INFLUENCE OF VOLATILE ANESTHETICS ON THROMBOXANE A(2) SIGNALING

Background: Thromboxane A(2) (TXA(2)) is a member of the prostaglandin family; activation of its receptor induces several important effects, including platelet aggregation and smooth muscle contraction. Because volatile anesthetics interfere with aggregation and contraction, the authors investigated effects of halothane, isoflurane, and sevoflurane on TXA(2) signaling in an isolated receptor model. Methods: mRNA enco ding TXA(2) receptors was prepared in vitro and expressed in Xenopus o ocytes. The effects of halothane, isoflurane, and sevoflurane on Ca2+- activated Cl- currents induced by the TXA(2) agonist U-46619 and on th ose induced by intracellular injection of inositol 1-4-5 trisphosphate or guanosine 5'-O-(2-thiodiphosphate) were measured using the voltage -clamp technique. Results: Expressed TXA(2) receptors were functional (half maximal effect concentration [EC50], 3.2 x 10(-7) +/- 1.1 x 10(- 7),M; Hill coefficient (h), 0.8 +/- 0.2). Halothane and isoflurane inh ibition of TXA(2) signaling was reversible and concentration dependent (halothane half maximal inhibitory concentration [IC50], 0.46 +/- 0.0 4 nM; h, 1.6 +/- 0.21; isoflurane IC50, 0.69 +/- 0.12 nM; h, 1.3 +/- 0 .27), 0.56 mM halothane (1%) right-shifted the U-46619 concentration-r esponse relationship by two orders of magnitude (EC50, 1 x 10(-5) M). That h and maximal effect (E-max were unchanged indicates that halotha ne acts in a competitive manner, in contrast, isoflurane acted noncomp etitively, decreasing E-max by 30% (h and EC50 were unchanged). Both h alothane and isoflurane had no effect on intracellular signaling pathw ays, Sevoflurane (0-1.3 nM) did not affect TXA(2) signaling. Conclusio ns: Both halothane and isoflurane inhibit TXA(2) signaling at the memb rane receptor, but by different mechanisms. This suggests that the eff ects of these anesthetics on TXA(2) signaling are evoked at different locations of the receptor protein: halothane probably acts at the liga nd binding site and isoflurane at an allosteric site.