Anesthetic and Hemodynamic Effects of the Stereoisomers of Medetomidine, an ??2-Adrenergic Agonist, in Halothane-Anesthetized Dogs

Vickery, Ross G.; Sheridan, Brett C.; Segal, Ira S.; Maze, Mervyn

doi:10.1213/00000539-198807000-00001

Cited by 130 publications

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“…A clinically useful action of ␣ 2 AR agonists is their ability to reduce dose requirements for other anesthetic agents (24,25). We evaluated the ability of dex to reduce the dose requirements for a volatile agent, halothane.…”

Section: Resultsmentioning

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.

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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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Section: Resultsmentioning

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.

Self Cite

315

234

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“…Key Words: Sympathetic nervous system-a-2 ad renergic agonist-Dexmedetomidine-Cerebral blood flow-Human-Transcranial Doppler. Vickery et al, 1988) including humans (Aho et al, 1991). Dexmedetomidine is currently being investi gated for use as an anesthetic adjunct in humans.…”

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confidence: 99%

Dexmedetomidine Decreases Cerebral Blood Flow Velocity in Humans

Zornow

Maze

Dyck

et al. 1993

J Cereb Blood Flow Metab

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Summary: This study was designed to determine the ef fects of dexmedetomidine on CBP velocity as measured by transcranial Doppler sonography in human volunteers. Dexmedetomidine, a potent a-2 adrenergic agonist, was administered by computer-driven infusion pump to six male volunteers. Serial measurements of middle cerebral artery blood flow velocity at four steady-state plasma concentrations of dexmedetomidine were made with a 2-MHz transcranial Doppler transducer via the temporal window. The targeted plasma concentrations were 0.49, 0.65, 0.81, and 0.97 ng/ml. These represent 60, 80, 100, and 120%, respectively, of the mean peak concentration following the intramuscular administration of 2 fl-g/kg of dexmedetomidine. Subjects experienced a significant de gree of sedation at the highest infusion rates. Mean CBP velocity decreased with each increase in plasma concen tration of dexmedetomidine and then began to return to a-2 adrenergic agonists (e.g., xylazine and deto midine) have been extensively used in veterinary anesthesia. More recently, the analgesic-and anes thetic-sparing properties of the partial a-2 agonist, clonidine, have been documented in humans (Ghi gnone et ai., 1986; Flacke et ai., 1987; Engelman et ai., 1989;Bernard et al., 1989). Dexmedetomidine is a potent and selective agonist of the a-2 adrenergic receptor and has been shown to possess hypnotic/ anesthetic properties in a variety of species (Doze et al., 1989;Segal et al., 1988;Scheinin et al., 1987; Received July 20, 1992 350basal levels after termination of the infusion. A trend to ward an increase in the pulsatility index at the higher levels of dexmedetomidine suggests that the observed decrement in CBP velocity was due to an increase in cerebral vascular resistance. Upon initiation of the drug infusion, mean arterial pressure decreased from -95 mm Hg to 78 mm Hg. There were no further decreases in arterial pressure with subsequent increases in plasma concentrations of dexmedetomidine. Arterial carbon di oxide tension increased to a maximum of 45 mm Hg dur ing the drug infusion, but this increase from baseline was not statistically significant. These studies are in agree ment with previous animal studies which demonstrate a decrease in CBP after administration of dexmedetomi dine. Key Words: Sympathetic nervous system-a-2 ad renergic agonist-Dexmedetomidine-Cerebral blood flow-Human-Transcranial Doppler. Vickery et al., 1988) including humans (Aho et al., 1991). Dexmedetomidine is currently being investi gated for use as an anesthetic adjunct in humans.Previous studies have documented a 30-45% de crease in CBF following the administration of dexmedetomidine to halothane-and isoflurane anesthetized dogs (Karlsson et ai., 1990;Zornow et al., 1990). This decrease in blood flow occurred without any associated decrease in the cerebral metabolic rate for oxygen. Because of concerns re garding the applicability of these findings to hu mans, the current study was conducted to examine the effects of hypnotic doses of dexmedetomidine on CBF...

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“…Radiologistas demonstraram alta concentração de receptores adrenérgicos do tipo α-2 no corno dorsal da medula espinhal, onde as fibras nociceptivas possuem sinapses, e no tronco cerebral onde ocorre a modulação dos sinais álgicos (CULLEN, 1996). Estudos sugeriram o envolvimento de receptores pós-sinápticos mediando o possível efeito anestésico da dexmedetomidina em cães (VICKERY et al, 1988). Em modelos animais, verificou-se que não há um aparente efeito teto nos estudos realizados com a dexmedetomidina e o halotano, sugerindo que o agonista α-2 possa ser um agente anestésico completo (KAMIBAYASHI; MAZE, 2000).…”

Section: Efeito Analgésicounclassified

Dexmedetomidina, uma nova opção na anestesiologia veterinária

Baldo

Nunes

2003

Sem. Ci. Agr.

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ResumoCom este trabalho, os autores procuram fornecer informações sobre o uso da dexmedetomidina, um novo agonista dos receptores adrenérgicos do tipo α-2, na prática anestésica. São tecidas considerações relativas ao emprego e a farmacologia desse novo agente, suas vantagens e restrições de uso, bem como a avaliação quanto à sua eficiência e segurança quando utilizado em associação a outros agentes anestésicos. Complementarmente, procurou-se atualizar com literatura recente os conhecimentos dos profissionais que militam na área de Anestesiologia Veterinária. Palavras-chave: Dexmedetomidine, anestesiologia veterinária. AbstractThe aim of this work was to provide information about the use of dexmedetomidine, a new α-2 agonist, in anesthetic practice. They comment about the pharmacology, its advantages and disadvantages, its efficiency and safety when associated with others anesthetic agents. Complementary, it was aimed to update the professionals that work with Veterinary Anesthesiology, through new papers and reports.

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Anesthetic and Hemodynamic Effects of the Stereoisomers of Medetomidine, an ??2-Adrenergic Agonist, in Halothane-Anesthetized Dogs

Cited by 130 publications

References 0 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

Dexmedetomidine Decreases Cerebral Blood Flow Velocity in Humans

Dexmedetomidina, uma nova opção na anestesiologia veterinária

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Anesthetic and Hemodynamic Effects of the Stereoisomers of Medetomidine, an ??2-Adrenergic Agonist, in Halothane-Anesthetized Dogs

Cited by 130 publications

References 0 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

Dexmedetomidine Decreases Cerebral Blood Flow Velocity in Humans

Dexmedetomidina, uma nova opção na anestesiologia veterinária

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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