Ion Channel Targeted Mechanisms of Anti-arrhythmic Chinese Herbal Medicine Xin Su Ning

Xin Su Ning (XSN) is a China patented and certified herbal medicine used to treat premature ventricular contractions (PVCs) since 2005. A recent completed clinical trial of 861 patients showed that XSN had similar PVC inhibition rate to the class I antiarrhythmic drug mexiletine, at 65.85% for XSN and 63.10% for mexiletine. We have previously reported that XSN prolongs action potential duration (APD) and suppresses action potential amplitude (APA) of the cardiac ventricular myocytes. In this report we aim to reveal the effect of XSN on the ionic channels that govern APD and APA, which would help to explain the cellular electrophysiological mechanism of XSN. Our main findings are: (1) On ECG recorded in isolated rat, in the presence of XSN the amplitude of R wave was significantly decreased and the amplitude of T wave was increased significantly; (2) XSN blocked hNaV1.5 channel stably transfected cell line in a dose-dependent manner with an IC50 of 0.18 ± 0.02 g/L; and (3) XSN suppresses hERG channels in a dose-dependent manner with an IC50 of 0.34 ± 0.01 g/L. In conclusion, the clinical antiarrhythmic efficacy of XSN is based on its class I and Class III antiarrhythmic properties by suppression hNaV1.5 channel and hERG channels, which are directly responsible for XSN’s effect on APA suppression and APD prolongation

Zinc transport across cell membranes

The mechanism of zinc transport has been investigated in red cells from normal humans, lampreys, sheep, sickle cell anaemia patients and in bovine chondrocytes. In all the cell types investigated except for lamprey red cells, zinc transport is mainly via the anion exchanger (band 3), which accounts for over 80% of total measured zinc uptake, when the medium contains no zinc binding ligands. Zinc uptake via the band 3 pathway is stimulated by the presence of bicarbonate (5mM) and inhibited by treatment with DIDS or SITS (10andmu;M). This anion-dependent mechanism represents the major route for zinc transport across the cell membrane in vitro. The presence of the zinc binding ligands albumin and histidine in the media greatly reduced the uptake of zinc via the anion exchanger due to the decrease in free zinc concentration. Histidine, in addition to its chelating effect, shows a specific facilitating effect on zinc uptake in all the cell types. This stimulating effect of histidine was stereospecific (significantly different between L-, and D-histidine) in red cells from normal humans and sickle cell anaemia patients, but not in red cells from lampreys, sheep, and bovine chondrocytes. Evidence from all cell types strongly suggests that the stimulus is due to the cotransport of zinc and histidine via the histidine transport systems, which are system L, and y* in normal human and sickle red cells; a non-stereospecific L-like system in lamprey red cells and bovine chondrocytes; system C or unknown specific histidine transporter in sheep red cells. The amino acid linked zinc uptake may represent a physiologically significant mechanism for zinc transport into cells.</p

Membrane transport abnormalities in patients with renal failure

The possibility that changes in membrane transport systems may contribute to the pathophysiology of the uraeraic syndrome has not been extensively studied. This thesis presents a study of eight erythrocyte membrane transport systems, namely the Na/K pump, the amino acid systems y+, ASC, gly, L and T, the nucleoside and choline transporters. The results indicate that, compared to normal controls, K+ flux through the Na/K pump was reduced in chronic renal failure patients (CRF), on haemodialysis (HD), and on continuous ambulatory peritoneal dialysis (CAPD), but was normal in functional transplant (FT) patients' erythrocytes. The number of Na/K pumps per erythrocyte was decreased in CRF and CAPD but showed no differences between HD, FT and Normal controls. The mean turnover rate per pump site was reduced in patients on HD, whereas other groups were not significantly different from controls. Cross-incubation experiments suggest that the lowered pump flux seen in the HD group was due to plasma factors since reversibility of the defect was achieved when those cells were incubated in normal plasma. The defect was completely reversed with a successful transplant. Erythrocytes from haemodialysis patients exhibited an increased uptake of L-lysine through the y+ system. The uptake of L-serine was decreased and the affinity of the ASC system for L-serine was increased in these patients compared with controls. The glycine transporter showed a significant increase in affinity for glycine. The flux of L-leucine and L-tryptophan showed no differences from control cells. Erythrocyte membrane transport of uridine was similar in normal control cells and in those obtained from uraemic patients. Choline influx rates were significantly increased and affinity of the transporter for choline reduced in dialysis patients' erythrocytes. Renal transplant and CRF patients showed variable influx rates which gave a significant negative correlation with creatinine clearance. These results show that there are selective abnormalities in some membrane transport system of the erythrocyte in patients with renal failure. The mechanism and possible significance of these changes are discussed.</p

Regulation of the intestinal sodium/ glucose cotransporter SGLT1 in health and disease

&nbsp;The full text file and abstract for this thesis are not currently available in ORA