British Journal of Anaesthesia, Vol 78, Issue 2 185-188, Copyright © 1997 by The Board of Management and Trustees of the British Journal of Anaesthesia
K. Hirota, T. Browne, B. L. Appadu and D. G. Lambert
We have examined the interaction of procaine, prilocaine, lignocaine,
bupivacaine, amylocaine and R(+) and S(-) ropivacaine with L-type
voltage-sensitive Ca2+ channels in rat cerebrocortical membranes. Membranes
were prepared in Tris HCl 50 mmol litre-1, pH 7.4, by homogenization and
centrifugation. Binding assays were performed in 1- ml volumes of Tris HCl
50 mmol litre-1, pH 7.4, for 90 min at room temperature using approximately
200 micrograms of protein. Non-specific binding was defined in the presence
of nifedipine 10(-5) mol litre-1, and bound and free radioactivity were
separated by vacuum filtration. The effects of local anaesthetics were
determined by displacement of [3H]PN200-110 (approximately 0.2 nmol
litre-1), a radiolabelled 1,4- dihydropyridine (DHP) L-channel antagonist.
The concentration of displacer producing 50% displacement was corrected for
the competing mass of [3H]PN200-110 to yield the affinity constant, K50.
All local anaesthetics displaced [3H]PN200-110 in a dose-dependent manner
with a rank order potency of (K50, mmol litre-1) bupivacaine (0.48),
amylocaine (0.74), lignocaine (1.09), prilocaine (2.06) and procaine
(2.09). Ropivacaine enantiomers did not show stereo-selective displacement,
with K50 values of 0.99 and 0.92 mmol litre-1 for R(+) and S(-)
ropivacaine, respectively. There was a significant correlation between pK50
and p (octanol:buffer partition coefficient) (r2 = 0.872, P = 0.020), pK50
and p (local anaesthetic potency) (r2 = 0.816, P = 0.036), pK50 and p
(relative conduction blocking potency) (r2 = 0.843, P = 0.028) and between
pK50 and p (IC50 for inhibition of cardiac output) (r2 = 0.897, P = 0.015).
These data suggest that DHP binding sites may be involved in both the
mechanism of local anaesthesia and the cardiotoxicity of these agents.
LABORATORY INVESTIGATIONS
Do local anaesthetics interact with dihydropyridine binding sites on neuronal L-type Ca2+ channels?
University Department of Anaesthesia, Leicester Royal Infirmary, Leicester LE1 5WW
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