Inhibition of 5-HT3 receptors by propofol: equilibrium and kinetic measurements.
Patch-clamp/rapid solution exchange experiments as well as tracer ([14C]-guanidinium) influx measurements were applied to investigate effects of propofol on 5-HT3 receptor channels and compare the results with those obtained with pentobarbital. Currents induced by 30 microM 5-HT were recorded in outside-out patches from N1E-115 cells. Application of propofol 45 s before and during 5-HT application inhibited peak-currents and integrated current responses in a concentration-dependent manner (IC50 values=14.5 and 10.5 microM; Hill coefficients -1.5 and -1.3, respectively). The inhibitory effect of propofol in the current measurements was similar to the propofol-induced inhibition in tracer influx experiments in whole N1E-115 cells (Barann et al., 1993. Naunyn-Schmiedeberg's Archives of Pharmacology 347, 125-132). Pentobarbital-induced inhibition of 5-HT3 receptors in both patch-clamp (Barann et al., 1997. Neuropharmacology 36, 655-664) and tracer influx measurements indicated a lower potency and lower slope (IC50 values=130 and 55 microM; Hill coefficients -0.8 and -0.7, respectively) compared to propofol. Propofol, in contrast to pentobarbital, showed nearly the full potency when applied to the patches exclusively 45 s before 5-HT. Propofol was least effective when administered exclusively during 5-HT. The onset of inhibition of 5-HT-induced peak currents by propofol had a time constant of 220 ms, similar to the kinetics of 5-HT-induced desensitization.
Barann
M
M
Klinik für Anästhesiologie und spezielle Intensivmedizin, Universitätskliniken Bonn, Sigmund-Freud Strasse 25, D-53105, Bonn, Germany. barann@mailer.meb.uni-bonn.de
Dilger
J P
JP
Bönisch
H
H
Göthert
M
M
Dybek
A
A
Urban
B W
BW
D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D019791:Guanidine / Q000378:metabolism; D015640:Ion Channel Gating; D007700:Kinetics; D051379:Mice; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology*
D018681:Anesthetics, General; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D010424:Pentobarbital; D019791:Guanidine; D015742:Propofol