The α2 adrenergic agonist, dexmedetomidine, selectively attenuates ischemia-induced increases in striatal norepinephrine concentrations

Matsumoto, Mishiya; Zornow, Mark H.; Rabin, Bradford C.; M, Mase

doi:10.1016/0006-8993(93)90337-m

Cited by 54 publications

(33 citation statements)

References 22 publications

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“…The supernatant was filtered to exclude molecules exceeding 5000 kDa. The biogenic amines were assayed using HPLC͞electrochemical detection as described (19).…”

Section: Methodsmentioning

confidence: 99%

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Lakhlani

MacMillan

Guo

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

315

234

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Norepinephrine contributes to antinociceptive, sedative, and sympatholytic responses in vivo, and ␣ 2 adrenergic receptor (␣ 2 AR) agonists are used clinically to mimic these effects. Lack of subtype-specific agonists has prevented elucidation of the role that each ␣ 2 AR subtype (␣ 2A , ␣ 2B , and ␣ 2C ) plays in these central effects. ␣ 2 -adrenergic receptors (␣ 2 ARs) present in the central nervous system (CNS) respond to norepinephrine (NE) and epinephrine and mediate sympatholytic, sedative-hypnotic, analgesic, anesthetic-sparing, hypotensive, and anxiolytic responses (1). Many of these responses are therapeutically useful and are exploited clinically, for example, during anesthesia and to attenuate the symptoms of opioid withdrawal (2). Three ␣ 2 AR subtypes have been revealed by pharmacological (␣ 2A AR, ␣ 2B AR, and ␣ 2C AR) and molecular cloning (␣ 2a AR, ␣ 2b AR, and ␣ 2c AR) strategies (3), and all couple, via pertussis toxin-sensitive G i ͞G o proteins, to attenuation of adenylyl cyclase, suppression of voltage-gated Ca 2ϩ channels, and activation of inwardly rectifying K ϩ channels (4).Multiple experimental limitations have precluded clarifying the involvement of each ␣ 2 AR subtype in catecholaminemediated physiological responses in the CNS. Subtype-specific ␣ 2 AR agonists and antagonists are not available (5); even when subtype selectivity has been noted in vitro, varying and unknown in vivo bioavailability precludes confident correlation of the administered dose with the amount of drug at the receptor site. Previous studies to explore ␣ 2 AR involvement in various responses have used prazosin to block catecholamine responses mediated by ␣ 1 adrenergic receptors (␣ 1 AR); however, it is now known that the ␣ 2B AR and ␣ 2C AR subtypes also are blocked by prazosin (5), thus confounding the interpretations of these earlier studies. In addition, because ␣ 1 AR can functionally antagonize ␣ 2 AR-mediated responses in some settings, ␣ 2 AR responses in the presence of prazosin (added to block ␣ 1 AR, ␣ 2B AR, and ␣ 2C AR) may reflect the disturbance of the balance between the functionally antagonistic ␣ 2 AR and ␣ 1 AR systems rather than provide insights concerning the role of the ␣ 2A AR subtype. Consequently, we manipulated the mouse genome to provide definitive evidence regarding the role of the ␣ 2A AR subtype in CNS responses.We used the ''hit and run'' targeting variant of homologous recombination (6, 7) to substitute a subtle mutation of the ␣ 2a AR, D79N into the mouse genome as a tool to explore the role of the ␣ 2a AR in vivo (8). The aspartate residue at position 79 (D79) is highly conserved in a topologically identical position in the second transmembrane span in a large subset of G protein-coupled receptors (9). Mutation of this residue has been shown to eliminate allosteric regulation of receptor binding by monovalent cations (10-13) and to perturb receptor-G protein-effector coupling (14-17) in heterologous expression systems. Thus, the animals expressing the D79N ␣ 2a AR provi...

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“…The supernatant was filtered to exclude molecules exceeding 5000 kDa. The biogenic amines were assayed using HPLC͞electrochemical detection as described (19).…”

Section: Methodsmentioning

confidence: 99%

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Lakhlani

MacMillan

Guo

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

315

234

View full text Add to dashboard Cite

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“…DEX attenuates the ischemia-induced excessive NA release by activating presynaptic α 2 -ARs (38,39), which may lead to the formation of free radicals (40). In addition, the protective action of α 2 -AR agonists may be due to a postsynaptic reduction in neuronal excitability and/or a possible presynaptic decrease in glutamate release (41)(42)(43)(44), which is linked to the suppression of voltage-dependent Ca 2+ channels and mitogen-activated protein kinase activity (42).…”

Section: Transmitter Releasementioning

confidence: 99%

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

Cai

Jia

et al. 2014

Molecular Medicine Reports

116

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Abstract. Dexmedetomidine (DEX), a highly specific α 2 -adrenergic agonist, which exhibits anaesthetic-sparing, analgesia and sympatholytic properties. DEX modulates gene expression, channel activation, transmitter release, inflammatory processes and apoptotic and necrotic cell death. It has also been demonstrated to have protective effects in a variety of animal models of ischemia/reperfusion (I/R) injury, including the intestine, myocardial, renal, lung, cerebral and liver. The broad spectrum of biological activities associated with DEX continues to expand, and its diverse effects suggest that it may offer a novel therapeutic approach for the treatment of human diseases with I/R involvement.

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“…[9][10][11] The effects of alpha-2 adrenergic receptors on apoptosis have been studied, and their effects on cell proliferation have been estimated to occur through glutamate, inhibition of catecholamine release and N-methyl D-aspartate receptor blockage. [12][13][14][15][16] The effects of different dosages of dexmedetomidine, an alpha-2 adrenergic receptor agonist, on neuronal protection and oxidative stress have been studied in experimental models. Dexmedetomidine has been shown to lack neuroprotective effects at some dosages (1,15,27 and 30 lg/kg) and to attenuate cerebral vasospasm and reduce excitotoxic brain damage and ischaemic damage in cerebral ischaemia at other dosages (3-9 lg/kg), suggesting the possibility of neuroprotective effects.…”

Section: Introductionmentioning

confidence: 99%

The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model

Ayoğlu

Gül

Hancı

et al. 2010

Journal of Clinical Neuroscience

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The α2 adrenergic agonist, dexmedetomidine, selectively attenuates ischemia-induced increases in striatal norepinephrine concentrations

Cited by 54 publications

References 22 publications

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model

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The α2 adrenergic agonist, dexmedetomidine, selectively attenuates ischemia-induced increases in striatal norepinephrine concentrations

Cited by 54 publications

References 22 publications

Substitution of a mutant α 2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Substitution of a mutant α 2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model

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Product

Resources

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Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo