Dexmedetomidine diminishes halothane anesthetic requirements in rats through a postsynaptic alpha 2 adrenergic receptor.
The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the alpha 2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (d-enantiomer) or levomedetomidine (l-enantiomer) 10, 30, and 100 micrograms/kg or vehicle ip. There was a dose-dependent decrease in MAC with the d-, but not the l-, stereoisomer. At the highest dose of dexmedetomidine (100 micrograms/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether alpha 2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg ip, a highly selective alpha 2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg ip, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg ip, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP-4) or reserpine and alpha-methyl-para-tyrosine and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine depleted rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Segal
I S
IS
Department of Anesthesia, Stanford University School of Medicine, California.
Vickery
R G
RG
Walton
J K
JK
Doze
V A
VA
Maze
M
M
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology; D006221:Halothane; D019329:Idazoxan; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D009271:Naltrexone / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013237:Stereoisomerism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D001596:Benzylamines; D004146:Dioxanes; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D017981:Receptors, Neurotransmitter; D009271:Naltrexone; D013806:Theophylline; C028322:8-phenyltheophylline; D020926:Medetomidine; C012102:DSP 4; D006221:Halothane; D009638:Norepinephrine; D019329:Idazoxan