Inhibition of Cardiomyocyte Contractile/Relaxation by MN9202 and Mechanisms Involved

Zhu, Xiang Yang; Zhu, Xiongwei; Niu, Xiaolin; Pei, Jianming; Xiong, Lize; Chen, Shaoyang; Lu, Shun-Yan; Wei, Jin; Xing, Bin; Liu, Li; Mei, Qibing; Zhu, Miao-Zhang

doi:10.1016/j.arcmed.2008.02.010

Cited by 1 publication

(4 citation statements)

References 18 publications

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“…Consistent with previous results regarding the inhibition of cardiomyocyte contraction and ⁄ or relaxation by racemic MN9202 due to blocking of L-type Ca 2+ channels, 14 in the present study we found that S-())-MN9202 is responsible for the inhibition by racemic MN9202 of cardiomyocyte mechanical properties. The present findings also explain the precise mechanisms involved, with racemic MN9202 and S-())-MN9202 inhibiting I Ca,L by speeding up steady state inactivation, resulting in a reduction of [Ca 2+ ] i and, accordingly, attenuated ventricular myocyte shortening.…”

Section: Discussionsupporting

confidence: 93%

“…The present findings also explain the precise mechanisms involved, with racemic MN9202 and S‐(−)‐MN9202 inhibiting I Ca,L by speeding up steady state inactivation, resulting in a reduction of [Ca 2 + ] i and, accordingly, attenuated ventricular myocyte shortening. It is also possible that MN9202 may have other mechanisms by which it blocks calcium influx in addition to suppression of the dihydropyridine receptor 14 . For example, it was reported that MN9202 attenuated the positive effect of tetraethylammonium, a calcium‐activated potassium channel blocker, on cell shortening and intracellular CaT 14 .…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that MN9202 may have other mechanisms by which it blocks calcium influx in addition to suppression of the dihydropyridine receptor 14 . For example, it was reported that MN9202 attenuated the positive effect of tetraethylammonium, a calcium‐activated potassium channel blocker, on cell shortening and intracellular CaT 14 . Therefore, the relevant issues and mechanisms require further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] Based on these findings, in the present study we focused on the cardiac effects of MN9202. Although there are data available regarding the effects of MN9202 on cardiac myocytes, 14 it is unclear whether the optical isomers of MN9202 have different effects on ventricular myocytes.…”

Section: Introductionmentioning

confidence: 99%

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Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca²⁺ channel modulator, in rat ventricular myocytes

Cao²,

Zeng

et al. 2010

Clin Exp Pharma Physio

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1. We have shown previously that 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid pentyl methyl ester (MN9202), a new 1,4-dihydropyridine Ca(2+) channel modulator, has significant hypotensive effects and favourable pharmacokinetic characteristics. As a chiral molecule, MN9202 has two optical isomers. The aim of the present study was to evaluate the pharmacological properties of the two enantiomers. 2. The two enantiomers, S-(-)- and R-(+)-MN9202, were obtained by HPLC. At 1 micromol/L, both racemic MN9202 and S-(-)-MN9202 decreased the contractility of rat ventricular myocytes by 54.0 and 64.4%, respectively, compared with control, whereas R-(+)-MN9202 enhanced cell shortening by 10.1%. At 1 micromol/L, racemic MN9202 markedly reduced calcium transient (CaT) and L-type Ca(2+) channel current (I(Ca,L)) by 60.0 and 50.7%, respectively, whereas the reductions in CaT and I(Ca,L) produced by 1 micromol/L S-(-)-MN9202 were greater still (62.2 and 65.7%, respectively). In contrast, 1 micromol/L R-(+)-MN9202 increased CaT and I(Ca,L) by 11.4 and 10.6%, respectively. Furthermore, findings from kinetics studies of I(Ca,L) revealed that the steady state inactivation curve of I(Ca,L) was shifted towards a hyperpolarizing potential by S-(-)-MN9202, but towards a depolarizing potential by R-(+)-MN9202. These results demonstrate different effects of R-(+)-MN9202 and S-(-)-MN9202. 3. In conclusion, the findings of the present study suggest that the chirality of MN9202 results in opposing pharmacological properties of its two enantiomers: S-(-)-MN9202 may be responsible for the therapeutic effects of racemic MN9202, whereas R-(+)-MN9202 contributes to it unwanted effects. The findings of the present study also indicate that MN9202 may be used as a new probe with which to investigate the structure-function relationships of Ca(2+) channels.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca²⁺ channel modulator, in rat ventricular myocytes

Cao²,

Zeng

et al. 2010

Clin Exp Pharma Physio

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Inhibition of Cardiomyocyte Contractile/Relaxation by MN9202 and Mechanisms Involved

Cited by 1 publication

References 18 publications

Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca²⁺ channel modulator, in rat ventricular myocytes

Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca²⁺ channel modulator, in rat ventricular myocytes

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Inhibition of Cardiomyocyte Contractile/Relaxation by MN9202 and Mechanisms Involved

Cited by 1 publication

References 18 publications

Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca2+ channel modulator, in rat ventricular myocytes

Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca2+ channel modulator, in rat ventricular myocytes

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Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca²⁺ channel modulator, in rat ventricular myocytes

Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca²⁺ channel modulator, in rat ventricular myocytes