Anesthetic properties of 4-iodopropofol implications for mechanisms of anesthesia

Ratnakumari LINGAMANENI; Matthew D KRASOWSKI; Andrew JENKINS; Tuyen TRUONG; Austin L GIUNTA; Julie BLACKBEER; M. Bruce MACLVER; Neil L HARRISON; Hugh C HEMMINGS

doi:10.1097/00000542-200106000-00020

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Anesthetic properties of 4-iodopropofol implications for mechanisms of anesthesia

Journal article

Open access

Peer reviewed

Anesthetic properties of 4-iodopropofol implications for mechanisms of anesthesia

Ratnakumari LINGAMANENI, Matthew D KRASOWSKI, Andrew JENKINS, Tuyen TRUONG, Austin L GIUNTA, Julie BLACKBEER, M. Bruce MACLVER, Neil L HARRISON and Hugh C HEMMINGS

Anesthesiology (Philadelphia), Vol.94(6), pp.1050-1057

2001

DOI: 10.1097/00000542-200106000-00020

PMID: 11465597

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Abstract

Background: Positive modulation of gamma-aminobutyric acid type A (GABAA) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including propofol. The role for GABAA receptors as an essential site in the anesthetic actions of propofol was recently challenged by a report that the propofol analog 4-iodopropofol (4-iodo-2,6-diisopropylphenol) potentiated and directly activated GABAA receptors, yet was devoid of sedative-anesthetic effects in rats after intraperitoneal injection. Given the important implications of these findings for theories of anesthesia, the authors compared the effects of 4-iodopropofol with those of propofol using established in vivo and in vitro assays of both GABAA receptor-dependent and -independent anesthetic actions. Methods: The effects of propofol and 4-iodopropofol were analyzed on heterologously expressed recombinant human GABAA alpha1beta2gamma2 receptors, evoked population spike amplitudes in rat hippocampal slices, and glutamate release from rat cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in Xenopus laevis tadpoles, in mice after intraperitoneal injection, and in rats after intravenous injection. Results: Like propofol, 4-iodopropofol enhanced GABA-induced currents in recombinant GABAA receptors, inhibited synaptic transmission in rat hippocampal slices, and inhibited sodium channel-mediated glutamate release from synaptosomes, but with reduced potency. After intraperitoneal injection, 4-iodopropofol did not produce anesthesia in mice, but it was not detected in serum or brain. However, 4-iodopropofol did produce anesthesia in tadpoles (EC50 = 2.5 +/- 0.5 microM) and in rats after intravenous injection (ED50 = 49 +/- 6.2 mg/kg). Conclusions: Propofol and 4-iodopropofol produced similar actions on several previously identified cellular and molecular targets of general anesthetic action, and both compounds induced anesthesia in tadpoles and rats. The failure of 4-iodopropofol to induce anesthesia in rodents after intraperitoneal injection is attributed to a pharmacokinetic difference from propofol rather than to major pharmacodynamic differences.

Neuropharmacology

Biological and medical sciences

Medical sciences

Pharmacology. Drug treatments

Anesthetics. Neuromuscular blocking agents

Details

Title: Subtitle: Anesthetic properties of 4-iodopropofol implications for mechanisms of anesthesia
Creators: Ratnakumari LINGAMANENI - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Matthew D KRASOWSKI - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Andrew JENKINS - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Tuyen TRUONG - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Austin L GIUNTA - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Julie BLACKBEER - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
M. Bruce MACLVER - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Neil L HARRISON - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Hugh C HEMMINGS - Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, United States
Resource Type: Journal article
Publication Details: Anesthesiology (Philadelphia), Vol.94(6), pp.1050-1057
DOI: 10.1097/00000542-200106000-00020
PMID: 11465597
NLM abbreviation: Anesthesiology
ISSN: 0003-3022
eISSN: 1528-1175
Publisher: Lippincott; Hagerstown, MD
Language: English
Date published: 2001
Academic Unit: Pathology
Record Identifier: 9984046805202771

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