 mM, but was significantly less inhibited when (Ca-2+)-e was lt 1 mu-M. NiCl-2 (2 mM), that blocks Ca-2+ influx, caused inhibition comparable to penicillin. MnCl-2 (1 mM), that quenches the intracellular fura-2 signal, significantly decreased the rise in 1 mM (Ca-2+)-i when (Ca-2+)-e was 1 mM, but did not increase the inhibition caused by penicillin. Penicillin did not inhibit the rise in (Ca-2+)-i stimulated by inositol-1,4,5-trisphosphate or GTP-gamma-S. Therefore, beta-lactam antibiotics inhibit agonist-induced elevations of (Ca-2+)-i primarily through inhibition of Ca-2+ influx, which probably accounts for the irreversible inhibition of platelet function seen after prolonged in vitro or in vivo treatment.