Correlation of Blood Levels of 4-Hydroxybutyrate with State of Consciousness

Helrich, Martin; McAslan, T. Crawford; Skolnik, Sandra J.; Bessman, Samuel P.

doi:10.1097/00000542-196411000-00007

Cited by 73 publications

(31 citation statements)

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“…Millimolar concentrations of GHB, similar to levels commonly observed during anesthesia in humans (30,31), and micromolar doses of baclofen clearly increase the background inward rectifier conductance. This effect is reversibly inhibited by GABA B antagonists, prevented by pertussis toxin pretreatment, and appears to be mediated by GABA B R1 and GABA B R2 receptors colocalized within the sarcolemma and the transverse axialtubular system of the cardiomyocyte.…”

Section: Discussionsupporting

confidence: 54%

“…GHB (sodium salt), (Ϯ)-baclofen, and pertussis toxin were obtained from Sigma. In most cases, 2 mM GHB was used because this concentration correlates with blood levels clinically reached by this hypnotic during anesthesia (30,31). The specific antagonist GABA B R CGP36742 was from Ciba-Geigy.…”

Section: Methodsmentioning

confidence: 99%

“…Taken together, these observations raise the question of a possible role of GHB in cardiomyocytes, although very little evidence for any physiological function for GABA B mechanisms has been reported in peripheral organs (29). Pharmacological doses required to induce anesthesia in humans (100-200 mg͞kg) raise GHB blood levels from the micromolar (3) to the millimolar range (30,31), in keeping with concentrations that are able to produce significant electrophysiological changes in neurons (10)(11)(12)(13)19). We were interested in looking for electrophysiological alterations induced by these GHB concentrations in other excitable cells, namely mammalian cardiomyocytes.…”

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confidence: 99%

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γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

Lorente

Lacampagne

Pouzeratte

et al. 2000

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

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␥-Hydroxybutyrate (GHB), an anesthetic adjuvant analog of ␥-aminobutyrate (GABA), depresses cell excitability in hippocampal neurons by inducing hyperpolarization through the activation of a prominent inwardly rectifying K ؉ (Kir3) conductance. These GABA type B (GABAB)-like effects are clearly shown at high concentrations of GHB corresponding to blood levels usually reached during anesthesia and are mimicked by the GABAB agonist baclofen. Recent studies of native GABAB receptors (GABABRs) have favored the concept that GHB is also a selective agonist. Furthermore, cloning has demonstrated that GABABRs assemble heteromeric complexes from the GABABR1 and GABABR2 subtypes and that these assemblies are activated by GHB. The surprisingly high tissue content, together with anti-ischemic and protective effects of GHB in the heart, raises the question of a possible influence of GABAB agonists on excitable cardiac cells. In the present study, we provide electrophysiological evidence that GHB activates an inwardly rectifying K ؉ current in rat ventricular myocytes. This effect is mimicked by baclofen, reversibly inhibited by GABAB antagonists, and prevented by pertussis toxin pretreatment. Both GABA BR1 and GABABR2 are detected in cardiomyocytes by Western blotting and are shown to coimmunoprecipitate. Laser scanning confocal microscopy discloses an even distribution of the two receptors in the sarcolemma and along the transverse tubular system. Hence, we conclude that GABABRs are distributed not only in neuronal tissues but also in the heart, where they can be activated and induce electrophysiological alterations through G-protein-coupled inward rectifier potassium channels.

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Section: Discussionsupporting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

Lorente

Lacampagne

Pouzeratte

et al. 2000

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

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“…Early work on GHB as an anaesthetic demonstrated altered levels of consciousness associated with the following serum concentrations: (a) greater than 260 mg/L, patients were unresponsive to painful stimuli (comatose); (b) 156-260 mg/L, patients were asleep but responsive; (c) 52-156 mg/L, patients exhibited spontaneous movement with occasional eye opening; and (d) less than 52 mg/L, patients awoke (Helrich et al, 1964).…”

Section: Effectsmentioning

confidence: 99%

Gamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD; BDO): A literature review with a focus on UK fatalities related to non-medical use

Corkery

Loi

Claridge

et al. 2015

Neuroscience & Biobehavioral Reviews

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Misuse of gamma hydroxybutrate (GHB) and gamma butyrolactone (GBL) has increased greatly since the early 1990s, being implicated in a rising number of deaths. This paper reviews knowledge on GHB and derivatives, and explores the largest series of deaths associated with their non-medical use. Descriptive analyses of cases associated with GHB/GBL and 1,4-butanediol (1,4-BD) use extracted from the UK's National Programme on Substance Abuse Deaths database. From 1995 to September 2013, 159 GHB/GBL-associated fatalities were reported. Typical victims: White (92%); young (mean age 32 years); male (82%); with a drug misuse history (70%). Most deaths (79%) were accidental or related to drug use, the remainder (potential) suicides. GHB/GBL alone was implicated in 37%; alcohol 14%; other drugs 28%; other drugs and alcohol 15%. Its endogenous nature and rapid elimination limit toxicological detection. Post-mortem blood levels: mean 482 (range 0-6500; SD 758)mg/L. Results suggest significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, opiates, stimulants, and ketamine. More awareness is needed about risks associated with consumption.

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“…The subjective symptoms may be disagreeable. Depression of the reticular formation of the brain stem with a small dose of barbiturate markedly hastens induction and abolishes the muscle movements; this is associated with a rise in blood level of gamma-OH (Helrich et al 1964). Sedative phenothiazines also suppress the tendency to extrapyramidal movements.…”

mentioning

confidence: 99%

Gamma Hydroxybutyric Acid Clinical Pharmacology and Current Status

Vickers¹

1969

Survey of Anesthesiology

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Correlation of Blood Levels of 4-Hydroxybutyrate with State of Consciousness

Cited by 73 publications

References 0 publications

γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

Gamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD; BDO): A literature review with a focus on UK fatalities related to non-medical use

Gamma Hydroxybutyric Acid Clinical Pharmacology and Current Status

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