Potassium channels in health, disease & development of channel modulators.

Ion channels present in the plasma membrane and intracellular organelles of all cells, play an important role in maintaining cellular integrity, smooth muscle contraction, secretion of hormones and neurotransmitters. Among the ion channels, potassium channels (K+) are the most abundant having important role in cardiac repolarization, smooth muscle relaxation and insulin release. These are also involved in the regulation of physiological functions like gastrointestinal peristalsis. These channels are the most diverse of all ion channels and are coded by at least 75 genes. Moreover, these have different subunits which co-assemble to form diverse functional channels. Abnormalities in K+ channels are associated with diseases like long QT syndrome, Anderson Tawil syndrome, epilepsy, type 2 diabetes mellitus, etc. A number of naturally occurring as well as synthetic compounds have been identified that modulate the opening and closure of KATP Channels. Some of the currently available K+ channel modulators like sulphonylureas, minoxidil, amiodarone, etc. lack tissue selectivity and have adverse effects. Hence, the success of KATP channel modulators depend on their tissue selectivity. Molecular level studies are needed to understand the type of K+ channels as this can lead to the development of newer drugs with tissue selectivity for various diseases.

Effect of dofetilide on Na~+/Ca~(2+) exchange in ventricular myocytes of adult guinea pigs / 中国药理学通报

Aim This paper aims at investigating the effect of dofetilide on Na+/Ca 2+exchange in ventricular myocytes of adult guinea pigs. Methods Rapid enzymatic isolation procedure was performed to get single ventricular myocytes from adult guinea pigs. After the whole cell configuration was formed, a ramp voltage-clamp pulse depolarized from a holding potential of -40 mV to +60 mV, then hyperpolarized to -120 mV at a rate of 90 mV/s to record the Na+/Ca 2+ exchange current (I Na/Ca) and the influence of dofetilide from 0.03～1.0 ?mol?L -1. Result Dofetilide from 0.03～1.0 ?mol?L -1 concentration-dependently increased the I Na/Ca in both outward and inward mode. The EC 50 of dofetilide on I Na/Ca in outward and inward mode of NCE was 0.178 ?mol?L -1 (95% confidence interval was 0.040～0.787 ?mol?L -1) and 0.178 ?mol?L -1 (95% confidence interval was 0.038～0.842 ?mol?L -1), respectively. Conclusion Dofetilide concentration-dependently increased the outward and inward Na+/Ca 2+ exchange current in ventricular myocytes of adult guinea pigs.

Reduction in ~(125)I-Dofetilide B_(max) and elevation of verapamil in L-thyroxin induced hypertrophied guinea pig ventricular membrane / 中国药理学通报

AIM To determine whether the I Kr channel protein is altered and its response to dofetilide and verapamil in cardiac remodeling by L thy roxin. METHODS Saturation binding assays in guinea pig ventricular membrane preparation with 125 I dofetilide, a radioligand for the cardiac rapidly activating delayed outward rectifier channel (I Kr ) was conducted respectively in normal, hypertrophied, Verapamil or dofetilide intervened group. RESULTS Scatchard analysis revealed two binding sites with different affinities in normal guinea pig ventricle: a high affinity site [ K d=(1 27?0 11) nmol, B max =(34 67?3 23) nmol?g -1 ] and a low affinity site [ K d=(43 48?4 83) nmol, B max =(76 41?5 37) nmol?g -1 ] ( n =5), only the high affinity site was associated with the I Kr in guinea pig ventricle. The B max of high affinity site in the hypertrophied ventricle induced by L thyroxin was down regulated to (18 13?2 27) nmol?g -1 ( n =6). Verapamil was effective to up regulate the high affinity B max to (37 26?4 32) nmol?g -1 ( n =5) but dofetilide had hardly effect on it. CONCLUSION The I Kr channel protein in guinea pig ventricular membrane was down regulated in remodeling ventricle by chronic L thyroxin treatment and improved by verapamil.

Comparison of effects of dofetilide derivative V03(CPU228) and dofetilide on coronary occlusion and reperfusion arrhythmia, vascular contractions and proarrhythmic potential of torsade de pointes / 中国药理学通报

AIM To investigate the cardiovascular activity of new compound V03(CPU228) derived from dofetilide. METHODS Arrhythmias was induced by the occlusion and reperfusion of left anterior descending coronary artery. The effects of CPU228 and dofetilide on QT interval and inducing Tdp were compared in anesthetized rabbits during stimulation with methoxamine. The contractions of thoracic aortic rings induced by KCl (rat) and Phe (guinea pig) in Ca 2+-free and calcium recovered K-H solution was studied to determinate the activity of CPU228 on intracellular calcium mobilization and calcium entry. RESULTS ① CPU228 suppressed the maximal arrhythmia scores, decreased the AUC of arrhythmia score( reduced the duration of VF and VT significantly). PU228 is more potent than dofetilide.②The potency of CPU228 of inducing Tdp is significantly weaker than that of dofetilide.③There were significantly inhibitions of CPU228 on the contractions of aortic rings induced by KCl and Phe in Ca 2+-free solution and dofetilide only had a inhibition on the former. CPU228 inhibited contractions of aortic ring by adding calcium which influx via L-type calcium channel while dofetilide had no effects on these. CONCLUSION CPU228 has stronger inhibition on coronary occlusion and reperfusion arrhythmia and lower potency of inducing Tdp than dofetilide. All the results suggest that CPU228 is a nonselective I Kr-blocker combined with a blockade on the L-type Ca 2+ channel and?adrenergic receptor.