Butterworth J F, Brownlow R C, Leith J P, Prielipp R C, Cole L R
Department of Anesthesia, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1009.
Anesthesiology. 1993 Jul;79(1):88-95. doi: 10.1097/00000542-199307000-00014.
It was hypothesized that local anesthetic inhibition of cyclic-3',5'-adenosine monophosphate (cAMP) production may contribute to cardiovascular toxicity. This study was undertaken to determine whether bupivacaine is a more potent inhibitor of cAMP production than are chemically related local anesthetics that are less prone to produce cardiovascular toxicity.
Volunteers provided venous blood from which lymphocytes were isolated. Production of cAMP was measured under basal conditions, and in response to stimulation with either forskolin or epinephrine. Inhibition of basal, epinephrine-stimulated, and forskolin-stimulated cAMP production by mepivacaine, ropivacaine, and bupivacaine was assessed.
Both forskolin and epinephrine produced concentration-dependent increases in cAMP production; the 50% effective concentrations (EC50S) for these drugs were 3.6 x 10(-8) and 4.6 x 10(-8) M, respectively. Maximal forskolin-stimulated cAMP production (6.6 +/- 0.8 pmol/10(6) [corrected] cells/10 min at 10(-6) M) was greater than maximal epinephrine-stimulated cAMP production (4.2 +/- 0.6 pmol/10(6) [corrected] cells/10 min at 10(-5) M). Bupivacaine (IC50 = 2.3 x 10(-6) M) more potently inhibited basal cAMP production than either ropivacaine (IC50 = 4 x 10(-6) M) or mepivacaine (IC50 = 3.2 x 10(-5) M). Similarly, bupivacaine (IC50 = 2.3 x 10(-6) M) was as potent as ropivacaine (IC50 = 1.7 x 10(-6) M) and more potent than mepivacaine (IC50 = 8.9 x 10(-6) M) at inhibiting epinephrine-stimulated cAMP production. Bupivacaine (IC50 = 5.3 x 10(-6) M) was only marginally more potent than ropivacaine (IC50 = 9.7 x 10(-6) M) or mepivacaine (IC50 = 6.8 x 10(-6) M) at inhibition of forskolin-stimulated cAMP production. Comparison of epinephrine concentration-response curves in the presence and absence of bupivacaine (0.35, 3.5, and 35 microM) demonstrated noncompetitive inhibition of cAMP production by the local anesthetic.
Inhibition of basal and epinephrine-stimulated cAMP production may contribute to local anesthetic cardiovascular toxicity. Inhibition of cAMP production may limit the success of resuscitative measures and drugs administered for bupivacaine cardiovascular toxicity. Increasing the resuscitation dose of epinephrine may be required to restore cardiac contractile function after bupivacaine intoxication.
据推测，局部麻醉药对环磷腺苷（cAMP）生成的抑制作用可能与心血管毒性有关。本研究旨在确定布比卡因是否比那些较少引发心血管毒性的化学结构相关局部麻醉药更有效地抑制cAMP生成。
志愿者提供静脉血，从中分离淋巴细胞。在基础条件下以及用福斯高林或肾上腺素刺激后，测量cAMP的生成。评估甲哌卡因、罗哌卡因和布比卡因对基础、肾上腺素刺激和福斯高林刺激的cAMP生成的抑制作用。
福斯高林和肾上腺素均使cAMP生成呈浓度依赖性增加；这些药物的半数有效浓度（EC50）分别为3.6×10⁻⁸和4.6×10⁻⁸M。最大福斯高林刺激的cAMP生成（在10⁻⁶M时为6.6±0.8 pmol/10⁶[校正后]细胞/10分钟）大于最大肾上腺素刺激的cAMP生成（在10⁻⁵M时为4.2±0.6 pmol/10⁶[校正后]细胞/10分钟）。布比卡因（IC50 = 2.3×10⁻⁶M）比罗哌卡因（IC50 = 4×10⁻⁶M）或甲哌卡因（IC50 = 3.2×10⁻⁵M）更有效地抑制基础cAMP生成。同样，布比卡因（IC50 = 2.3×10⁻⁶M）在抑制肾上腺素刺激的cAMP生成方面与罗哌卡因（IC50 = 1.7×10⁻⁶M）效力相当，且比甲哌卡因（IC50 = 8.9×10⁻⁶M）更有效。布比卡因（IC50 = 5.3×10⁻⁶M）在抑制福斯高林刺激的cAMP生成方面仅略比罗哌卡因（IC50 = 9.7×10⁻⁶M）或甲哌卡因（IC50 = 6.8×10⁻⁶M）更有效。比较有无布比卡因（0.35、3.5和35μM）时肾上腺素浓度 - 反应曲线表明，局部麻醉药对cAMP生成具有非竞争性抑制作用。
对基础和肾上腺素刺激的cAMP生成的抑制作用可能与局部麻醉药的心血管毒性有关。cAMP生成的抑制可能会限制用于布比卡因心血管毒性的复苏措施和药物的效果。布比卡因中毒后可能需要增加肾上腺素的复苏剂量以恢复心脏收缩功能。
