RESUMEN
Clinically, drug-induced torsades de pointes (TdP) are rare events, whereas the reduction of the human ether-à-go-go-related gene (hERG) current is common. In this study, we aimed to explore the specific factors that contribute to the deterioration of hERG inhibition into malignant ventricular arrhythmias. Cisapride, a drug removed from the market because it caused long QT (LQT) syndrome and torsade de pointes (TdP), was used to induce hERG inhibition. The effects of cisapride on the hERG current were evaluated using a whole-cell patch clamp. Based on the dose-response curve of cisapride, models of its effects at different doses (10, 100, and 1,000 nM) on guinea pig heart in vitro were established. The effects of cisapride on electrocardiogram (ECG) signals and QT interval changes in the guinea pigs were then comprehensively evaluated by multi-channel electrical mapping and high-resolution fluorescence mapping, and changes in the action potential were simultaneously detected. Cisapride dose-dependently inhibited the hERG current with a half inhibitory concentration (IC50) of 32.63 ± 3.71 nM. The complete hERG suppression by a high dose of cisapride (1,000 nM) prolonged the action potential duration (APD), but not early after depolarizations (EADs) and TdP occurred. With 1 µM cisapride and lower Mg2+/K+, the APD exhibited triangulation, dispersion, and instability. VT was induced in two of 12 guinea pig hearts. Furthermore, the combined administration of isoproterenol was not therapeutic and increased susceptibility to ventricular fibrillation (VF) development. hERG inhibition alone led to QT and ERP prolongation and exerted an anti-arrhythmic effect. However, after the combination with low concentrations of magnesium and potassium, the prolonged action potential became unstable, triangular, and dispersed, and VT was easy to induce. The combination of catecholamines shortened the APD, but triangulation and dispersion still existed. At this time, VF was easily induced and sustained.
RESUMEN
BACKGROUND: The prevention and treatment of Microwave-caused cardiovascular injury remains elusive. This study investigated the cardiovascular protective effects of compound Chinese medicine "Kang Fu Ling" (KFL) against high power microwave (HPM)-induced myocardial injury and the role of the mitochondrial permeability transition pore (mPTP) opening in KFL protection. METHODS: Male Wistar rats (100) were divided into 5 equal groups: no treatment, radiation only, or radiation followed by treatment with KFL at 0.75, 1.5, or 3 g/kg/day. Electrocardiography was used to Electrophysiological examination. Histological and ultrastructural changes in heart tissue and isolated mitochondria were observed by light microscope and electron microscopy. mPTP opening and mitochondrial membrane potential were detected by confocal laser scanning microscopy and fluorescence analysis. Connexin-43 (Cx-43) and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemistry. The expression of voltage-dependent anion channel (VDAC) was detected by western blotting. RESULTS: At 7 days after radiation, rats without KFL treatment showed a significantly lower heart rate (P<0.01) than untreated controls and a J point shift. Myocyte swelling and rearrangement were evident. Mitochondria exhibited rupture, and decreased fluorescence intensity, suggesting opening of mPTP and a consequent reduction in mitochondrial membrane potential. After treatment with 1.5 g/kg/day KFL for 7 d, the heart rate increased significantly (P<0.01), and the J point shift was reduced flavorfully (P<0.05) compared to untreated, irradiated rats; myocytes and mitochondria were of normal morphology. The fluorescence intensities of dye-treated mitochondria were also increased, suggesting inhibition of mPTP opening and preservation of the mitochondrial membrane potential. The microwave-induced decrease of Cx-43 and VDAC protein expression was significantly reversed. CONCLUSION: Microwave radiation can cause electrophysiological, histological and ultrastructural changes in the heart. KFL at 1.5 g/kg/day had the greatest protective effect on these cardiovascular events. mPTP plays an important role in the protective effects of KFL against microwave-radiation-induced myocardial injury.