Pregnancy is known to increase myocardial susceptibility to bupivacaine-induced cardiovascular collapse, and prolonged pretreatment of rabbits with high doses of progesterone potentiates bupivacaine's depression of the maximal rate of increase ((V) over dot(max)) of the cardiac action potential. Short-term effects of progesterone are not detected in vitro, but other steroids elevated during pregnancy might be acutely active in this model. These experiments tested whether acute exposure to beta-estradiol potentiates local anesthetic/antiarrhythmic depression of (V) over dot(max) and conduction velocity in rabbit cardiac tissue in vitro. Standard intracellular microelectrodes were used to measure electrophysiologic changes produced by beta-estradiol, local anesthetics. or both in dissected segments of heart containing the Purkinje fiber and ventricular muscle cells from ovariectomized rabbits. In tissues preincubated in beta-estradiol (3.3 nM), addition of bupivacaine (10.4 mu M), or lidocaine (85.4 and 129 mu M) decreased (V) over dot(max) significantly more than in steroid-free Tyrode's (p < 0.001). Alone, beta-estradiol had no effect on (V) over dot(max), and depression of (V) over dot(max) by the nonanesthetic Na+ channel blocker tetrodotoxin (TTX, 3 mu M) was not potentiated by beta-estradiol. In preparations initially exposed to bupivacaine for 30 min, subsequent addition of beta-estradiol decreased (V)over dot(max) further within 10 min (p < 0.05). Bupivacaine's greater depression of (V) over dot(max) at higher frequencies (3 Hz) was exaggerated by beta-estradiol. However, the rate-dependent slowing of conduction by bupivacaine was lessened or even reversed by beta-estradiol addition. Such rapid physiologic changes cannot be due to genomic actions by the hormone that rake hours to manifest. Nor is the potentiation due to a general decrease in membrane excitability because the comparable inhibition by by is insensitive to estradiol. Because beta-estradiol potentiates the inhibition of myocardial excitability, but alleviates the slowing of impulse conduction between the Purkinje fiber and ventricular muscle produced by local anesthetics, the hormone must produce changes in more than one ionic conductance. Both pregnancy and conditions that abnormally alter levels of steroid hormones have ramifications for local anesthetic-induced cardiotoxicity and antiarrhythmic pharmacotherapeutics.
