Comparative effects of ultra-short-acting beta1-blockers on voltage-gated tetrodotoxin-resistant Na+ channels in rat sensory neurons.
OBJECTIVE
To examine a possible mechanism for their antinociceptive actions, we compared the effects of two clinically used ultra-short-acting beta1-blockers, landiolol and esmolol, on tetrodotoxin-resistant sodium (TTX-r Na) channels in rat dorsal root ganglion neurons, which are important for nociception.


METHODS
In small (<30 microm) dorsal root ganglion neurons from Sprague-Dawley rats, recordings of whole-cell membrane currents were made using the patch-clamp technique. To examine the effects of landiolol and esmolol on TTX-r Na currents, whole-cell membrane Na currents were evoked every 10 s by stepping for 50 ms from a holding potential of -70 to -10 mV. Each drug was applied at stepwise-increased concentrations every 2 min. The voltage dependence of the steady-state inactivation of the TTX-r Na current was investigated by using a conventional double-pulse protocol. To test for use-dependent blockade of TTX-r Na channels by beta-blockers, trains of depolarizing pulses (to -10 from a holding potential of -70 mV) were applied at one of three frequencies (0.2, 5 or 20 Hz) in the absence or presence of drug (landiolol 8 mmol l, esmolol 140 micromol l).


RESULTS
Esmolol blocked TTX-r Na currents in a dose-dependent and use-dependent manner, but a very high concentration of landiolol was required to block TTX-r Na channel activities. The half-maximal inhibitory concentrations (IC50) for the TTX-r Na current were (holding potential, -70 mV) landiolol 7.66 +/- 0.62 mmol l (n = 6) and esmolol 145 +/- 7.5 micromol l (n = 6), and the Hill coefficients were landiolol 1.06 +/- 0.09 (n = 6) and esmolol 0.96 +/- 0.05 (n = 6).


CONCLUSIONS
Esmolol, but not landiolol, may have useful effects against pain related to TTX-r Na channel activity.
Tanahashi
Shigeaki
S
Department of Anesthesiology and Pain Medicine, Gifu University School of Medicine, Gifu city, Japan. rushex7775@yahoo.co.jp
Iida
Hiroki
H
Dohi
Shuji
S
Oda
Akiyoshi
A
Osawa
Yoko
Y
Yamaguchi
Shinobu
S
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D004351:Drug Resistance / Q000187:drug effects*; D055724:Electrophysiological Phenomena; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology*; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D009025:Morpholines; D011412:Propanolamines; D015222:Sodium Channels; D013779:Tetrodotoxin; C077049:landiolol; D014508:Urea; C036604:esmolol