Central alpha 1-adrenoceptor stimulation functionally antagonizes the hypnotic response to dexmedetomidine, an alpha 2-adrenoceptor agonist.
Previously, we demonstrated that dexmedetomidine, an alpha 2 agonist, produces a hypnotic-anesthetic response in rats via activation of central alpha 2 adrenoceptors and that this response could be enhanced by the alpha 1 antagonist prazosin. In the current experiment we investigated whether central alpha 1 adrenoceptor stimulation antagonizes the alpha 2 adrenoceptor-mediated hypnotic response. Cirazoline, an alpha 1 adrenoceptor agonist that partitions into the central nervous system, attenuated dexmedetomidine's hypnotic response whether administered systemically (0.3-1 mg.kg-1 intraperitoneally [ip]) or centrally (0.1 mg.kg-1 intracerebroventricularly). Prazosin, an alpha 1 adrenoceptor antagonist that effectively crosses the blood-brain barrier, fully blocked cirazoline's attenuating effect on dexmedetomidine-induced hypnosis, whereas doxazosin, which partitions poorly into the brain, did not block cirazoline's effect. Administration of phenylephrine, 0.3-3 mg.kg-1 ip, an alpha 1 adrenoceptor agonist that does not penetrate into the brain, did not attenuate dexmedetomidine's hypnotic effect. These results indicate that central alpha 1-adrenoceptor stimulation functionally antagonizes the hypnotic response to an alpha 2-adrenoceptor agonist. These data underscore the important requirement for alpha 2 adrenoceptor selectivity if these agonists are to be useful in the anesthetic setting.
Department of Anesthesia, Stanford University School of Medicine, Palo Alto, California.
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Guo
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Tinklenberg
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Oliker
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Maze
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D007093:Imidazoles / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D020926:Medetomidine; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D012890:Sleep / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D020926:Medetomidine; C014282:cirazoline; D011224:Prazosin