Effects of inhalational anesthetics on α2-adrenergic signaling in isolated platelets

Abstract

(1) The hypothesis that inhalational anesthetics affect G-protein linked α 2 adrenergic signaling pathway was investigated using human platelets as a model system. (2) α 2 receptor stimulation by UK-14304, a potent and selective agonist, inhibits cAMP production induced by prostaglandin I 2 (PGI 2). (3) Brief stimulation (30 s) with PGI 2 raised cAMP levels in platelets by 25-fold; UK-14304 suppressed the PGI 2 stimulus by 80%. (4) Halothane at fractional minimum alveolar concentration (MAC) through super physiological levels (16 MAC) had no effect on basal or prostacyclin stimulated levels of cAMP, nor did it have any effect on the inhibition of cAMP production by UK-14304. Moreover, isoflurane, enflurane and sevoflurane had no significant effect on cAMP production at 1.5 or 8 MAC. The results suggest α 2 and PGI 2 signaling pathways are not sensitive to volatile anesthetics including the α 2 or PGI 2 receptor/G-protein complex, G-protein/adenylyl cyclase complex and adenylyl cyclase itself. (5) The possibility that halothane and related anesthetics act more distally in the pathway, on cAMP-dependent protein kinase (PKA), was investigated by measuring the phosphorylation pattern of endogenous platelet proteins by PKA. (6) An increase in the [ 32P]phosphate incorporation was observed in platelets exposed to either, low doses of PGI 2 or isobutylmethylxanthine (IBMX). Halothane, isoflurane, enflurane or sevoflurane further increased the level of [ 32P]-incorporation. The apparent increase in PKA activity suggests that at least in platelets, volatile anesthetics activate PKA-dependent pathways which should antagonize α 2 adrenergic signaling.