Anesthetic properties of 4-iodopropofol - Implications for mechanisms of anesthesia

Background: Positive modulation of gamma -aminobutyric acid type A (GABA(A) ) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including pr opofol, The role for GABA(A) receptors as an essential site in the anesthet ic actions of propofol was recently challenged by a report that the propofo l analog 4-iodopropofol (4-iodo-2,6-diisopropylphenol) potentiated and dire ctly activated GABA, receptors, yet was devoid of sedative-anesthetic effec ts in rats after intraperitoneal injection. Given the important implication s of these findings for theories of anesthesia, the authors compared the ef fects of 4-iodopropofol with those of propofol using established in vivo an d in vitro assays of both GABA(A) receptor-dependent and -independent anest hetic actions. Methods: The effects of propofol and 4-iodopropofol were analyzed on hetero logously expressed recombinant human GABA(A) alpha (1)beta (2)gamma (2) rec eptors, evoked population spike amplitudes in rat hippocampal slices, and g lutamate release from rat cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in Xenopus laevis tadpol es, in mice after intraperitoneal injection, and in rats after intravenous injection. Results: Like propofol, 4-iodopropofol enhanced GABA-induced currents in re combinant GABA(A) receptors, inhibited synaptic transmission in rat hippoca mpal slices, and inhibited sodium channel-mediated glutamate release from s ynaptosomes, but with reduced potency. After intraperitoneal injection, 4-i odopropofol 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 mum) and in rats after intravenous injection (ED50 = 49 +/- 6.2 mg/kg). Conclusions: Propofol and 4-iodopropofol produced similar actions on severa l previously identified cellular and molecular targets of general anestheti c action, and both compounds induced anesthesia in tadpoles and fats. The f ailure of 4-iodopropofol to induce anesthesia in rodents after intraperiton eal injection is attributed to a pharmacokinetic difference from propofol r ather than to major pharmacodynamic differences.