β-Estradiol Acutely Potentiates the Depression of Cardiac Excitability by Lidocaine and Bupivacaine

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 (JOURNAL/jcph/04.03/00005344-199911000-00014/OV0312/v/2021-02-06T192238Z/r/image-pngmax) 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 β-estradiol potentiates local anesthetic/antiarrhythmic depression of JOURNAL/jcph/04.03/00005344-199911000-00014/OV0312/v/2021-02-06T192238Z/r/image-pngmax and conduction velocity in rabbit cardiac tissue in vitro. Standard intracellular microelectrodes were used to measure electrophysiologic changes produced by β-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 β-estradiol (3.3 nM), addition of bupivacaine (10.4 μM), or lidocaine (85.4 and 129 μM) decreased JOURNAL/jcph/04.03/00005344-199911000-00014/OV0312/v/2021-02-06T192238Z/r/image-pngmax significantly more than in steroid-free Tyrode's (p < 0.001). Alone, β-estradiol had no effect on JOURNAL/jcph/04.03/00005344-199911000-00014/OV0312/v/2021-02-06T192238Z/r/image-pngmax, and depression of JOURNAL/jcph/04.03/00005344-199911000-00014/OV0312/v/2021-02-06T192238Z/r/image-pngmax by the nonanesthetic Na+ channel blocker tetrodotoxin (TTX, 3 μM) was not potentiated by β-estradiol. In preparations initially exposed to bupivacaine for 30 min, subsequent addition of β-estradiol decreased JOURNAL/jcph/04.03/00005344-199911000-00014/OV0312/v/2021-02-06T192238Z/r/image-pngmax further within 10 min (p < 0.05). Bupivacaine's greater depression of JOURNAL/jcph/04.03/00005344-199911000-00014/OV0312/v/2021-02-06T192238Z/r/image-pngmax at higher frequencies (3 Hz) was exaggerated by β-estradiol. However, the rate-dependent slowing of conduction by bupivacaine was lessened or even reversed by β-estradiol addition. Such rapid physiologic changes cannot be due to genomic actions by the hormone that take hours to manifest. Nor is the potentiation due to a general decrease in membrane excitability because the comparable inhibition by TTX is insensitive to estradiol. Because β-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.