Publications (2)5.28 Total impact
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ABSTRACT: 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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ABSTRACT: To study the effects of 5-hydroxytryptamine (5-HT) on L-type calcium current (ICa) in norepinephrine (NE)-induced hypertrophic ventricular myocytes. Left ventricular hypertrophy was induced by injecting NE intraperitoneally in rats. The single myocytes were isolated enzymatically from left ventricle. ICa was recorded with the whole-cell configuration of the patch-cl amp technique. (1) The ratio of left heart weight to body weight (LHW/BW) was higher (P < 0.01) in the NE-treated rats compared with the control rats on d 15. LHW/BW was increased 31.8 % in NE-treated rats. (2) ICa was larger in hypertrophic cells than that in normal cells (4.5 p A/pF +/- 0.5 pA/pF vs 3.5 pA/pF +/- 0.3 pA/pF, respectively, at testing potential of 0 mV; P < 0.01). (3) 5-HT (1, 10 micromol/L) increased ICa and decreased the peak current potential from 0 mV to -10 mV in both myocytes. The augmentation of ICa induced by 5-HT was larger in hypertrophic ones. (4) 5-HT did not markedly influence the steady-state activation kinetics. However, 5-HT shifted steady-state inactivation curve with half inactivation voltage V 1/2 changing from -39.5 mV +/- 1.8 mV to -27.8 mV +/- 1.7 m V (P < 0.05), while not changing the voltage responsiveness of calcium channel (slope factor k was not changed markedly). 5 -HT increased ICa in ventricular myocytes by changing the kinetics of steady-st ate inactivation. A larger alteration of ICa induced by 5-HT i n hypertrophic ventricular myocytes suggests that 5-HT be more prone to induce arrhythmia in hypertrophic heart than in normal one.
Fourth Military Medical University
Xi’an, Liaoning, China
- Department of Pharmacology