ABSTRACT
BACKGROUND: The mechanisms responsible for the effects of Ginkgo biloba extract (GbE) are not fully understood. Krüppel-like factor 2 (KLF2), a zinc transcription factor, has vasculoprotective effects if activated. The present study attempted to explore whether GbE may activate KLF2 and its consequences. METHODS: To determine the effects of GbE on endothelial cells, human umbilical vein endothelial cells (HUVECs) were incubated with various concentrations of GbE. KLF2 expression levels were determined by quantitative reverse transcription polymerase chain reaction. Cytoskeleton staining and cell migration assays were performed to determine the effects of KLF2 activation. Moreover, endothelial NO synthase (eNOS) expression levels were detected by PCR and Western blot testing. Nitric oxide (NO) production was also measured with 4,5-diaminofluorescein. A knockdown of KLF2 was performed to identify the role of KLF2 in GbE-induced eNOS expression and NO production. RESULTS: HUVECs that were incubated with GbE increased KLF2 expression. These cells demonstrated an altered cell morphology, cytoskeleton rearrangement, and inhibited migration activity. Moreover, eNOS expression and NO production increased in a dose-dependent manner when cells were treated with GbE. Correspondingly, silencing of KLF2 in HUVECs decreased eNOS expression and NO production in GbE-treated cells. CONCLUSIONS: GbE significantly activated KLF2 expression and KLF2-related endothelial function, including cytoskeleton rearrangement, inhibition of migration, eNOS activation, and NO production. These findings suggest that GbE may induce a vasculoprotective effect in endothelial cells. KEY WORDS: Endothelial cells; eNOS; Ginkgo biloba extract; KLF2; NO.
ABSTRACT
BACKGROUND: The objective of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous levosimendan and the metabolites (OR1855 and OR1896) in healthy Chinese male subjects and to post hoc compare with Caucasian subjects. METHODS: One single 2 mg dose of levosimendan was infused intravenously over 10 minutes to each of 14 healthy male subjects. Plasma levosimendan was analyzed by high performance liquid chromatography. Pharmacodynamics was evaluated using echocardiography. RESULTS: The Cmax (peak concentration) and AUC∞ (area under the curve from time 0 to infinity) of levosimendan of Chinese subjects were significantly higher than for Caucasian subjects as 256.1 ± 37.8 (mean ± SD) vs. 142.1 ± 17.5 ng/mL and 207.5 ± 35.2 vs. 117.0 ± 17.0 hr·ng/mL, respectively. The clearance of Chinese subjects was significantly lower than Caucasian subjects at 9.9 ± 1.8 vs. 17.4 ± 2.7 L/hr, respectively. The elimination half-life of Chinese subjects was significantly longer than for Caucasian subjects (1.18 ± 0.18 vs. 0.76 ± 0.10 hr, respectively). Chinese subjects eliminated levosimendan significantly slower than Caucasian subjects, leading to a higher exposure of levosimendan in Chinese subjects. However, this higher exposure did not significantly change the most pharmacodynamic properties of levosimendan except for ejection fraction (EF). The EF increased 12.2 ± 11.4% in Chinese subjects 20 min after the end of intravenous infusion, which was significantly lower than Caucasian subjects with EF increased by 22.7 ± 7.0%. CONCLUSIONS: The intravenous levosimendan in healthy Chinese volunteers was safe, and well-tolerated with significant inotropic effect. The clearance of levosimendan of Chinese subjects was significantly lower and elimination half-life longer than Caucasian subjects. KEY WORDS: Chinese; Ethnic comparison; Levosimendan; Pharmacodynamics; Pharmacokinetics; Volunteer.
