Volatile anesthetics, not intravenous anesthetic propofol bind to and attenuate the activation of platelet receptor integrin ?IIb?3.

ABSTRACT:

Background

In clinical reports, the usage of isoflurane and sevoflurane was associated with more surgical field bleeding in endoscopic sinus surgeries as compared to propofol. The activation of platelet receptor ?IIb?3 is a crucial event for platelet aggregation and clot stability. Here we studied the effect of isoflurane, sevoflurane, and propofol on the activation of ?IIb?3.

Methods

The effect of anesthetics on the activation of ?IIb?3 was probed using the activation sensitive antibody PAC-1 in both cell-based (platelets and ?IIb?3 transfectants) and cell-free assays. The binding sites of isoflurane on ?IIb?3 were explored using photoactivatable isoflurane (azi-isoflurane). The functional implication of revealed isoflurane binding sites were studied using alanine-scanning mutagenesis.

Results

Isoflurane and sevoflurane diminished the binding of PAC-1 to wild-type ?IIb?3 transfectants, but not to the high-affinity mutant, ?3-N305T. Both anesthetics also impaired PAC-1 binding in a cell-free assay. In contrast, propofol did not affect the activation of ?IIb?3. Residues adducted by azi-isoflurane were near the calcium binding site (an important regulatory site termed SyMBS) just outside of the ligand binding site. The mutagenesis experiments demonstrated that these adducted residues were important in regulating integrin activation.

Conclusions

Isoflurane and sevoflurane, but not propofol, impaired the activation of ?IIb?3. Azi-isoflurane binds to the regulatory site of integrin ?IIb?3, thereby suggesting that isoflurane blocks ligand binding of ?IIb?3 in not a competitive, but an allosteric manner.

SUBMITTER: Yuki K 

PROVIDER: S-EPMC3616120 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature