RESUMO
OBJECTIVE： To study the effect mechanism of iridoid glycosides extracted from Scrophularia ningpoensis inhibiting cardiomyocytes apoptosis in myocardial infarction model rats. METHODS： The male Wistar rats were randomly divided into sham operation group， model group and S. ningpoensis iridoid glycosides low-dose， medium-dose and high-dose groups， with 10 rats in each group. Myocardial infarction models were established by ligating the left anterior descending coronary artery of the rats， and sham operation group was only threaded without ligation. After the model was established， each administration group was given S. ningpoensis iridoid glycosides suspension intragastrically at three different doses of 50，100，200 mg/kg （by the amount of total glycosides extract） with 10 mL/time， twice a day， for consecutive 7 days. Sham operation group and model group were given constant volume of normal saline intragastrically with same method. The changes of S-T segment of lead ECG Ⅱ were recorded before， after and during 7 days of administration. Cardiac function of rats was examined. The serum levels of LDH， CK-MB， cTnⅠ， NT-pro BNP and TNF-α were determined by colorimetry， immunosuppression or ELISA. The apoptosis of myocardial cells was observed by TUNEL method. SOD activity and MDA content in cardiac myocytes were detected by colorimetry. The expressions of Bcl-2， Bax， Cyt C， Caspase-8， Caspase-9， Caspase-12， Caspase-3 and Calpain in cardiac myocytes were detected by ELISA， enzymolysis colorimetry or enzymatic fluorescence assay. RESULTS： Compared with sham operation， electrocardiogram S-T segment was significantly elevated and the left ventricular end-diastolic diameter and left ventricular end-systolic diameter were significantly increased in the model group； left ventricular ejection fraction and short axis shortening rate decreased significantly； serum levels of LDH， CK-MB， cTnⅠ， NT-pro BNP and TNF-α were increased significantly； there were a large number of yellow-brown apoptotic cells in myocardial tissue； the activity of SOD in myocardial tissue was significantly decreased while the content of MDA was significantly increased； the protein expression level of Bcl-2 and Bcl-2/Bax were significantly decreased， while the levels of Bax， Cyt C， Caspase-3， Caspase-8， Caspase-9， Caspase-12 and Calpain were significantly increased （P＜0.05 or P＜0.01）. Compared with model group， above indexes and pathological changes of myocardial tissue were improved significantly in administration group； the level of Bcl-2 and Bcl-2/Bax in cardiomyocytes increased significantly， while the levels of Bax， Cyt C， Caspase-3， Caspase-8， Caspase-9， Caspase-12 and Calpain decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS： S. ningpoensis iridoid glycosides can inhibit the activation of Caspase-3 by inhibiting three apoptotic pathways related to Caspase-8， Caspase-9 and Caspase-12， and then inhibit the apoptosis of cardiomyocytes.
RESUMO
OBJECTIVE:To establish the pharmacokinetic-pharmacodynamic(PK-PD) model of Nisoldipine controlled-release patches(NCRP)in spontaneously hypertensive rats(SHR). METHODS:SHR were randomized into a patch(NCRP)group and a tablet(Nisoldipine tablets)group,with 6 rats in each group. The microdialysis probes were implanted in SHR. Each rat was given 5 mg nisoldipine. Plasma microdialysate was collected within 36 h after administration. HPLC was adopted to determine the plasma concentration of nisoldipine,and WinNonlin 5.3 was employed to calculate Pharmacokinetic parameters. With heart rate and blood pressure as pharmacodynamic indexes,PK-PD model study was conducted. RESULTS:Vs. nisoldipine tablets,NCRP has con-trolled release effect. The relationship between NCRP drug effect and effect-site concentration met the Sigmoid-Emax model. The main parameters of the PK-PD model for heart rate and systolic blood pressure were as follows as Emax of (2.65 ± 0.06) and (10.71 ± 0.87),EC50 of (83.65 ± 35.25) and (1.29 ± 0.26) ng/ml,γ of (0.83 ± 0.91) and (1.2 ± 0.35),Keo of (0.37 ± 0.53) and (0.91±0.24)h-1. CONCLUSIONS:PK-PD model of NCRP in SHR has been established successfully.