Bupivacaine Inhibits Cyclic-3', 5'-Adenosine Monophosphate Production A Possible Contributing Factor to Cardiovascular Toxicity

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Abstract
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.

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