Papaverine, a vasodilator used as a therapeutic agent for a range of diseases, has been reported to increase the risk of occasional serious ventricular arrhythmias. To examine the mechanism for this effect, we herein tested the effects of papaverine on human ether-a-go-go (HERG) K channels expressed in HEK293 cells and Xenopus oocytes. Our results revealed that papaverine dose-dependently decreased the tail currents of HERG channel expressed in HEK293 cells with the IC50 and the Hill coefficient of 0.58 microM and 0.58, respectively, at +20 mV and 36 degrees C. The IC50 for the papaverine-induced blockade of HERG current in Xenopus oocytes was found to decrease progressively relative to depolarization (38.8, 30.0, and 24.8 microM at -10, +20, and +40 mV, respectively). The papaverine-induced blockade of HERG current was time-dependent; the fractional current was 0.92 +/- 0.03 of the control at the beginning of the pulse, but it declined to 0.18 +/- 0.06 after 6 seconds at a test potential of 0 mV. These results collectively indicate that papaverine blocks HERG channel in a concentration-, voltage-, and time-dependent manner. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that papaverine blocks HERG channel at the pore of the channel. This was consistent with the computational simulation that showed papaverine interacts with Tyr652 and Phe656. Therefore, ventricular arrhythmias induced by papaverine could be resulted from the blockage of the HERG channel at the cardiac myocytes.
The cytoprotective mechanism of 7, 8-dihydroxyflavone (DHF) against oxidative stress-induced cell damage with respect to its stimulatory effect on the expression of heme oxygenase-1 (HO-1), a potent antioxidant enzyme, was investigated in the present study. Up-regulation of HO-1 expression by DHF was both dose and time dependent in lung fibroblast V79-4 cells. DHF also increased the protein expression level of the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), and induced the translocation of Nrf2 from the cytosol into the nucleus, leading to elevated HO-1 expression. The siNrf2 RNA-transfection attenuated HO-1 expression induced by DHF treatment. In addition, DHF induced the activation of extracellular signal-regulated kinase (ERK), while U0126 (a specific pharmacological inhibitor of ERK kinase) abrogated DHF-activated Nrf2 and HO-1 expression. This suggests that DHF increased the levels of Nrf2 and HO-1 via ERK-dependent pathways. Furthermore, DHF significantly prevented the reduction of cell viability in response to oxidative stress; however, U0126 attenuated the protective effect of DHF. Taken together, these results demonstrate that DHF protected cells from oxidative stress via the activation of an ERK/Nrf2/HO-1 signaling pathway.
C(pbs), C(cit), and C(it) are good discrimination parameters. Rasch model can estimate item difficulty parameter and examinee's ability parameter with standard error. The fit statistics can identify bad items and unpredictable examinee's responses.
Objectives: We analyzed the dosage pattern of anesthetic drugs administered to maintain anesthesia during rigid bronchoscopy. Methods: We enrolled a total of 81 patients who underwent rigid bronchoscopy under total intravenous anesthesia between April 2015 and March 2019. Anesthesia was maintained using propofol (target brain concentration 2.0 - 6.0 µg/mL) and remifentanil (target brain concentration 2.0 - 6.0 ng/mL). We analyzed the dosage patterns of the anesthetic agents during the procedure, as well as the changes in the dose of the anesthetic agents and the number of procedures repeated in the same patient. Results: The dose of propofol administered per minute to maintain anesthesia was inversely correlated with the total operation time (r2 = 0.355, β = -0.067, P < 0.000) but was not significantly correlated with the number of times the procedure was repeated. The dose of remifentanil did not significantly differ during repeated procedures in the same patient. Conclusions: The dose of propofol infusion tended to decrease over time during the rigid bronchoscopy procedure. This pattern was specific to propofol but not to remifentanil using TIVA. Understanding the pharmacokinetic properties of anesthetic drugs will help in their appropriate administration.
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