Role of signal transduction in anesthetic action. Alpha 2 adrenergic agonists.
The molecular mechanism for general anesthetic action is not known. The alpha 2 adrenergic agonists represent a novel class of "anesthetic-like" agent because of their selectivity for receptor binding sites and because the transmembrane signaling systems mediating their biologic responses in non-CNS systems are known. We have begun to characterize the signal transduction pathway involved in the anesthetic-like action of the alpha 2 adrenergic agonists. The alpha 2 adrenergic agonists potently decrease both central noradrenergic neurotransmission and halothane anesthetic requirements (MAC). Since MAC is only reduced by 30-40% when noradrenergic neurotransmission is totally abolished and since the reduction in MAC with the highly selective alpha 2 adrenergic agonists exceeds 90%, factors in addition to noradrenergic neurotransmission must be contributing to the anesthetic action of the alpha 2 agonists. Studies with the superselective alpha 2 agonist dexmedetomidine confirmed this, as the alpha 2 agonist could still reduce the MAC for halothane in rats depleted of their central norepinephrine stores. The profound reduction in anesthetic requirements with dexmedetomidine raised the possibility that alpha 2 adrenergic agonists may be considered an anesthetic hypnotic agent by itself. This sole anesthetic hypnotic response was established together with the confirmation that a central alpha 2 adrenoceptor mediated this action. Subsequently, data using molecular biologic techniques suggested that the alpha 2 C4 isoreceptor was the probable receptor that mediated the anesthetic response. We further explored the postreceptor effector mechanism for the signal transduction pathway for alpha 2 anesthetic action and identified the participation of two other molecular components, namely, a pertussis-toxin-sensitive G protein and a 4-aminopyridine-sensitive ion channel. Whether the signal transduction pathway for alpha 2 anesthetic action mediates the further response to other non-alpha 2 anesthetic agents needs to be defined.
Maze
M
M
Department of Anesthesia, Stanford University School of Medicine, Veteran Affairs Hospital, Palo Alto, California 94304.
Regan
J W
JW
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000768:Anesthesia, General; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D018118:Chloride Channels; D007473:Ion Channels / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000777:Anesthetics; D018118:Chloride Channels; D007473:Ion Channels; D008565:Membrane Proteins; D011942:Receptors, Adrenergic, alpha; D011963:Receptors, GABA-A