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Aim: To investigate the changes of endothelin( ET) receptors by isoproterenol in myocardial cells, and the invervention effects of CPU86017 and its RS isomer. Methods: Primary cultures of neonatal rat cardiomyo-cytes were prepared, and isoproterenol was added to each group for modeling, followed by drug interventions with propranolol, CPU86017 and RS chiral isomer respectively. Results: The expressions of ET_A and ET_B were increased by isoproterenol, in which the level of ET_B was higher than ET_A . This phenomenon was adjusted to different degrees by using propranolol, CPU86017 and RS chiral isomer in a dosage-relevant manner. The infervention effect of RS isomer was better than that of CPU86017 at the high dosage( 10 μmol/L). Conclusion: The cardiovascular effects of CPU86017 and RS chiral isomer could be correlative to the inhibition of the over-expressions of ET_A and ET_B.
RESUMO
AIM: To investigate the CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin and compare the effect of CPU86017 (racemate) with its 4 enantiomers: (7S, 13R), (7S, 13S), (7R,13S), and (7R,13R)-CPU86017 in this model. METHODS: The animals were randomly divided into 7 groups. The rat hypertrophied model was produced by treatment with L-thyroxin 0.2 mg·kg-1·d-1, sc for 10 d and treated with CPU86017 or its enantiomers 4 mg·kg-1·d-1, sc from d 6 to d 10. The changes in left ventricular (LV) weight index, redox system, and the NO and iNOS activity in the myocardium were investigated. The expression of mRNA of calcineurin、NF-κB in the left ventricle was measured. RESULTS: There were significant cardiac hypertrophy and oxidative stress in rats treated by L-thyroxin. The expression of calcineurin, NFκB mRNA were upregulated (P<0.05, compared with that of control). After treatment with CPU86017 (racemate and enantiomers), LV remodeling and the redox system were improved. CPU86017 and (7S,13R)-CPU86017 showed a better improvement on LV remodeling and the redox than the other isomers and restored the normal expression of calcineurin, NF-κB (P<0.05, P<0.01), respectively. CONCLUSION: It suggested that an up-regulation of calcineurin and NFκB possibly related to the altered intracellular calcium handling system plays a role in the progression of L-thyroxin induced cardiomyopathy and CPU-86017 and its 7S,13R-CPU86017 enantiomer effectively inhibit the abnormal expression of calcineurin and NFκB genes, the NOS enzyme and oxidant stress in the cardiomyopathy.
RESUMO
AIM:To investigate the bi-directional penetration of CPU-86017 across the BBB (Blood Brain Barrier) following iv and icv (intracerebroventricular) administration in mice.METHOD:The levels of CPU-86017 (p-Chlorobenzyltetrahydroberberine hydrochloride) in the brain, heart, kidney and blood of mice after acute administration of 3.0 mg/kg of CPU-86017 were measured by validated HPLC assay at several time points: 5, 10, 20, 30 and 60 minutes. RESULT:The maximum concentrations of CPU-86017 in the brain, heart, kidney and plasma achieved at 10 minutes by both routes of administration were 0.83±0.335, 25.13±4.17, 56.0±19.69, and 2.23±0.97 μg/ml in the iv group and 23.68±4.2,15.9±10.24, 7.93±4.68 and 3.32±2.3 μg/ml in the icv group, respectively. The decline in concentrations was rapid in plasma. The highest concentration of CPU-86017 was found in the kidney (56.0±19.69 μg/g) after iv administration and in the brain (23.68±4.2 μg/g) after icv injection. The difference in concentrations in the kidney and heart was not significant at 60 min after iv administration. Given by icv administration CPU-86017 reached the peripheral tissues and plasma at each of the five time points, whereas by the iv route at 20, 30 and 60 min the drug could not be detected in the brain.CONCLUSION:The permeability of CPU-86017 through the BBB was well established by two ways: blood circulation to the brain and brain to general circulation. However, a big difference exists between these ways. It is more difficult to penetrate from the blood to the brain than from brain to the peripheral.