cardiovascular-agents and oxymatrine

The human ether-a-go-go-related gene (hERG) encodes the rapidly activating, delayed rectifier potassium channel (IKr) important for cardiac repolarization. Dysfunction of the hERG channel can cause Long QT Syndrome (LQTS). A wide variety of structurally diverse therapeutic compounds reduce the hERG current by acute direct inhibition of the hERG current or/and selective disruption of hERG protein expression. Arsenic trioxide (As(2)O(3)), which is used to treat acute promyelocytic leukemia, can cause LQTS type 2 (LQT2) by reducing the hERG current through the diversion of hERG trafficking to the cytoplasmic membrane. This cardiotoxicity limits its clinical applications. Our aim was to develop cardioprotective agents to decrease As(2)O(3)-induced cardiotoxicity. We reported that superfusion of hERG-expressing HEK293 (hERG-HEK) cells with matrine (1, 10 μM) increased the hERG current by promoting hERG channel activation. Long-term treatment with 1 μM matrine or oxymatrine increased expression of the hERG protein and rescued the hERG surface expression disrupted by As(2)O(3). In addition, Matrine and oxymatrine significantly shortened action potential duration prolonged by As(2)O(3) in guinea pig ventricular myocytes. These results were ascribed to the up-regulation of hERG at both mRNA and protein levels via an increase in the expression of transcription factor Sp1, an established transactivator of the hERG gene. Therefore, matrine and oxymatrine may have the potential to cure LQT2 as a potassium channel activator by promoting hERG channel activation and increasing hERG channel expression.

Topics: Action Potentials; Alkaloids; Animals; Arsenic Trioxide; Arsenicals; Cardiovascular Agents; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; HEK293 Cells; Humans; In Vitro Techniques; Matrines; Myocytes, Cardiac; Oxides; Patch-Clamp Techniques; Promoter Regions, Genetic; Quinolizines; Sp1 Transcription Factor; Up-Regulation

Oxymatrine is one of the main alkaloid components extracted from SOPHORA roots and has been shown to play various protective roles in the cardiovascular system. The present study was designed to study the protective effect of oxymatrine on arrhythmias and their ionic channel mechanism. Rat arrhythmic models were established by aconitine injection and coronary artery ligation. Rat cardiomyocytes were acutely isolated, and the whole-cell patch clamp technique was employed to investigate the effects of oxymatrine on sodium channels. Pretreatment with oxymatrine markedly increased the dose of aconitine required to induce arrhythmias in rats. Additionally, oxymatrine significantly delayed the initial time and shortened the duration time of rat arrhythmias induced by coronary artery ligation. Cardiac mortality rate in coronary artery ligation-induced arrhythmias was also effectively decreased by oxymatrine in rats. The electrophysiological study showed that oxymatrine could significantly inhibit sodium and calcium currents in isolated rat cardiomyocytes in a concentration-dependent manner. In summary, oxymatrine plays a remarkably preventive role in rat arrhythmias through the inhibition of sodium and calcium currents.

Topics: Aconitine; Alkaloids; Animals; Arrhythmias, Cardiac; Calcium; Cardiovascular Agents; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Myocytes, Cardiac; Phytotherapy; Plant Extracts; Plant Roots; Quinolizines; Rats; Rats, Wistar; Sodium; Sodium Channels; Sophora