ABSTRACT
The present study was designed to determine the effects of Guanfu base A (GFA) on the late sodium current (INa.L), transient sodium current (INa.T), HERG current (IHERG), and Kv1.5 current (IKv1.5). The values of INa.L, INa.T, IHERG and IKv1.5 were recorded using the whole-cell patch clamp technique. Compared with other channels, GFA showed selective blocking activity in late sodium channel. It inhibited INa.L in a concentration-dependent manner with an IC50 of (1.57 ± 0.14) μmol · L(-1), which was significantly lower than its IC50 values of (21.17 ± 4.51) μmol · L(-1) for the INa.T. The inhibitory effect of GFA on INa,L was not affected by 200 μmol · L(-1) H2O2. It inhibited IHERG with an IC50 of (273 ± 34) μmol · L(-1) and has slight blocking effect on IKv1.5, decreasing IKv1.5 by only 20.6% at 200 μmol · L(-1). In summary, GFA inhibited INa.L selectively and remained similar inhibition in presence of reactive oxygen species. These findings may suggest a novel molecular mechanism for the potential clinical application of GFA in the treatment of cardiovascular disorders.
Subject(s)
Animals , Female , Humans , Male , Analysis of Variance , Anti-Arrhythmia Agents , Pharmacology , Dose-Response Relationship, Drug , Guinea Pigs , HEK293 Cells , Heart Ventricles , Heterocyclic Compounds, 4 or More Rings , Pharmacology , Inhibitory Concentration 50 , Membrane Potentials , Myocytes, Cardiac , Metabolism , Patch-Clamp Techniques , Sodium Channel Blockers , Pharmacology , Sodium ChannelsABSTRACT
AIM@#In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized.@*METHOD@#Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, β1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria.@*RESULTS@#Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited β1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%).@*CONCLUSION@#The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.
Subject(s)
Animals , Humans , Male , Rats , Adrenergic beta-Antagonists , Chemistry , Pharmacology , Antihypertensive Agents , Chemistry , Pharmacology , Benzopyrans , Chemistry , Pharmacology , Drugs, Chinese Herbal , Chemistry , Pharmacology , Hypertension , Drug Therapy , Molecular Structure , Oximes , Chemistry , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Due to the complicated pathogenesis of cardiac arrhythmia, the safe and effective therapeutic strategies for cardiac arrhythmia remain an urgent medical problems in the recent years. In this paper, we introduced the research practice of anti-arrhythmic agents targeting on potassium ion channel. The research progress of anti-arrhythmic agents in up-to-date literatures were also reviewed and prospected.