Abstract
BackgroundThe potential mechanism of mepivacaine’s myocardial depressant effect observed in papillary muscle has not yet been investigated at cellular level. Therefore, we evaluated mepivacaine’s effects on Ca2+ transient in isolated adult mouse cardiomyocytes.MethodsSingle ventricular myocytes were enzymatically isolated from wild-type C57Bl/6 mice and loaded with 10 μM fluorescent Ca2+ indicator Fluo-4-AM to record intracellular Ca2+ transients upon electrical stimulation. The mepivacaine effects at half-maximal inhibitory concentration (IC50) was determined on calibrated cardiomyocytes’ Ca2+ transients by non-parametric statistical analyses on biophysical parameters. Combination of mepivacaine with NCX blockers ORM-10103 or NiCl2 were used to test a possible mechanism to explain mepivacaine-induced Ca2+ transients’ reduction.ResultsA significant inhibition at mepivacaine’s IC50 (50 μM) on Ca2+ transients was measured in biophysical parameters such as peak (control: 528.6 ± 73.61 nM vs mepivacaine: 130.9 ± 15.63 nM; p < 0.05), peak area (control: 401.7 ± 63.09 nM*s vs mepivacaine: 72.14 ± 10.46 nM*s; p < 0.05), slope (control: 7699 ± 1110 nM/s vs mepivacaine: 1686 ± 226.6 nM/s; p < 0.05), time to peak (control: 107.9 ± 8.967 ms vs mepivacaine: 83.61 ± 7.650 ms; p < 0.05) and D50 (control: 457.1 ± 47.16 ms vs mepivacaine: 284.5 ± 22.71 ms; p < 0.05). Combination of mepivacaine with NCX blockers ORM-10103 or NiCl2 showed a significant increase in the baseline of [Ca2+] and arrhythmic activity upon electrical stimulation.ConclusionAt cellular level, mepivacaine blocks Na+ channels, enhancing the reverse mode activity of NCX, leading to a significant reduction of Ca2+ transients. These results suggest a new mechanism for the mepivacaine-reduction contractility effect.
Highlights
The potential mechanism of mepivacaine’s myocardial depressant effect observed in papillary muscle has not yet been investigated at cellular level
The incubation of cardiomyocytes with 50 μM (IC50) of mepivacaine induced a drastic reduction of the Ca2+ transient compared to control (Fig. 2a)
Using a combination of Ca2+ transient data recording technique and data analysis based on biophysical parameters we described a new possible role of mepivacaine observed in murine isolated cardiomyocyte’s Ca2+ homeostasis
Summary
The potential mechanism of mepivacaine’s myocardial depressant effect observed in papillary muscle has not yet been investigated at cellular level. Hemodynamic changes caused by local anesthetics may be of major clinical concern Among others, these hemodynamic effects associated with local anesthetics include a decrease in ventricular conduction velocity leading to arrhythmias and a decrease in myocardial contractility [1,2,3]. We hypothesized that known mepivacaine’s effect on INa might cause a reduction of Ca2+ transient at the IC50 for isolated murine cardiomyocyte, explaining the negative inotropic effect of mepivacaine previously described. To test this hypothesis we analyzed Ca2+ transients’ biophysical parameters established in our laboratory [10,11,12]. The final result supports this hypothesis showing that the combination of mepivacaine and an specific NCX blocker ORM10103 or NiCl2 alters the Ca2+ homeostasis
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