Beta-lactam antibiotics inhibit agonist-stimulated platelet calcium influx.
beta-lactam antibiotics cause platelet dysfunction with reversible agonist-receptor inhibition, irreversible [14C]-penicillin binding, and inhibition of agonist-stimulated elevation in cytosolic Ca2+ ([Ca2+]i), occurring after 24 h exposure in vitro and after in vivo treatment. We investigated beta-lactam antibiotic-induced inhibition of rises in [Ca2+]i stimulated by thrombin, sodium arachidonate or A23187 to determine whether Ca2+ influx or intracellular release was primarily affected. The mean rise in [Ca2+]i, measured with fura-2-AM, was inhibited 43.7-84.1% by penicillin when the extracellular Ca2+ concentration ([Ca2+]e) was 1 mM, but was significantly less inhibited when [Ca2+]e was < 1 microM. NiCl2 (2 mM), that blocks Ca2+ influx, caused inhibition comparable to penicillin. MnCl2 (1 mM), that quenches the intracellular fura-2 signal, significantly decreased the rise in 1 mM [Ca2+]i when [Ca2+]e was 1 mM, but did not increase the inhibition caused by penicillin. Penicillin did not inhibit the rise in [Ca2+]i stimulated by inositol-1,4,5-trisphosphate or GTP gamma S. Therefore, beta-lactam antibiotics inhibit agonist-induced elevations of [Ca2+]i primarily through inhibition of Ca2+ influx, which probably accounts for the irreversible inhibition of platelet function seen after prolonged in vitro or in vivo treatment.
Burroughs
S F
SF
Department of Veterans Affairs Medical Center, Minneapolis, MN.
Johnson
G J
GJ
D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D001692:Biological Transport / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000001:Calcimycin / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism*; D003864:Depression, Chemical; D006801:Humans; D015636:Magnesium Chloride / Q000494:pharmacology; D008802:Mezlocillin / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D010400:Penicillin G / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D015636:Magnesium Chloride; D016718:Arachidonic Acid; D000001:Calcimycin; C022838:nickel chloride; D000667:Ampicillin; D009532:Nickel; D013917:Thrombin; D008802:Mezlocillin; D010400:Penicillin G; D002118:Calcium