Effects of inhalational anesthetics on alpha2-adrenergic signaling in isolated platelets.
(1) The hypothesis that inhalational anesthetics affect G-protein linked alpha2 adrenergic signaling pathway was investigated using human platelets as a model system. (2) Alpha2 receptor stimulation by UK-14304, a potent and selective agonist, inhibits cAMP production induced by prostaglandin I2 (PGI2). (3) Brief stimulation (30 s) with PGI2 raised cAMP levels in platelets by 25-fold; UK-14304 suppressed the PGI2 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 alpha2 and PGI2 signaling pathways are not sensitive to volatile anesthetics including the alpha2 or PGI2 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 PGI2 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 alpha2 adrenergic signaling.
Department of Anesthesiology, School of Medicine, State University of New York, Stony Brook 11794-8480, USA.
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Pentyala
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Moller
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Chowdhury
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Sung
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Rebecchi
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000242:Cyclic AMP / Q000097:blood; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
D018685:Anesthetics, Inhalation; D010975:Platelet Aggregation Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D011464:Epoprostenol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases