Do local anaesthetics interact with dihydropyridine binding sites on neuronal L-type Ca2+ channels?

被引:25
作者
Hirota, K [1 ]
Browne, T [1 ]
Appadu, BL [1 ]
Lambert, DG [1 ]
机构
[1] UNIV LEICESTER,LEICESTER ROYAL INFIRM,DEPT ANAESTHESIA,LEICESTER LE1 5WW,LEICS,ENGLAND
关键词
anaesthetics local; ions; ion channels; calcium; model; rat;
D O I
10.1093/bja/78.2.185
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
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 mu g 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 [H-3]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 [H-3]PN200-110 to yield the affinity constant, K-50. All local anaesthetics displaced [H-3]PN200-110 in a dose-dependent manner with a rank order potency of (K-50, mmol litre(-1)) bupivacaine (0.48), amylocaine (0.74), lignocaine (1.09), prilocaine (2.06) and procaine (2.09). Ropivacaine enantiomers did not show stereoselective displacement, with K-50 values of 0.99 and 0.92 mmol litre(-1) for R(+) and S(-) ropivacaine, respectively. There was a significant correlation between pK(50) and p (octanol:buffer partition coefficient) (r(2)=0.872, P=0.020), pK(50) and p (local anaesthetic potency) (r(2)=0.816, P=0.036), pK(50) and p (relative conduction blocking potency) (r(2)=0.843, P=0.028) and between pK(50) and p (IC50 for inhibition of cardiac output) (r(2)=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.
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收藏
页码:185 / 188
页数:4
相关论文
共 22 条
[1]   FURTHER ANALYSIS OF INHIBITORY EFFECTS OF PROPRANOLOL AND LOCAL-ANESTHETICS ON THE CALCIUM CURRENT IN HELIX NEURONS [J].
AKAIKE, N ;
ITO, H ;
NISHI, K ;
OYAMA, Y .
BRITISH JOURNAL OF PHARMACOLOGY, 1982, 76 (01) :37-43
[2]   CARDIAC-ARREST FOLLOWING REGIONAL ANESTHESIA WITH ETIDOCAINE OR BUPIVACAINE [J].
ALBRIGHT, GA .
ANESTHESIOLOGY, 1979, 51 (04) :285-287
[3]  
BOLGER GT, 1987, J PHARMACOL EXP THER, V240, P922
[4]   ELECTROPHYSIOLOGICAL EFFECTS OF TETRACAINE IN SINGLE GUINEA-PIG VENTRICULAR MYOCYTES [J].
CARMELIET, E ;
MORAD, M ;
VANDERHEYDEN, G ;
VEREECKE, J .
JOURNAL OF PHYSIOLOGY-LONDON, 1986, 376 :143-161
[5]  
CARTA F, 1990, ANESTHESIA ANALGESIA, V217, P137
[6]   THE MECHANISM BY WHICH PROCAINE INHIBITS CATECHOLAMINE SECRETION FROM BOVINE CHROMAFFIN CELLS [J].
CHARLESWORTH, P ;
JACOBSON, I ;
POCOCK, G ;
RICHARDS, CD .
BRITISH JOURNAL OF PHARMACOLOGY, 1992, 106 (04) :802-812
[7]  
COURTNEY KR, 1980, J PHARMACOL EXP THER, V213, P114
[8]  
Feldman Hal S., 1994, P107
[9]   Iv anaesthetic agents inhibit dihydropyridine binding to L-type voltage-sensitive Ca2+ channels in rat cerebrocortical membranes [J].
Hirota, K ;
Lambert, DG .
BRITISH JOURNAL OF ANAESTHESIA, 1996, 77 (02) :248-253
[10]   EFFECT OF LOCAL-ANESTHETICS ON THE STIMULUS-SECRETION COUPLING IN BOVINE ADRENAL CHROMAFFIN CELLS [J].
KAWABATA, K ;
SUMIKAWA, K ;
KAMIBAYASHI, T ;
FUKUMITSU, K ;
HAYASHI, Y ;
TAKADA, K ;
YOSHIYA, I .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 1993, 45 (07) :632-635