K Sugiyama1, T Muteki. 1. Department of Anesthesiology, Kurume University School of Medicine, Japan.
Abstract
BACKGROUND: Local anesthetics are known to inhibit the voltage-gated sodium current (INa) of the nerve membrane, but it has not been fully studied whether anesthetic concentrations of local anesthetics depress the voltage-gated calcium current (ICa) of mammalian neurons. The effects of local anesthetics on ICa evoked in cultured rat dorsal root ganglion cells were studied. METHODS: Whole cell patch clamp recordings were made from rat dorsal root ganglion cells cultured for 1-3 weeks. ICa was recorded using patch electrodes filled with Cs-aspartate in Na(+)-free external solution containing 5 mM-Ba2+. All drugs, including local anesthetics, were applied by miniperfusion from micropipettes by pressure ejection. RESULTS: Tetracaine (300 microM) depressed the peak amplitudes of high voltage-activated (HVA)-ICa to 22.6 +/- 8.8% of control values (n = 14) without affecting the current-voltage relation. A tetracaine dose-response curve for HVA-ICa indicated an apparent dissociation constant of 79.5 microM. Tetracaine (30 microM) depressed nicardipine-sensitive HVA-I(Ca) (L-type) to 14.3 +/- 6.7% (n = 6), omega-conotoxin-sensitive HVA-ICa (N-type) to 81.6 +/- 9.6% (n = 7), and low voltage-activated (LVA)-ICa (T-type) to 65.1 +/- 11.1% (n = 6) of their respective controls. Local anesthetics other than tetracaine also depressed HVA-ICa but were of different potency; the rank sequence was dibucaine > tetracaine > bupivacaine >> procaine = lidocaine. CONCLUSIONS: These results suggest that both HVA-ICa and LVA-ICa are depressed by tetracaine used at the concentrations required for spinal anesthesia and that the L-type Ca2+ channel among Ca2+ channel subtypes is the most susceptible to tetracaine. A good correlation between local anesthetic potencies to inhibit HVA-ICa and their anesthetic potencies implies that the inhibition of calcium influx through voltage-gated channels may contribute to spinal anesthetic mechanisms.
BACKGROUND: Local anesthetics are known to inhibit the voltage-gated sodium current (INa) of the nerve membrane, but it has not been fully studied whether anesthetic concentrations of local anesthetics depress the voltage-gated calcium current (ICa) of mammalian neurons. The effects of local anesthetics on ICa evoked in cultured rat dorsal root ganglion cells were studied. METHODS: Whole cell patch clamp recordings were made from rat dorsal root ganglion cells cultured for 1-3 weeks. ICa was recorded using patch electrodes filled with Cs-aspartate in Na(+)-free external solution containing 5 mM-Ba2+. All drugs, including local anesthetics, were applied by miniperfusion from micropipettes by pressure ejection. RESULTS:Tetracaine (300 microM) depressed the peak amplitudes of high voltage-activated (HVA)-ICa to 22.6 +/- 8.8% of control values (n = 14) without affecting the current-voltage relation. A tetracaine dose-response curve for HVA-ICa indicated an apparent dissociation constant of 79.5 microM. Tetracaine (30 microM) depressed nicardipine-sensitive HVA-I(Ca) (L-type) to 14.3 +/- 6.7% (n = 6), omega-conotoxin-sensitive HVA-ICa (N-type) to 81.6 +/- 9.6% (n = 7), and low voltage-activated (LVA)-ICa (T-type) to 65.1 +/- 11.1% (n = 6) of their respective controls. Local anesthetics other than tetracaine also depressed HVA-ICa but were of different potency; the rank sequence was dibucaine > tetracaine > bupivacaine >> procaine = lidocaine. CONCLUSIONS: These results suggest that both HVA-ICa and LVA-ICa are depressed by tetracaine used at the concentrations required for spinal anesthesia and that the L-type Ca2+ channel among Ca2+ channel subtypes is the most susceptible to tetracaine. A good correlation between local anesthetic potencies to inhibit HVA-ICa and their anesthetic potencies implies that the inhibition of calcium influx through voltage-gated channels may contribute to spinal anesthetic mechanisms.