Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel.

Propafenone has been shown to affect the delayed-rectifier potassium currents in cardiomyocytes of different animal models. In this study we investigated effects and mechanisms of action of propafenone on HERG potassium channels in oocytes of Xenopus laevis with the two-electrode voltage-clamp technique. Propafenone decreased the currents during voltage steps and the tail currents. The block was voltage-dependent and increased with positive going potentials (from 18% block of tail current amplitude at -40 mV to 69% at +40 mV with 100 micromol/l propafenone). The voltage dependence of block could be fitted with the sum of a monoexponential and a linear function. The fractional electrical distance was estimated to be delta=0.20. The block of current during the voltage step increased with time starting from a level of 83% of the control current. Propafenone accelerated the increase of current during the voltage step as well as the decay of tail currents (time constants of monoexponential fits decreased by 65% for the currents during the voltage step and by 37% for the tail currents with 100 micromol/l propafenone). The threshold concentration of propafenone effect was around 1 micromol/l and the concentration of half-maximal block (IC50) ranged between 13 micromol/l and 15 micromol/l for both current components. With high extracellular potassium concentrations, the IC50 value rose to 80 degrees mol/l. Acidification of the extracellular solution to pH 6.0 increased the IC50 value to 123 micromol/l, alkalization to pH 8.0 reduced it to 10 micromol/l and coexpression of the beta-subunit minK had no statistically significant effect on the concentration dependence. In conclusion, propafenone has been found to block HERG potassium channels. The data suggest that propafenone affects the channels in the open state and give some hints for an intracellular site of action.

Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes.

The effects of 17 commonly used antiarrhythmic drugs on the rapidly activating cardiac voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1 and Kv4.2) were studied in the expression system of the Xenopus oocyte. A systematic overview on basic properties was obtained using a simple and restricted experimental protocol (command potentials 10 mV and 50 mV positive to the threshold potential; concentration of 100 micromol/l each). The study revealed that 8 of 17 drugs yielded significant effects (changes >10% of control) on at least one type of potassium channel in the oocyte expression system. These drugs were ajmaline, diltiazem, flecainide, phenytoin, propafenone, propranolol, quinidine and verapamil, whereas the effects of adenosine, amiodarone, bretylium, disopyramide, lidocaine, mexiletine, procainamide, sotalol and tocainide were negligible. The drug effects were characterized by reductions of the potassium currents (except for quinidine and ajmaline). A voltage-dependence of drug effect was found for quinidine, verapamil and diltiazem. The different effect of the drugs was not related to the fast or slow current inactivation of the potassium channels (except for verapamil). Profiles of the individual drug effects at the different potassium channel types were identical for propafenone and flecainide and differed for all other substances. The study demonstrates marked differences in sensitivity to antiarrhythmic drugs within the group of voltage-operated cardiac potassium channel types. Taking the restrictions of the oocyte system into consideration, the findings suggest that several antiarrhythmic drugs exert significant effects at rapidly activating cardiac potassium channels.

Molecular genetics of arrhythmias--a new paradigm.

The molecular genetic background of inherited cardiac arrhythmias has only recently been uncovered. This late development in comparison to other inherited cardiac disorders has partly been due to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus families. Thus, traditional genetic linkage studies, which are based on the genetic information obtained from large multi-generation families, were made difficult. Inherited arrhythmogenic disorders can be divided into 'primary electrical disorders' (e.g., long-QT [LQT] syndrome) in which a detectable, organic heart disease is not evident, and into inherited diseases of the myocardial structure (e.g., hypertrophic cardiomyopathies) in which the arrhythmias occur combined with the structural alterations. To date, all inherited arrhythmogenic disorders in which the causative genes have been identified turned out to be channelopathies, since the genes encode channel subunits that regulate important ion currents that tune the cardiac action potential. The discovery of the genetic bases of the LQT syndrome became a new methodologic paradigm; because with the use of 'classical' genetic linkage strategies (named [positional] candidate strategies) not only the causative genes have been found, but moreover, functional components with a previously unknown but fundamental role for a normal repolarization process were discovered. Disease mutations turned out to be not only a family-specific event with a distinct phenotype and the potential of an additional diagnostic tool, but also, when expressed in heterologous expression systems, characterize the defective ion channel in a topological way and lead to a more specific understanding of ion channel function. Most, if not all, primary electrical cardiac disorders show a high genetic diversity. For the LQT syndromes, sixth disease loci and the responsible gene have been recently discovered (so-called locus or genetic heterogeneity). Within all disease genes, the mutations are spread over the entire gene (allelic heterogeneity); in addition, more than one disease mutation may be present. This complexity requires, at least, complete mutation analysis of all LQT genes before medical advice should be given. Meanwhile, genotype-phenotype correlations in large families are being used to evaluate intergene, interfamilial and intrafamilial differences in the clinical phenotype, reflecting gene specific, gene-site specific and individual consequences of a given mutation. A widespread phenotypic heterogeneity even within mutation carriers in the same family raises the importance of modifying factors and genes that are mostly unknown to date. The reduced penetrance and variable expressivity associated with the LQT mutations remain still to be explained. First insights into the complex actions of mutations are being extracted, from expression data; these preliminary results may lead to potential implications for a specific (gene-site directed) therapy. This paper discusses the current data on molecular genetics and genotype-phenotype correlations in LQT syndrome and related disorders and the potential implications for diagnosis and treatment.

Intraoperative radiofrequency ablation of chronic atrial fibrillation: a left atrial curative approach by elimination of anatomic "anchor" reentrant circuits.

INTRODUCTION: The percutaneous approach to radiofrequency (RF) catheter ablation for curative treatment of atrial fibrillation (AF) is an investigational technique, and the optimal composition of lesion lines is unknown. We tested an intraoperative RF ablation concept with elimination of left atrial anatomic "anchor" reentrant circuits. METHODS AND RESULTS: In 12 patients with an indication for valve surgery and chronic AF, a right atrial-transseptal approach was chosen for access to the left atrium. AF had been present for 4.3 +/- 3.9 years; the left atria measured 56 +/- 7 mm. Under direct vision, contiguous lesion lines were placed endocardially with temperature-guided RF energy applications for treatment of AF with a specially designed probe. The lesion lines were placed between the mitral annulus and the left lower pulmonary vein, further to the left upper pulmonary vein, from there to the right upper pulmonary vein, and finally to the right lower pulmonary vein. The antiarrhythmic ablation procedure lasted 19 +/- 4 minutes. One patient died postoperatively of low cardiac output. During follow-up of 11 +/- 6 months, chronic AF was ablated successfully in 9 of 11 patients (82%). Six patients were in stable sinus rhythm or intermittent pacemaker rhythm, and three patients were in sinus rhythm with intermittent atypical atrial flutter. CONCLUSIONS: Intraoperative RF energy application for induction of contiguous lesion lines is feasible. Elimination of anatomically defined "anchor" reentrant circuits within the left atrium prevented chronic AF in > 80% of the patients treated. Intraoperative validation of lesion line concepts for curative treatment of AF may be transferred to percutaneous ablation techniques.

Pressure, temperature, and ozone profile retrieval from simulated atmospheric earthlimb infrared emission.

A method is presented for retrieving pressure, temperature, and ozone mixing ratio profiles from multilevel high resolution earthlimb emission data taken in the spectral region near the CO(2)Q-branch at 791.5 cm(-1). Theory is developed for the construction of a retrieval algorithm which brings the magnitudes of calculated and measured CO(2) and O(3) features into agreement by adjusting a hydrostatic trial atmosphere having one fixed reference pressure. It is shown that overlap between the CO(2) and O(3) features can be used to determine the correct reference pressure. The method is examined using simulations to demonstrate the retrieval of vertical profiles of pressure, temperature, and ozone mixing ratio in the stratosphere. Numerical studies of the effects of uncertainties in line parameters and instrument calibration errors are also presented.

Approximation for the vibrational excitation of middle atmospheric NO by upwelling radiation.

A plane-parallel approximation using FASCODE to calculate upward and downward IR flux density and angle-averaged radiance is described and tested against results that account for planetary curvature. The method is further developed to calculate the excitation of NO(v = 1) due to absorption of upwelling radiation in the earth's atmosphere. The algorithm is applied to a standard set of atmospheric models, in addition to typical and extreme desert atmospheric models which are included to maximize the effect. The results of this work show that upwelling radiation typically contributes <2.5% to the total NO(v = 1) excitation in the midstratosphere rises to ~5% at 50 km and becomes increasingly significant at higher altitudes. It is shown that in the mesosphere excitation due to upwelling and solar radiation become important compared to the dominant processes, thermal collisions, and chemical excitation. An approximate technique utilizing meteorological data, namely, tropospheric temperature, pressure, and humidity profiles, is developed to estimate the excitation of NO(v = 1) in the middle atmosphere. This technique would facilitate the retrieval of the NO mixing ratio from earthlimb emission data, as might be obtained from a satellite-borne limb sounding experiment, since it could be used to approximate the contribution of upwelling radiation to the NO(v = 1) non-LTE vibrational temperature efficiently.

Reflectance and albedo differences between wet and dry surfaces.

It is commonly observed that natural multiple-scattering media such as sand and soils become noticeably darker when wet. The primary reason for this is that changing the medium surrounding the particles from air to water decreases their relative refractive index, hence increases the average degree of forwardness of scattering as determined by the asymmetry parameter (mean cosine of the scattering angle). As a consequence, incident photons have to be scattered more times before reemerging from the medium and are, therefore, exposed to a greater probability of being absorbed. A simple theory incorporating this idea yields results that are in reasonable agreement with the few measurements available in the literature, although there are differences. Our measurements of the reflectance of sand wetted with various liquids are in reasonably good agreement with the simple theory. We suggest that the difference between reflectances of wet and dry surfaces may have implications for remote sensing.