Beta-Lactam Antibiotics Inhibit Agonist-Stimulated Platelet Calcium Influx

Summary

(β-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 β-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 μM. 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 GTPγS. Therefore, β-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.

• References

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