Chronic treatment with dexmedetomidine desensitizes alpha 2-adrenergic signal transduction.
Tolerance to the hypnotic response was induced in rats by chronically infusing dexmedetomidine, a novel alpha 2-adrenergic agonist. The alpha 2-adrenoceptor affinity for dexmedtomidine and para-iodoclonidine was significantly reduced in tolerant rats, while Bmax was uncharged. The ability of pertussis toxin (PTX) to ribosylate guanine nucleotide regulatory proteins (G proteins) ex vivo was reduced in tolerant rats; the quantity of PTX-sensitive G proteins was unchanged. Forskolin-stimulated adenylyl cyclase was less sensitive to inhibition by dexmedetomidine in the tolerant rats; however, acute intraperitoneal injection of dexmedetomidine still reduced cyclic adenosine monophosphate levels in tolerant rats. Both the decrease in ribosylation and the lower alpha 2-adrenoceptor binding affinity may reflect a decrease in the ability of the G protein to couple to the alpha 2-adrenoceptors in the locus coeruleus of tolerant rats. In this state, the alpha 2 adrenoceptors are less capable of transducing the effector response (inhibition of adenylyl cyclase).
Reid
K
K
Department of Anesthesia, Stanford University, CA, USA.
Hayashi
Y
Y
Hsu
J
J
Maguire
P A
PA
Rabin
B C
BC
Guo
T Z
TZ
Maze
M
M
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004361:Drug Tolerance; D019204:GTP-Binding Proteins / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D020926:Medetomidine; D037342:Pertussis Toxin; D011869:Radioligand Assay; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D037361:Adenylate Cyclase Toxin; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D010566:Virulence Factors, Bordetella; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D020926:Medetomidine