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Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes.

ABSTRACT: BACKGROUND:The 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. METHODS:Single ventricular myocytes were enzymatically isolated from wild-type C57Bl/6 mice and loaded with 10??M 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. RESULTS:A significant inhibition at mepivacaine's IC50 (50??M) 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?

SUBMITTER: Mosqueira M

PROVIDER: S-EPMC6947945 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes.

Mosqueira Matias M Aykut Güçlü G Fink Rainer H A RHA

BMC anesthesiology 20200108 1

<h4>Background</h4>The 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 Ca<sup>2+</sup> transient in isolated adult mouse cardiomyocytes.<h4>Methods</h4>Single ventricular myocytes were enzymatically isolated from wild-type C57Bl/6 mice and loaded with 10 μM fluorescent Ca<sup>2+</sup> indicator Fluo-4-AM to record intracellular Ca<sup>2+</sup> transient ...[more]

PMID: 31914932

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Project description:AIMS:The EMPA-REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca2+ -dependent activation of Ca2+ /calmodulin-dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin reduces CaMKII- activity and improves Ca2+ -handling in human and murine ventricular myocytes. METHODS AND RESULTS:Myocytes from wild-type mice, mice with transverse aortic constriction (TAC) as a model of HF, and human failing ventricular myocytes were exposed to empagliflozin (1 μmol/L) or vehicle. CaMKII activity was assessed by CaMKII-histone deacetylase pulldown assay. Ca2+ spark frequency (CaSpF) as a measure of sarcoplasmic reticulum (SR) Ca2+ leak was investigated by confocal microscopy. [Na+ ]i was measured using Na+ /Ca2+ -exchanger (NCX) currents (whole-cell patch clamp). Compared with vehicle, 24 h empagliflozin exposure of murine myocytes reduced CaMKII activity (1.6 ± 0.7 vs. 4.2 ± 0.9, P < 0.05, n = 10 mice), and also CaMKII-dependent ryanodine receptor phosphorylation (0.8 ± 0.1 vs. 1.0 ± 0.1, P < 0.05, n = 11 mice), with similar results upon TAC. In murine myocytes, empagliflozin reduced CaSpF (TAC: 1.7 ± 0.3 vs. 2.5 ± 0.4 1/100 μm-1 s-1 , P < 0.05, n = 4 mice) but increased SR Ca2+ load and Ca2+ transient amplitude. Importantly, empagliflozin also significantly reduced CaSpF in human failing ventricular myocytes (1 ± 0.2 vs. 3.3 ± 0.9, P < 0.05, n = 4 patients), while Ca2+ transient amplitude was increased (F/F0 : 0.53 ± 0.05 vs. 0.36 ± 0.02, P < 0.05, n = 3 patients). In contrast, 30 min exposure with empagliflozin did not affect CaMKII activity nor Ca2+ -handling but significantly reduced [Na+ ]i . CONCLUSIONS:We show for the first time that empagliflozin reduces CaMKII activity and CaMKII-dependent SR Ca2+ leak. Reduced Ca2+ leak and improved Ca2+ transients may contribute to the beneficial effects of empagliflozin in HF.

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Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes.

Publications

Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes.

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