The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones.
1. The interaction of the intravenous general anaesthetic propofol (2,6-diisopropylphenol) with the GABAA receptor has been investigated in voltage-clamped bovine chromaffin cells and rat cortical neurones in cell culture. Additionally, the effects of propofol on the glycine and GABAA receptors of murine spinal neurones were determined. 2. Propofol (1.7-16.8 microM) reversibly and dose-dependently potentiated the amplitude of membrane currents elicited by GABA (100 microM) applied locally to bovine chromaffin cells. Intracellular application of propofol (16.8 microM) was ineffective. In rat cortical neurones and murine spinal neurones, extracellular application of 8.4 microM and 1.7-16.8 microM propofol respectively produced a potentiation of GABA-evoked currents qualitatively similar to that seen in the bovine chromaffin cell. 3. The potentiation by propofol (1.7 microM) was not associated with a change in the reversal potential of the GABA-evoked whole cell current. On outside-out membrane patches isolated from bovine chromaffin cells, propofol (1.7 microM) had little or no effect on the GABA single channel conductances, but greatly increased the probability of the GABA-gated channel being in the conducting state. 4. The potentiation of GABA-evoked whole cell currents by propofol (1.7 microM) was not influenced by the benzodiazepine antagonist flumazenil (0.3 microM). A concentration of propofol (1.7 microM) that substantially potentiated GABA currents had little effect on currents induced by the activation of the GABAA receptor by pentobarbitone (1 mM). 5. Bath application of propofol (8.4-252 microM), to bovine chromaffin cells voltage clamped at -60 mV, induced an inward current associated with an increase in membrane current noise on all cells sensitive to GABA. Intracellular application of propofol (16.8 microM) was ineffective in this respect. Local application of propofol (600 microM) induced whole cell currents with a reversal potential dependent upon the Cl- gradient across the cell membrane. 6. On outside-out membrane patches formed from bovine chromaffin cells, propofol (30 microM) induced single channels with mean chord conductances of 29 and 12 pS. The frequency of propofol channels was greatly reduced by coapplication of 1 microM bicuculline. Under identical ionic conditions, GABA (1 microM) activated single channels with mean chord conductances of 33, 16 and 10pS. 7. Bath applied propofol (0.84-16.8 microM) dose-dependently potentiated strychnine-sensitive currents evoked by glycine (100 microM) in murine spinal neurones. 8. The relevance of the present results to the general anaesthetic action of propofol is discussed.
Hales
T G
TG
Department of Pharmacology & Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee.
Lambert
J J
JJ
D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002838:Chromaffin System / Q000187:drug effects*; D004558:Electric Stimulation; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D009431:Neural Conduction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010424:Pentobarbital / Q000494:pharmacology; D011247:Pregnancy; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors
D058787:GABA-A Receptor Antagonists; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D005442:Flumazenil; D010424:Pentobarbital; D015742:Propofol